modulação hormonal
Transcription
modulação hormonal
SOBRAF DIRETRIZES PARA A UTILIZAÇÃO DE HORMÔNIOS HOMÓLOGOS HUMANOS POR MÚLTIPLAS ESPECIALIDADES MÉDICAS NA PRÁTICA CLÍNICA A- INTRODUÇÃO: As diretrizes aqui elencadas representam a posição oficial da Sociedade Brasileira Para Estudos da Fisiologia – SOBRAF - com relação ao uso de hormônios homólogos humanos por múltiplas especialidades médicas na prática clínica, e estão fundamentadas no Projeto Diretrizes, iniciativa conjunta da Associação Médica Brasileira e Conselho Federal de Medicina, que tem por objetivo conciliar informações da área médica a fim de padronizar condutas que auxiliem o raciocínio e a tomada de decisão do médico. As informações contidas neste documento devem ser submetidas à avaliação e à crítica do médico, responsável pela conduta a ser seguida, frente à realidade e ao estado clínico de cada paciente. B- DESCRIÇÃO DO MÉTODO DE COLETA DE EVIDÊNCIA: A revisão bibliográfica de artigos científicos destas diretrizes foi realizada na base de dados MEDLINE. A busca de evidências partiu de cenários clínicos reais, e utilizou palavras-chaves (MeSH terms): (aging hormone replacement therapy) OR (gynecology hormone replacement therapy) OR (endocrinology hormone replacement therapy) (hormones OR Estradiol OR Testosterone OR Progesterone OR Thyroid Hormones OR DHEA OR Pregnenolone OR Melatonin OR Growth Hormone OR IGF-1 OR deficiency OR therapeutic OR replacement) AND quality of life AND risk factors AND bone density AND osteoporosis AND osteopenia, (hormone replacement therapy OR hormones) AND (cancer) AND (Monitoring) AND (sexual function) AND glucose metabolism AND plasma lipids AND inflammatory factors AND visceral fat) AND cardiovascular disease AND antioxidant activity AND immune function AND fatigue AND depression AND sleep disorders AND anxiety AND hypertension AND obesity AND body composition AND lean mass AND muscle mass AND sarcopenia AND longevity AND alzheimer´s disease AND cancer risk AND cancer prevention AND low hormone levels . C- GRAU DE RECOMENDAÇÃO E FORÇA DE EVIDÊNCIA: A: Estudos experimentais e observacionais de melhor consistência. B: Estudos experimentais e observacionais de menor consistência. C: Relatos de casos (estudos não controlados). D: Opinião desprovida de avaliação crítica, baseada em consensos, estudos fisiológicos ou modelos animais. D- OBJETIVOS: Estabelecer a definição, interferências do uso de hormônios no metabolismo lipoproteico, na vida sexual, na baixa densidade mineral óssea, nas mamas, na redução do percentual de gordura corporal, na redução dos riscos de hipertensão arterial sistêmica, na redução dos riscos de diabetes, na redução do risco de demência de Alzheimer, na melhora da massa muscular, na promoção de bem estar físico e mental, na redução dos riscos de doenças, na melhora da qualidade de vida, na prevenção das perdas funcionais da velhice, na melhora da capacidade laboral, física e funcional, na melhora da libido, na melhora da qualidade do sono, na melhora da depressão, na melhora da ansiedade, na melhora do estresse, na atenuação da formação de espécies oxigênio-reativas, na redução do estresse oxidativo celular, na preservação da integridade celular, na preservação da integridade mitocondrial, na otimização metabólica, na otimização imunológica, na redução e ou reversão da placa ateromatosa, na redução do risco cardiovascular, na prevenção de doenças crônicas, na prevenção do câncer, na redução do risco de câncer e na promoção de um envelhecimento saudável e determinar as indicações da terapêutica hormonal baseadas nas melhores evidências atuais. E- CONFLITO DE INTERESSE: Nenhum conflito de interesse declarado. 1. MENOPAUSA a. Quadro clínico i. Amenorréia secundária em mulheres com mais de 35 anos ou amenorréia secundária em mulheres, por período superior a seis meses; ii. Fogachos, sudorese noturna, insônia, labilidade emocional, secura vaginal, dispareunia, declínio cognitivo, fragilidade imunológica, ressecamento da pele, queda de cabelos, aumento do peso total, aumento do percentual de gordura, perda de massa magra, perda de massa óssea, redução da libido e comprometimento da qualidade de vida. b. Quadro Laboratorial i. FSH > 15 u/L ii. LH > 8 u/L c. Observações complementares diagnóstico clínico-laboratorial: acerca do i. Quando o diagnóstico laboratorial mostrar-se coerente e compatível com o quadro clínico, este será considerado na confirmação do diagnóstico da menopausa. Por outro lado, nas situações em que ocorrer clara discrepância, divergência ou distorções entre os dados clínicos e laboratoriais, o diagnóstico de menopausa será confirmado tomando-se como referência as manifestações e o quadro clínico apresentados pelo paciente e devidamente avaliados e registrados pelo médico. Tal conduta se justifica pela baixa acurácia dos métodos de diagnóstico laboratorial das deficiências hormonais, falhas de técnicas intrínsecas aos métodos, uso de metodologia inadequada na coleta da amostra de sangue, horário em que a amostra foi colhida, nível de hidratação do paciente no momento da coleta e limitações técnicas dos métodos laboratoriais. A coleta de uma amostra matinal de sangue para dosar um dado hormônio, expressa um retrato estático de um fenômeno intensamente dinâmico e complexo, que sofre influência de múltiplas variáveis, o que torna qualquer método diagnóstico potencialmente falho, limitado e pouco confiável, até que sejam desenvolvidas tecnologias e métodos mais eficazes. d. No momento da instituição da proposta terapêutica hormonal para a menopausa, a SOBRAF recomenda que seus médicos associados utilizem-se do termo de consentimento padrão adotado pela mesma e que deverá ser devidamente assinado pelo médico e pelo seu paciente. e. CONSENSO DA SOBRAF PARA O TRATAMENTO HORMONAL DA MENOPAUSA i. Após criteriosa revisão da literatura científica, discussões com médicos representantes de todos os continentes e discussões entre médicos brasileiros, todos profissionais versados e adequadamente qualificados em utilizar e prescrever hormônios em seres humanos com a finalidade primária de promoção da saúde e, ainda, em total consonância com os preceitos e diretrizes da Sociedade Brasileira Para Estudos da Fisiologia – SOBRAF, da International Hormone Society e da World Society of Anti-Aging Medicine, nós, médicos membros da SOBRAF, concluímos haver chegado o momento de reconsiderar os conceitos atualmente vigentes acerca da reposição hormonal na menopausa. A presente controvérsia acerca da reposição hormonal na menopausa, teve início após a publicação dos resultados do chamado estudo WHI ( Women’s Health Iniciative ), publicado em 2002, bem como do British One Million Women Study, publicado em 2003. Em ambos os estudos, o uso de hormônios em mulheres na pós-menopausa foi associado a uma maior incidência de câncer de mama, quando comparadas ao grupo placebo-controle ou ao de não usuárias. No estudo WHI, o uso de hormônios em mulheres foi associado a um aumento no risco de doenças cardiovasculares e cerebrovasculares. Para os médicos membros da SOBRAF, ambos os estudos apresentam, dentre outras, duas falhas graves de desenho que consistem, respectivamente, em primeiro lugar: estas mulheres estavam utilizando estrogênios conjugados de urina equina. Consiste em um coquetel de 38 hormônios obtidos da urina de éguas prenhes, portanto, um dejeto animal, sendo que nenhum destes hormônios existe em seres humanos ou é produzido pelos mesmos, tendo, portanto, propriedades farmacológicas e comportamento completamente distintos do 17-beta-estradiol, hormônio que deixa de ser produzido por mulheres na fase pósmenopausal. Em segundo lugar, à esta combinação, foi associado o acetato de medroxiprogesterona, molécula que consiste em um progestogênio sintético, igualmente não existente em seres humanos, e, consequentemente, substância com propriedades químicas e fisiológicas diferentes da progesterona humana. Revisando cuidadosamente a literatura científica existente, é possível encontrar vários outros estudos que demonstram, de maneira inquestionável, a potencial toxicidade e os riscos inerentes ao uso destas substâncias. De acordo com as recentes recomendações de um grupo cada vez maior de sociedades médicas ao redor de todo o mundo, nós, igualmente, não recomendamos o uso de hormônios não-homólogos humanos a reposição hormonal da menopausa. Em contraste com as recomendações de algumas sociedades, que não recomendam a reposição hormonal na menopausa, ou ainda, algumas outras que a recomendam por um período limitado a cinco anos, no máximo, nós recomendamos o uso de hormônios em mulheres antes e após a menopausa, por tanto tempo quanto se fizer necessário, desde que as indicações e as necessidades clínicas justifiquem e que nenhum evento adverso ocorra que contraindique o seu uso. Contudo, nós recomendamos o uso da combinação de estradiol e estriol homólogos humanos, associados à progesterona homóloga humana para a correção da deficiência ovariana da menopausa, exceto para casos específicos e bem pontuais e por um período de tempo limitado, aonde o uso de hormônios não-homólogos humanos possa apresentar resultados clínicos melhores, com é o caso de algumas metrorragias e sangramentos da perimenopausa. A via de administração , é, igualmente, parâmetro de considerável importância. A via transdérmica, é, sem dúvida bem mais segura e fisiológica do que a via oral. Esta via não oferece risco de elevação do câncer de mama, e, quando se associa progesterona homóloga humana à reposição de estradiol e estriol, vários estudos, na verdade, demonstram uma clara redução dos riscos para aquela patologia. A mulher que teve câncer de mama, pode fazer reposição hormonal? A tendência observada na atualidade é de se evitar a administração de hormônios em mulheres que tiveram câncer de mama. Esta observação pode não se justificar nas mulheres em que a lesão foi removida cirurgicamente de forma completa. Revendo cuidadosamente todos os estudos científicos atuais que envolvem mulheres que tiveram câncer de mama e receberam reposição hormonal na menopausa, nenhum risco de recorrência foi reportado ou identificado. Ao contrário, a reposição hormonal na menopausa está associada a uma notória redução do risco de recorrência do câncer, bem como uma clara diminuição das taxas gerais de mortalidade na maioria dos estudos. Mesmo a despeito de fartas evidências em contrário, ainda é muito cedo para recomendar-se a reposição hormonal para mulheres em menopausa portadoras de câncer de mama. Nós recomendamos que estudos em larga escala placebocontrole sejam efetivados com a finalidade de identificar com a maior clareza possível, em quais mulheres que tiveram câncer de mama a terapia de reposição hormonal da menopausa estaria mais indicada. Nós recomendamos aos médicos que fazem a reposição hormonal da menopausa, que submetam suas clientes à propedêutica e monitoração mamária periódicos, antes e durante o período de duração da reposição, obedecendo aos intervalos regulares preconizados e consensuados, consistindo de inspeção, palpação e mamografia de alta resolução, acompanhada de ultrassonografia complementar de alta resolução. Importante, igualmente, ressaltar a necessidade de vigilância periódica do endométrio, através de monitoramento ultrassonográfico transvaginal. CONCLUSÃO DO CONSENSO: Tendo em vista as enormes repercussões biopsicossociais da menopausa e os crescentes e exorbitantes gastos para o tratamento e controle das doenças chamadas “inevitáveis” da velhice, nós recomendamos aos médicos estimularem a reposição hormonal da menopausa, sempre observando os bons preceitos da prática médica e utilizando-se de hormônios homólogos humanos, preferencialmente administrados pela via transdérmica, no caso da associação estradiol-estriol, e, no caso da progesterona, via transdérmica ou transvaginal. Para os casos anteriores, a via oral também pode ser uma alternativa, desde que os hormônios administrados sejam, igualmente, homólogos humanos. São Paulo, 12 de Novembro de 2012 Grupo de Consensos da SOBRAF 1. 2. 3. 4. 5. 6. 7. Professora Doutora Ana Cristina Vendramini, PhD Professora Doutora Andreia Conceição Milan B. Antoniolli, PhD Professora Doutora Andrea Thomaz Soccol, PhD Professor Doutor Eduardo Faria, PhD Professor Doutor Marcelo Alexandre de Mattos, PhD Professor Doutor Marcos Renato Scholz, PhD Dr. Ítalo Emmanuel Valeriano Rachid 2. ANDROPAUSA a. Quadro clínico i. Cansaço, redução da libido e do desempenho sexual, redução da força muscular, adinamia, fragilidade imunológica, ginecomastia, redução da capacidade física, ressecamento da pele, déficit de memória, aversão ao convívio social, aumento da circunferência abdominal, queda de cabelos, aumento do percentual de gordura corporal, alterações do sono, alterações do humor, perda de massa óssea, e comprometimento da qualidade de vida. b. Quadro Laboratorial i. ii. iii. iv. v. FSH > 5 u/L LH > 8 u/L Testosterona Total < 700 ng/dL Índice de Androgênio Livre < 0,7 Testosterona livre < 2% vi. Testosterona biodisponível < 400 ng/dL c. Observações complementares diagnóstico clínico-laboratorial: acerca do i. Quando o diagnóstico laboratorial mostrar-se coerente e compatível com o quadro clínico, este será considerado na confirmação do diagnóstico da andropausa. Por outro lado, nas situações em que ocorrer clara discrepância, divergência ou distorções entre os dados clínicos e laboratoriais, o diagnóstico de andropausa será confirmado tomando-se como referência as manifestações e o quadro clínico apresentados pelo paciente e devidamente avaliados e registrados pelo médico. Tal conduta se justifica pela baixa acurácia dos métodos de diagnóstico laboratorial das deficiências hormonais, falhas de técnicas intrínsecas aos métodos, uso de metodologia inadequada na coleta da amostra de sangue, horário em que a amostra foi colhida, nível de hidratação do paciente no momento da coleta e limitações técnicas dos métodos laboratoriais. A coleta de uma amostra matinal de sangue para dosar um dado hormônio, expressa um retrato estático de um fenômeno intensamente dinâmico e complexo, que sofre influência de múltiplas variáveis, o que torna qualquer método diagnóstico potencialmente falho, limitado e pouco confiável, até que sejam desenvolvidas tecnologias e métodos mais eficazes. d. No momento da instituição da proposta terapêutica hormonal para a andropausa, a SOBRAF recomenda que seus médicos associados utilizem-se do termo de consentimento padrão adotado pela mesma e que deverá ser devidamente assinado pelo médico e pelo seu paciente. e. CONSENSO DA SOBRAF PARA O TRATAMENTO HORMONAL DA ANDROPAUSA Após criteriosa revisão da literatura científica, discussões com médicos representantes de todos os continentes e discussões entre médicos brasileiros, todos profissionais versados e adequadamente qualificados em utilizar e prescrever hormônios em seres humanos com a finalidade primária de promoção da saúde e, ainda, em total consonância com os preceitos e guidelines diretrizes da Sociedade Brasileira Para Estudos da Fisiologia – SOBRAF, da International Hormone Society e da World Society of Anti-Aging Medicine, nós, médicos membros da SOBRAF, concluímos haver chegado o momento de considerar a deficiência hormonal masculina, e o conseqüente andropausa. tratamento de reposição hormonal da Desde que a estrutura química da testosterona e a técnica de obtê-la de forma sintética foram descobertos na década de 30, um grande número de estudos têm demonstrado, de forma indubitável, ser a testosterona um hormônio indispensável para a manutenção de um estado ótimo de saúde na população masculina. Na medida em que os homens envelhecem, as frações biodisponíveis da testosterona e de outros androgênios declinam crônica e cumulativamente. O declínio gradual da testosterona biodisponível responde por uma vasta e multivariada gama de sinais e sintomas, tais como fadiga, depressão, mudanças do humor, labilidade emocional, irritabilidade, perda de massa muscular, aumento da gordura corporal total, aumento da gordura intra-abdominal, perda do desejo e da performance sexual, fragilidade imunológica, ginecomastia, perda de massa óssea e muitas outras manifestações que são, invariavelmente, atribuídas a achados normais da idade. A persistência da deficiência hormonal masculina pode aumentar os riscos das comorbidades associadas ao envelhecimento, tais como obesidade, depressão, diabetes, osteoporose e doenças cardiovasculares. Embora o declínio hormonal não afete de maneira tão aguda e incisiva os homens como a queda hormonal da menopausa, de todo modo, compromete, pela sua cronicidade e efeito cumulativo, a sua qualidade de vida, sua saúde e, muito provavelmente, a sua própria expectativa de vida. O declínio androgênico masculino recebe uma vasta sinonímia: distúrbio androgênico do envelhecimento masculino (DAEM ), andropausa, climatério masculino, menopausa masculina, partial androgen deficiency in aging men ( PADAM ), hipogonadismo relacionado à idade, penopausa, dentre outros tantos. A quantidade de homens que recebe atenção e tratamento no transcurso da deficiência hormonal é incomparavelmente menor do que a quantidade de mulheres que recebe reposição e tratamento na menopausa. Isto se deve, principalmente, ao fato de que, ao contrário do declínio feminino, o declínio hormonal masculino ainda não é um fato plenamente aceito por boa parte da medicina tradicional. Com base na fisiologia do envelhecimento hormonal, nós acreditamos não haver qualquer justificativa válida para tal discriminação. Os oponentes da reposição hormonal da andropausa amparamse em estudos conflitantes e com sérios erros de desenho existentes na literatura, que demonstram diferenças não significativas entre os níveis séricos hormonais de homens jovens e homens velhos, outros sugerem que a testosterona pode aumentar a incidência de câncer de próstata, enquanto outros sugerem que a reposição de testosterona não apresenta efeitos clínicos significativos. Estes estudos atípicos são fartamente contrapostos por um imenso número de estudos que são claros e unânimes em demonstrar exatamente o oposto, destacando-se, principalmente, um indubitável efeito protetor da testosterona contra o câncer de próstata. Uma revisão global da literatura corrente não consegue fornecer qualquer evidência de que a reposição com testosterona ou seus derivados possa aumentar os riscos de câncer de próstata in vivo. Ao contrário, homens com baixos níveis de testosterona biodisponível são exatamente os que apresentam não só os maiores riscos de câncer de próstata, como a ocorrência de tumores de comportamento muito mais agressivo, aumento do processo de deposição aterosclerótica das artérias e piora gradual e cumulativa da qualidade de saúde. Além do mais, pacientes portadores de câncer de próstata que têm os seus níveis circulantes de testosterona drasticamente reduzidos por conta das terapias antiandrogênicas, não apresentam qualquer aumento ou melhora da sobrevivência. Com a finalidade de detectar com o maior grau de precisão possível a deficiência hormonal masculina, nós recomendamos não somente uma detalhada avaliação clínica, levando-se em conta os sinais e sintomas físicos e mentais sugestivos do declínio masculino, como a realização de testes laboratoriais que auxiliem e quantifiquem o diagnóstico, dentre os quais: dosagem da testosterona total, testosterona livre, SHBG, proteinograma, DHT, testosterona biodisponível, FSH, LH, e o índice de androgênio livre. Igualmente importante é avaliar os níveis séricos de estradiol, uma vez que a elevação destes níveis pode provocar um bloqueio da ação da testosterona nos homens. Levando-se em consideração o enorme impacto para a saúde masculina oriundo da queda de testosterona, nós recomendamos aos médicos que estimulem o tratamento desta deficiência para todos os casos, utilizando-se da testosterona homóloga humana ou de seus derivados quimicamente mais semelhantes possíveis, excetuando-se alguma contraindicação absoluta. Todos os homens que avançam na idade, devem expectar, cedo ou tarde, declínio dos seus níveis ótimos de testosterona, sendo, portanto, potenciais candidatos à terapia de reposição. A maioria dos homens irá experimentar declínio entre os 30 e 45 anos de idade. Vale, entretanto, salientar, que exceções a esta regra podem ocorrer, fazendo com que alguns homens venham a necessitar da reposição hormonal abaixo ou acima daquela faixa etária. Somente doses fisiológicas de testosterona devem ser administradas, objetivando-se manter os níveis séricos comparáveis ao de adultos jovens e saudáveis, na faixa etária dos 25 a 30 anos. As melhores vias de administração para este hormônio são a transdérmica e a intramuscular. Níveis excessivos de estradiol devem ser evitados durante o tratamento de reposição com testosterona, por conta do efeito biológico neutralizador e além de responder pela ocorrência de ginecomastia, hipertrofia prostática benigna e, possivelmente infarto agudo do miocárdio. Ajustes no padrão alimentar, evitar álcool e cafeína, além da prática regular de atividade física são importantes medidas de suporte para redução dos níveis excessivos de estradiol. Evitar a obesidade é um ponto importantíssimo neste contexto, uma vez que o tecido adiposo é rico em aromatase, enzima que catalisa a transformação de testosterona em estradiol. Quando estas medidas não surtirem o efeito desejado, o uso de inibidores da aromatase ou de pequenas doses de progesterona podem estar indicados. A progesterona aumenta a transformação de estradiol em estrona, diminuindo, portanto, as suas concentrações séricas. O câncer de próstata em atividade pode ser considerado como uma contraindicação para o uso de testosterona. Contudo, ao se rever cuidadosamente a literatura atual, parece haver uma inconsistente base de evidências para dar suporte a esta afirmação. Muitos estudos, ao contrário, demonstram que portadores de câncer de próstata que também possuem deficiência hormonal masculina têm a sua qualidade de saúde severamente comprometida e podem ser beneficiados com a reposição de doses pequenas de testosterona, trazendo benefícios suplementares que em muito superam qualquer suposto risco de estimulo ao crescimento tumoral. CONCLUSÃO DO CONSENSO: Nós não conseguimos identificar na literatura atual qualquer evidência de que repor doses fisiológicas de testosterona deponha contra ou traga riscos à saúde de homens portadores de declínio nos níveis daquele hormônio. Ao contrário. Uma vez que são múltiplos e multivariados os benefícios advindos da reposição hormonal masculina, nós recomendamos o uso de doses fisiológicas de testosterona ou de seu derivado químico mais próximo possível, com o intuito de corrigir esta deficiência, submetendo este homem em reposição a um programa de acompanhamento clínico periódico e regular. São Paulo, 12 de Novembro de 2012 Grupo de Consensos da SOBRAF 1. Professora Doutora Ana Cristina Vendramini, PhD 2. Professora Doutora Andreia Conceição Milan B. Antoniolli, PhD 3. Professora Doutora Andrea Thomaz Soccol, PhD 4. 5. 6. 7. Professor Doutor Eduardo Faria, PhD Professor Doutor Marcelo Alexandre de Mattos, PhD Professor Doutor Marcos Renato Scholz, PhD Dr. Ítalo Emmanuel Valeriano Rachid 3. SOMATOPAUSA a. Quadro clínico i. Deterioração da composição corporal, redução da massa muscular, aumento do percentual de gordura corporal total, aumento do percentual de gordura visceral, cansaço, redução do desempenho sexual, redução da força muscular, adinamia, fragilidade imunológica, redução da capacidade física, ressecamento e enrugamento da pele, déficit de memória, baixa autoestima, alterações do sono, alterações do humor, perda de massa óssea, e comprometimento da qualidade de vida. b. Quadro Laboratorial i. IGF-1 < 300 ng/dL em homens ii. IGF-1 < 280 ng/dL em mulheres c. Observações complementares diagnóstico clínico-laboratorial: acerca do i. Quando o diagnóstico laboratorial mostrar-se coerente e compatível com o quadro clínico, este será considerado na confirmação do diagnóstico da somatopausa. Por outro lado, nas situações em que ocorrer clara discrepância, divergência ou distorções entre os dados clínicos e laboratoriais, o diagnóstico de somatopausa será confirmado tomando-se como referência as manifestações e o quadro clínico apresentados pelo paciente e devidamente avaliados e registrados pelo médico. Tal conduta se justifica pela baixa acurácia dos métodos de diagnóstico laboratorial das deficiências hormonais, falhas de técnicas intrínsecas aos métodos, uso de metodologia inadequada na coleta da amostra de sangue, horário em que a amostra foi colhida, nível de hidratação do paciente no momento da coleta e limitações técnicas dos métodos laboratoriais. A coleta de uma amostra matinal de sangue para dosar um dado hormônio, expressa um retrato estático de um fenômeno intensamente dinâmico e complexo, que sofre influência de múltiplas variáveis, o que torna qualquer método diagnóstico potencialmente falho, limitado e pouco confiável, até que sejam desenvolvidas tecnologias e métodos mais eficazes. d. No momento da instituição da proposta terapêutica hormonal para a somatopausa, a SOBRAF recomenda que seus médicos associados utilizem-se do termo de consentimento padrão adotado pela mesma e que deverá ser devidamente assinado pelo médico e pelo seu paciente. e. CONSENSO DA SOBRAF PARA O TRATAMENTO HORMONAL DA SOMATOPAUSA Após criteriosa revisão da literatura científica, discussões com médicos representantes de todos os continentes e discussões entre médicos brasileiros, todos profissionais versados e adequadamente qualificados em utilizar e prescrever hormônios em seres humanos com a finalidade primária de promoção da saúde e, ainda, em total consonância com os preceitos e guidelines da Sociedade Brasileira Para Estudos da Fisiologia – SOBRAF, da International Hormone Society e da World Society of AntiAging Medicine, nós, médicos membros da SOBRAF, concluímos haver chegado o momento de considerar a reposição com o hormônio do crescimento humano recombinante não só em adultos portadores de patologias que impeçam ou dificultem a sua produção, como nos adultos que estão envelhecendo e decaindo a sua capacidade inata de síntese endógena. Nós concordamos e aprovamos os consensos já estabelecidos e consagrados em muitos países, que aconselham a reposição com o hormônio do crescimento humano recombinante em adultos portadores de patologias que impeçam ou dificultem a sua produção. Nestas situações, existe história pregressa de remoção, trauma, radiação, tumores ou severa inativação da hipófise, fatos que impedem a produção endógena do hormônio do crescimento. Pensamos já haver na literatura científica atual uma base suficiente de dados que demonstram e confirmam os múltiplos benefícios e segurança do uso clínico do hormônio do crescimento. Desta forma, tornou-se uma necessidade médica estendermos a indicação de reposição também aos adultos que estão envelhecendo e decaindo a sua capacidade inata de síntese endógena, por conta da progressiva redução funcional, consequente ao processo de envelhecimento. A evidência é de que o hormônio do crescimento é essencial não apenas para o crescimento de crianças, mas também essencial para a saúde física e mental de adultos, particularmente na manutenção da integridade dos sistemas muscular, adiposo, ósseo, imunológico e cardiovascular. A deficiência do hormônio do crescimento é frequentemente acompanhada de fadiga, ansiedade e depressão, além de um progressivo e cumulativo comprometimento da qualidade de vida. Por outro lado, a reposição com o hormônio do crescimento nestes casos tem demonstrado ser capaz de promover a parada e, por muitas vezes reversão da progressão de todos aqueles processos. A falta da reposição do hormônio do crescimento nos adultos que estão envelhecendo e decaindo a sua capacidade inata de síntese endógena, ao contrário do que se imagina, pode trazer consequências verdadeiramente desastrosas. Aumento considerável da velocidade de deposição da placa ateromatosa, aumento das taxas de mortalidade cardiovascular, deterioração da composição corporal através da perda de massa muscular e concomitante aumento da deposição de gordura corporal total e gordura intra-abdominal, fragilidade imunológica, perda de massa óssea, depressão, distúrbios progressivos do sono e redução da síntese de proteínas são, dentre outros, alguns dos fenômenos que se sucedem ao declínio da capacidade de manutenção da síntese de níveis fisiológicos do hormônio do crescimento, e que são parcial ou totalmente reversíveis através da reposição do mesmo. Nós recomendamos aos médicos submeterem os clientes em uso do hormônio do crescimento a um regime de avaliações regulares e aprazados. Isto inclui: anamnese, exame físico e exames laboratoriais complementares obedecendo a um intervalo de um a doze meses, dependendo da necessidade individual de cada cliente. Em relação a um eventual aumento no risco de desenvolvimento de certos tipos de câncer com o uso do hormônio do crescimento, os estudos mais sérios e respeitados realizados em pacientes que receberam o hormônio, comparados ao grupo controle de indivíduos não-tratados, mostram uma clara redução de aproximadamente 50% na incidência de câncer e na mortalidade por câncer no grupo de indivíduos que receberam o hormônio. Na realidade, inexiste qualquer argumento consistente ou fundamentação razoável para se acreditar que repor o hormônio do crescimento possa elevar o risco de câncer. De qualquer forma, uma pesquisa de rotina a cada seis a 12 meses para o câncer de próstata e mama, complementadas por ultrassom e mamografia quando necessário, constitui conduta essencial, segundo este grupo de consenso. Além do mais, nós também recomendamos que o tratamento de reposição seja programado de modo a se respeitar as doses fisiológicas preconizadas. Em casos clínicos muito específicos e pontuais, como, por exemplo, os grandes obesos e indivíduos com grande superfície corporal, pode ser justificável o uso de doses maiores, que deverão ser mantida por período de tempo não superior a 90 dias. Doses acima dos limites fisiológicos não são recomendadas por esta sociedade e fogem t ao escopo deste protocolo de consenso. Desta forma e seguindo estes princípios, o médico estará assegurando não só a eficácia como a segurança do tratamento. CONCLUSÃO DO CONSENSO: Na atualidade inexiste qualquer base científica de dados que contraindique a reposição do hormônio do crescimento humano recombinante em adultos que estão envelhecendo e decaindo a sua capacidade inata de síntese endógena. Ao contrário, uma multiplicidade de sinais, sintomas e problemas adversos e deletérios à saúde humana tem sido abundantemente reportada em indivíduos portadores de níveis endógenos infra fisiológicos do hormônio do crescimento, bem como tem sido fartamente reportada melhora, desaparecimento ou mesmo reversão dos problemas aludidos ao se promover a adequada reposição do mesmo. Ressaltamos, mais uma vez, a importância de se observar as doses fisiológicas do hormônio, bem como a realização de avaliações clínico-laboratoriais periódicas. São Paulo, 12 de Novembro de 2012 Grupo de Consensos da SOBRAF 1. 2. 3. 4. 5. 6. 7. Professora Doutora Ana Cristina Vendramini, PhD Professora Doutora Andreia Conceição Milan B. Antoniolli, PhD Professora Doutora Andrea Thomaz Soccol, PhD Professor Doutor Eduardo Faria, PhD Professor Doutor Marcelo Alexandre de Mattos, PhD Professor Doutor Marcos Renato Scholz, PhD Dr. Ítalo Emmanuel Valeriano Rachid 4. TIREOPAUSA a. Quadro clínico i. Deterioração da composição corporal, redução da massa muscular, aumento do percentual de gordura corporal total, aumento do percentual de gordura visceral, cansaço, depressão marcadamente matinal, apatia, incapacidade de concentração, dificuldade de perder peso, unhas fracas, queda de cabelos, dislipidemia, hipercolesterolemia, ateromatose precoce, intolerância ao frio, adinamia, fragilidade imunológica, constipação, redução da capacidade física, zumbidos, ressecamento e enrugamento da pele, déficit de memória, alterações do sono, alterações do humor, e comprometimento da qualidade de vida. b. Quadro Laboratorial i. ii. iii. iv. c. TSH ultrassensível > 2,0 pg/mL T3 livre < 0,37 ng/dL T4 livre < 0,7 ng/mL Média da Temperatura Basal < 36,5o C em cinco aferições matinais consecutivas. Observações complementares diagnóstico clínico-laboratorial: acerca do i. Quando o diagnóstico laboratorial mostrar-se coerente e compatível com o quadro clínico, este será considerado na confirmação do diagnóstico da tireopausa. Por outro lado, nas situações em que ocorrer clara discrepância, divergência ou distorções entre os dados clínicos e laboratoriais, o diagnóstico de somatopausa será confirmado tomando-se como referência as manifestações e o quadro clínico apresentados pelo paciente e devidamente avaliados e registrados pelo médico. Tal conduta se justifica pela baixa acurácia dos métodos de diagnóstico laboratorial das deficiências hormonais, falhas de técnicas intrínsecas aos métodos, uso de metodologia inadequada na coleta da amostra de sangue, horário em que a amostra foi colhida, nível de hidratação do paciente no momento da coleta e limitações técnicas dos métodos laboratoriais. A coleta de uma amostra matinal de sangue para dosar um dado hormônio, expressa um retrato estático de um fenômeno intensamente dinâmico e complexo, que sofre influência de múltiplas variáveis, o que torna qualquer método diagnóstico potencialmente falho, limitado e pouco confiável, até que sejam desenvolvidas tecnologias e métodos mais eficazes. d. No momento da instituição da proposta terapêutica hormonal para a tireopausa, a SOBRAF recomenda que seus médicos associados utilizem-se do termo de consentimento padrão adotado pela mesma e que deverá ser devidamente assinado pelo médico e pelo seu paciente. e. CONSENSO DA SOBRAF PARA O TRATAMENTO HORMONAL DA TIREOPAUSA Após criteriosa revisão da literatura científica, discussões com médicos representantes de todos os continentes e discussões entre médicos brasileiros, todos profissionais versados e adequadamente qualificados em utilizar e prescrever hormônios em seres humanos com a finalidade primária de promoção da saúde e, ainda, em total consonância com os preceitos e guidelines da Sociedade Brasileira Para Estudos da Fisiologia – SOBRAF, da International Hormone Society e da World Society of AntiAging Medicine, nós, médicos membros da SOBRAF, concluímos existir um sólido conjunto de evidências de ordem clínica, prática e teórica que já permitem expandir o tratamento do hipotireoidismo além dos parâmetros correntes convencionais. Existe, na atualidade, uma controvérsia entre grupos de médicos. Um grupo essencialmente define o diagnóstico do hipotireoidismo baseado em testes de laboratório, enquanto o outro toma como base parâmetro essencialmente clínicos. Uma sólida base de evidências científicas não dá suporte à ideia de que o diagnóstico do hipotireoidismo deva ou possa ser baseado apenas em testes laboratoriais. Isto implica em que a existência do hipotireoidismo só se confirma quando os níveis séricos de TSH encontram-se acima dos limites superiores atuais de referência, e os níveis séricos de tiroxina (T4) e triiodotireonina (T4), encontram-se abaixo dos limites inferiores atuais de referência, negligenciando os sinais e sintomas clínicos. Esta sociedade adota a posição intermediária. A decisão de iniciar a reposição com o hormônio tireoidiano deve ser baseada tanto em achados clínicos quanto laboratoriais, e não somente em resultados de um simples teste laboratorial, como se encontra atualmente expresso nos jornais JAMA e Thyroid, conduta que representa o atual consenso da Sociedade Americana de Tireoide. Entendemos que achados e informações clínicas são essenciais no diagnóstico de deficiências hormonais. Os dados necessários ao diagnóstico do hipotireoidismo incluem a pesquisa das queixas físicas e emocionais dos pacientes, sinais físicos e coleta de história pregressa pessoal e familiar sugestivas de deficiência tireoidiana, bem como eventuais anormalidades no volume glandular, expressos pela presença de hipertrofia ou bócio e/ou tireoidite autoimune. As seguintes evidências dão suporte à existência de hipotireoidismo clínico, em indivíduos erroneamente considerados laboratorialmente normais, e que são candidatos ao tratamento de reposição hormonal tireoidiana: Os níveis de referencia da normalidade são excessivamente largos e ignoram e existência dos níveis ótimos de referência. Estes níveis incluem largas margens de referência de normalidade para os níveis de T3, T4 e TSH, que são, na realidade, plenamente compatíveis com múltiplas disfunções tireoidianas. Não existe qualquer evidência atual que dê suporte à persistência do uso destes parâmetros, uma vez que são completamente incapazes de definir e diferenciar de maneira clara e adequada os estados de eutireoidismo e hipotireoidismo. A base de dados atuais sugere que sejam utilizados níveis de referencia incomparavelmente mais estreitos e específicos para esta situação. Os níveis convencionais de referência para detecção do hipotireoidismo sofrem variação de mais de 30 vezes ( 0.2 a 6.5 mUI/L ). Em muitos estudos clínicos atuais, níveis séricos de TSH acima de 1.5 a 2.0 mUI/L tem sido associados com dislipidemia, inflamação crônica subclínica, níveis elevados de homocisteína, proteína C reativa, hipercolesterolemia, depressão, pobre resposta ao tratamento com antidepressivos, maiores índices de massa corpórea, maior incidência de hipertensão arterial sistêmica, elevação dos triglicérides e hiperglicemia. Do mesmo modo, aqueles níveis tem sido associados a anormalidades cardíacas e vasculares, que incluem ateromatose acelerada e perda da elasticidade vascular. Neonatos com baixo peso e partos prematuros tem sido relatados em mães com TSH acima de 2.0 mUI/L. Mais importante, iniciar o tratamento do hipotireoidismo nestes casos, tem demonstrado ser uma medida capaz de minimizar ou reverter aqueles problemas. Com base ainda nestes múltiplos estudos, existem evidências que dão suporte a adoção de níveis de referencia bem mais estreitos para o TSH, cujos valores devem se situar entre 0.4 a 2.0 mUI/L. Torna-se importante ressaltar que 95% da população de indivíduos saudáveis e com a atividade tireoidiana normal exibem níveis séricos de TSH dentro do intervalo de 0.4 a 2.0 mUI/L. Um outro ponto de capital importância, é que os estudos demonstram resultados clínicos incomparavelmente superiores quando se utiliza no tratamento a associação entre T3 e T4, ao invés do tratamento isolado com T4. Isto se deve ao fato de que uma boa parte do T4 administrado isoladamente, sofre conversão para T3 reverso, forma hormonal inativa biologicamente. Além do mais, para que o estado de eutireoidismo seja alcançado, o organismo humano necessita de ambos os hormônios, T4, que tem a finalidade principal de atrair moléculas de TBG ( thyroid binding globulin ) e T3, que, livre do atrelamento da TBG, pode ligar-se rapidamente aos receptores celulares do hormônio tireoidiano nas células-alvo. A combinação fisiológica entre T3 e T4, obedecendo às proporções de uma parte de T3 para cinco partes de T4 , produz resultados clínicos inequivocamente superiores. Nós recomendamos aos médicos que excluam cuidadosamente outras patologias ou estados clínicos que produzam sintomatologia semelhante ao hipotireoidismo antes de iniciar a reposição do hormônio tireoidiano. Ao se iniciar o tratamento, utilizar doses menores e programar elevação gradual, de acordo com a necessidade clínica, visando evitar a presença de superdosagem, e, consequentemente, um possível quadro de hipertireoidismo iatrogênico, efeito adverso mais frequente no tratamento do hipotireoidismo. Intolerância ao tratamento pode ser causada por excessiva conversão de T4 em T3, acelerando, desta forma, a atividade tireoidiana. Devemos lembrar que a principal causa deste problema é a deficiência não diagnosticada de outros hormônios, principalmente a hipocortisolemia e a deficiência de estradiol na menopausa. Os médicos devem dedicar especial atenção aos níveis de cortisol. A fadiga adrenal crônica, que leva à queda excessiva dos níveis de cortisol provoca uma baixa tolerância ao tratamento do hipotireoidismo, principalmente quando a opção foi pela combinação T4/T3. A deficiência de cortisol provoca hiperatividade do sistema nervoso ortossimpático e uma excessiva e rápida conversão de T4 em T3. Desta forma, em pacientes com fadiga adrenal crônica, nós recomendamos que os médicos tratem a deficiência de cortisol antes de iniciarem o tratamento do hipotireoidismo ou, no mínimo, de forma concomitante ao início do mesmo. A segurança do tratamento do hipotireoidismo pode ser aumentada se o iniciarmos com doses menores, promovendo um aumento gradual nos casos em que tais ajustes se fizerem necessários. CONCLUSÃO DO CONSENSO: Hipotireoidismo clínico, em indivíduos erroneamente considerados laboratorialmente normais, constitui, sem nenhuma dúvida uma racional justificativa para se promover a inclusão destas pessoas no grupo de candidatos ao tratamento com os hormônios tireoidianos. Estes indivíduos podem se beneficiar com um programa de reposição com baixas dosagens, em que estejam associados T4 e T3 em proporções fisiológicas. Avaliação clínica e laboratorial aprazados, utilizando-se parâmetros mais estreitos para os níveis de referência do TSH, além de um cuidadoso monitoramento individual de cada caso, são as bases que conduzem a resultados clínicos favoráveis. São Paulo, 12 de Novembro de 2012 Grupo de Consensos da SOBRAF 1. 2. 3. 4. 5. 6. 7. Professora Doutora Ana Cristina Vendramini, PhD Professora Doutora Andreia Conceição Milan B. Antoniolli, PhD Professora Doutora Andrea Thomaz Soccol, PhD Professor Doutor Eduardo Faria, PhD Professor Doutor Marcelo Alexandre de Mattos, PhD Professor Doutor Marcos Renato Scholz, PhD Dr. Ítalo Emmanuel Valeriano Rachid 5. FADIGA ADRENAL CRÔNICA a. Quadro clínico i. Cansaço marcadamente matinal, apatia, incapacidade de concentração, adinamia, fragilidade imunológica, compulsão massas e doces, irritabilidade, intolerância ao estresse, déficit de memória, alterações do sono, alterações do humor, e comprometimento da qualidade de vida. b. Quadro Laboratorial i. Cortisol matinal < 15 mcg/dL ii. Cortisol livre < 10 ng/ml iii. Transcortina > 30 mg/L c. Observações complementares diagnóstico clínico-laboratorial: acerca do i. Quando o diagnóstico laboratorial mostrar-se coerente e compatível com o quadro clínico, este será considerado na confirmação do diagnóstico da fadiga adrenal crônica. Por outro lado, nas situações em que ocorrer clara discrepância, divergência ou distorções entre os dados clínicos e laboratoriais, o diagnóstico da fadiga adrenal crônica será confirmado tomando-se como referência as manifestações e o quadro clínico apresentados pelo paciente e devidamente avaliados e registrados pelo médico. Tal conduta se justifica pela baixa acurácia dos métodos de diagnóstico laboratorial das deficiências hormonais, falhas de técnicas intrínsecas aos métodos, uso de metodologia inadequada na coleta da amostra de sangue, horário em que a amostra foi colhida, nível de hidratação do paciente no momento da coleta e limitações técnicas dos métodos laboratoriais. A coleta de uma amostra matinal de sangue para dosar um dado hormônio, expressa um retrato estático de um fenômeno intensamente dinâmico e complexo, que sofre influência de múltiplas variáveis, o que torna qualquer método diagnóstico potencialmente falho, limitado e pouco confiável, até que sejam desenvolvidas tecnologias e métodos mais eficazes. d. No momento da instituição da proposta terapêutica hormonal para a fadiga adrenal crônica, a SOBRAF recomenda que seus médicos associados utilizem-se do termo de consentimento padrão adotado pela mesma e que deverá ser devidamente assinado pelo médico e pelo seu paciente. e. CONSENSO DA SOBRAF PARA O TRATAMENTO HORMONAL DA FADIGA ADRENAL CRÔNICA Após criteriosa revisão da literatura científica, discussões com médicos representantes de todos os continentes e discussões entre médicos brasileiros, todos profissionais versados e adequadamente qualificados em utilizar e prescrever hormônios em seres humanos com a finalidade primária de promoção da saúde e, ainda, em total consonância com os preceitos e guidelines da Sociedade Brasileira Para Estudos da Fisiologia – SOBRAF, da International Hormone Society e da World Society of AntiAging Medicine, nós, médicos membros da SOBRAF, concluímos ter chegado o momento de reconsiderar os conceitos atualmente vigentes acerca do tratamento da deficiência adrenal, em particular a deficiência de cortisol, não apenas nas pessoas afetadas por severas deficiências, mas também nos portadores de fadiga adrenal crônica. Nós concordamos plenamente e aprovamos o consenso mundial que foi atingido no que concerne ao tratamento com glicocorticoides para adultos portadores de severa deficiência de cortisol. Geralmente, naquela condição, existe uma deficiência total ou quase total da produção de cortisol, que ocorre por conta de remoção total ou parcial ou inativação total ou parcial das glândulas adrenais, as estruturas responsáveis pela produção de cortisol. Acreditamos que a quantidade de evidências existentes na atualidade demonstrando os efeitos benéficos do cortisol, bem como os seus eventuais efeitos adversos é suficiente para promover a extensão da recomendação da reposição de cortisol também para os portadores da condição clínica conhecida como fadiga adrenal crônica. Entre os quadros de deficiência de cortisol deve também ser incluído a forma que incide ao longo do processo do envelhecimento, ocasionada pela progressiva deterioração do eixo hipofisário-adrenal. A evidência é de que o cortisol é essencial não só para os portadores de estados de severa depleção, como também para a manutenção do equilíbrio físico e mental dos adultos que estão envelhecendo e declinando a sua capacidade de produção. Uma quantidade adequada de cortisol é essencial para o normal funcionamento de uma multiplicidade de órgãos e sistemas: cérebro, pele, articulações, músculos, trato digestório, sistemas imunológico e cardiovascular. A deficiência de cortisol encontra-se clinicamente relacionada com fadiga, baixa tolerância ao estresse, confusão mental e comprometimento da qualidade de vida. O tratamento com glicocorticoides tem se mostrado capaz de melhorar a qualidade de vida, humor e status mental dos pacientes. Consequências adversas da deficiência de cortisol variam desde potenciação dos efeitos debilitantes de doenças inflamatórias ( artrite reumatoide, gastrenterite, colite, desordens imunológicas e alergias ), até o aumento da mortalidade em condições de alto risco como o choque séptico. Os estados de deficiência leve de cortisol podem, igualmente, causar mais repercussões danosas à saúde humana do que se imaginava antes. Como a suplementação de cortisol e de outros glicocorticoides tem sido associada com importantes efeitos adversos, dentre os quais: imunossupressão, osteoporose, ganho de peso, atrofia cutânea, hipertensão, supressão adrenal e fácies cushingóide, nós recomendamos aos médicos que a reposição de cortisol deva ser pautada pela observância de guidelines de segurança. Acreditamos firmemente que os efeitos colaterais são consequentes ao uso de doses excessivas, bem como pelo fato de que a reposição de cortisol não pode ocorrer na ausência da correção dos desequilíbrios nos níveis de hormônios anabólicos (pausas humanas ), principalmente a queda dos níveis de DHEA. e T3. A presença de níveis fisiológicos de hormônios anabólicos pode bloquear os efeitos catabólicos da presença de doses excessivas de glicocorticoides. Em vários casos de deficiência de cortisol, reposição de derivados sintéticos produz efeitos clínicos muito menos efetivos do que a reposição do cortisol na sua forma homóloga humana. Em termos de diagnóstico laboratorial, pode-se lançar mão das dosagens séricas de cortisol total matinal, cortisol livre, transcortina ( CBG= cortisol binding globulin ), ACTH, bem como dosagens dos 17-hidroxiesteróides em urina de 24 horas, pela técnica de cromatografia a gás. O tratamento de reposição com cortisol nas formas leves pode ser feito observando-se os limites diários das doses fisiológicas. Em casos mais severos, as doses recomendadas podem sofrer um acréscimo de até 30-50%. Lembramos que os homens necessitam de doses maiores porque fisiologicamente secretam quantidades diárias cerca de 50% maiores do que as mulheres. Apenas 50 % da dose diária administrada é absorvida pelo trato gastrintestinal. Em situações de agravamento das condições de estresse, como: infecções, procedimentos cirúrgicos e abalo emocional intenso, recomendamos que as doses sejam temporariamente aumentadas. Importante lembrar que a reposição com cortisol pode agravar deficiências já existentes na produção dos hormônios tireoidianos e DHEA. Desta forma, recomendamos aos médicos corrigirem concomitantemente aquelas deficiências. CONCLUSÃO DO CONSENSO: Com base na literatura científica atual, inexistem quaisquer justificativas plausíveis que contraindiquem ou desestimulem o tratamento de reposição com cortisol em adultos com baixos níveis. Efeitos colaterais adversos podem ser evitados seguindo-se os guidelines já propostos, bem como utilizando-se doses fisiológicas da forma homóloga humana do cortisol. Novamente ressaltamos a capital importância da correção concomitante de outras deficiências na produção de hormônios anabólicos, particularmente DHEA e o hormônio tireoidiano. Monitorar os pacientes através de um programa regular de acompanhamento clínico-laboratorial. São Paulo, 12 de Novembro de 2012 Grupo de Consensos da SOBRAF 1. 2. 3. 4. 5. 6. 7. Professora Doutora Ana Cristina Vendramini, PhD Professora Doutora Andreia Conceição Milan B. Antoniolli, PhD Professora Doutora Andrea Thomaz Soccol, PhD Professor Doutor Eduardo Faria, PhD Professor Doutor Marcelo Alexandre de Mattos, PhD Professor Doutor Marcos Renato Scholz, PhD Dr. Ítalo Emmanuel Valeriano Rachid 6. ADRENOPAUSA a. Quadro clínico i. Depressão e cansaço em pessoas jovens, adinamia, apatia, fragilidade imunológica, ateromatose, irritabilidade, déficit de memória, alterações do sono, alterações do humor, ressecamento vaginal, queda de cabelos, rarefação de pelos pubianos, redução da libido, hipercolesterolemia, dislipidemia, perda de massa óssea e comprometimento da qualidade de vida. b. Quadro Laboratorial i. SDHEA < 350 ug/mL em homens ii. SDHEA < 300 ug/mL em mulheres c. Observações complementares diagnóstico clínico-laboratorial: acerca do i. Quando o diagnóstico laboratorial mostrar-se coerente e compatível com o quadro clínico, este será considerado na confirmação do diagnóstico da adrenopausa. Por outro lado, nas situações em que ocorrer clara discrepância, divergência ou distorções entre os dados clínicos e laboratoriais, o diagnóstico de adrenopausa será confirmado tomando-se como referência as manifestações e o quadro clínico apresentados pelo paciente e devidamente avaliados e registrados pelo médico. Tal conduta se justifica pela baixa acurácia dos métodos de diagnóstico laboratorial das deficiências hormonais, falhas de técnicas intrínsecas aos métodos, uso de metodologia inadequada na coleta da amostra de sangue, horário em que a amostra foi colhida, nível de hidratação do paciente no momento da coleta e limitações técnicas dos métodos laboratoriais. A coleta de uma amostra matinal de sangue para dosar um dado hormônio, expressa um retrato estático de um fenômeno intensamente dinâmico e complexo, que sofre influência de múltiplas variáveis, o que torna qualquer método diagnóstico potencialmente falho, limitado e pouco confiável, até que sejam desenvolvidas tecnologias e métodos mais eficazes. d. No momento da instituição da proposta terapêutica hormonal para a adrenopausa, a SOBRAF recomenda que seus médicos associados utilizem-se do termo de consentimento padrão adotado pela mesma e que deverá ser devidamente assinado pelo médico e pelo seu paciente. e. CONSENSO DA SOBRAF PARA O TRATAMENTO HORMONAL DA ADRENOPAUSA Após criteriosa revisão da literatura científica, discussões com médicos representantes de todos os continentes e discussões entre médicos brasileiros, todos profissionais versados e adequadamente qualificados em utilizar e prescrever hormônios em seres humanos com a finalidade primária de promoção da saúde e, ainda, em total consonância com os preceitos e guidelines da Sociedade Brasileira Para Estudos da Fisiologia – SOBRAF, da International Hormone Society e da World Society of AntiAging Medicine, nós, médicos membros da SOBRAF, concluímos ter chegado o momento de considerar a deficiência de dehidroepiandrosterona, bem como a sua reposição. Até o presente momento, as sociedades médicas convencionais relacionadas à endocrinologia, ainda não reconheceram a necessidade e a importância clínica de tratar e repor a deficiência adrenal de dehidroepiandrosterona (DHEA). Algumas poucas sociedades médicas convencionais ao redor do mundo, tem expressado de forma pontual e tímida a importância da reposição de DHEA. Em geral, se identifica a conclusão de que ainda não existe base de dados suficiente que dê suporte à reposição deste hormônio. Eles são da opinião de que a literatura cientifica sobre o DHEA ainda é muito escassa e sua eficácia clínica ainda não está suficientemente comprovada.. Eles, igualmente, expressam a preocupação de que a reposição de DHEA poderia estar relacionada a uma maior incidência do câncer genital e a uma redução do HDL – colesterol. Após uma cuidadosa e exaustiva revisão da literatura cientifica atual, bem como ler e discutir os relatórios negativos institucionais, concluímos não existir qualquer base de dados científica razoável que dê suporte à ideia de que o uso de DHEA possa trazer riscos à saúde humana. Nós reconhecemos e corroboramos um grande número de estudos aonde homens e mulheres com deficiência de DHEA tem sido tratados e tem apresentado significativa melhora em múltiplos aspectos físicos e mentais. Ao nos detalharmos com estudos que demonstram efeitos “pouco significativos” no tratamento com DHEA é possível observar que uma falha de desenho importante é frequentemente perceptível: o tempo excessivamente curto em que estas pessoas tem passado recebendo o hormônio, períodos inferiores a duas semanas, em boa parte das vezes, tempo notoriamente insuficiente para que resultados consistentes sejam alcançados. Ao lado de uma minoria de estudos que demonstram resultados negativos ou não significativos, existe um grande número de estudos que atesta de maneira inquestionável a importância e, mais ainda, uma multivariedade de benefícios oriundos da reposição com DHEA. Além do mais, estes estudos não só confirmam a eficácia como chegam à conclusão que a reposição de DHEA, o mais abundante hormônio esteroide produzido no corpo humano, é uma das formas de reposição mais seguras e eficientes que existem. Estudos randomizados, placebo-controle e duplo-cego, confirmam inexistirem quaisquer efeitos danosos à saúde humana, quando níveis fisiológicos de DHEA são suplementados. Efeitos colaterais porventura existentes, encontram-se completamente vinculados ao emprego de doses excessivas. Os sinais mais característicos de doses excessivas de DHEA são: pele oleosa, acne e leve hirsutismo, efeitos reversíveis através do devido ajuste nas dosagens. Em muitos estudos que analisam a reposição de DHEA, significativos benefícios foram obtidos no ganho de massa óssea, qualidade da pele, sistema imunológico, sensibilidade à glicose, sensibilidade à insulina e perfil lipídico. Benefícios também foram evidenciados na performance mental e emocional, qualidade de vida, fadiga, depressão, redução do risco cardiovascular, diabetes e obesidade. É a opinião deste grupo que os seguintes argumentos dão suporte e justificam plenamente o tratamento de reposição com DHEA em adultos com baixos níveis séricos: 1. DHEA é um hormônio natural aos seres humanos, está plenamente configurado para atender às nossas demandas metabólicas, e, na verdade, é o hormônio presente em maior quantidade no corpo humano. 2. DHEA exerce mais de 150 funções anabólicas no metabolismo humano. 3. Apresenta uma multiplicidade de benefícios quando usando em indivíduos adultos que apresentam baixos níveis, sendo uma valiosa ferramenta no combate às doenças relacionadas ao envelhecimento. 4. Reposição de DHEA é segura. 5. Reposição de DHEA tem um custo acessível. Com o intuito de elevar a segurança do tratamento de reposição com DHEA, nós recomendamos que os médicos submetam seus clientes a um programa de avaliações periódicas, incluindo anamnese, exame físico e exames laboratoriais complementares a cada 3 a 12 meses, dependendo das necessidades individuais de cada um. Entendemos ser igualmente relevante promover uma rotina de avaliações clínico-laboratoriais para o câncer de próstata e mama, obedecendo a um intervalo de seis a 12 meses, dependendo de cada caso. Na nossa experiência, os melhores métodos para o diagnóstico da deficiência de DHEA são a avaliação sérica dos níveis do sulfato de dehidroepiandrosterona e a avaliação da excreção dos metabólitos 17-cetoesteróidesDHEA em urina de 24 horas, pela técnica de cromatografia a gás. As doses de segurança são as chamadas doses fisiológicas, que devem ser seguidas e observadas pelos membros da sociedade. Ressaltamos que nos casos em que é clinicamente relevante evitar a conversão de DHEA para Testosterona ou Estradiol, pode-se lançar mão da reposição de 7-KetoDHEA, principal metabólito ativo do DHEA, que possui exatamente as mesmas propriedades do DHEA, porém, não sofre conversão para outros hormônios. Neste caso, devese, igualmente, observar as doses fisiológicas de segurança. CONCLUSÃO DO CONSENSO: Com base na literatura científica atual, inexistem justificativas plausíveis que contraindiquem ou desestimulem o tratamento de reposição de DHEA em adultos com baixos níveis, exceto para as mulheres que encontram-se na pós-menopausa e não estão fazendo a reposição hormonal da menopausa. Ao contrário, benefícios em quantidade e intensidade suficientes já tem sido demonstrados e servem como base para nos permitir recomendar o uso de doses fisiológicas de DHEA para corrigir as deficiências bem estabelecidas e previamente diagnosticadas em adultos, submetendo-os, daí por diante, a um programa regular de acompanhamento clínicolaboratorial. A reposição de DHEA encontra-se especialmente justificada em indivíduos portadores de condições de saúde tratadas com corticoides, uma vez que o seu uso pode neutralizar com segurança os efeitos catabólicos excessivos da corticoterapia. São Paulo, 12 de Novembro de 2012 Grupo de Consensos da SOBRAF 1. 2. 3. 4. 5. 6. 7. Professora Doutora Ana Cristina Vendramini, PhD Professora Doutora Andreia Conceição Milan B. Antoniolli, PhD Professora Doutora Andrea Thomaz Soccol, PhD Professor Doutor Eduardo Faria, PhD Professor Doutor Marcelo Alexandre de Mattos, PhD Professor Doutor Marcos Renato Scholz, PhD Dr. Ítalo Emmanuel Valeriano Rachid 7. MELATOPAUSA a. Quadro clínico i. Depressão, cansaço, adinamia, apatia, fragilidade imunológica, irritabilidade, déficit de memória, alterações do sono, alterações do humor, alterações gastrointestinais e comprometimento da qualidade de vida. b. Quadro Laboratorial i. 6-Sultatoxi-Melatonina < 40 ng/dia em urina de 24 horas c. Observações complementares diagnóstico clínico-laboratorial: acerca do i. Quando o diagnóstico laboratorial mostrar-se coerente e compatível com o quadro clínico, este será considerado na confirmação do diagnóstico da melatopausa. Por outro lado, nas situações em que ocorrer clara discrepância, divergência ou distorções entre os dados clínicos e laboratoriais, o diagnóstico de melatopausa será confirmado tomando-se como referência as manifestações e o quadro clínico apresentados pelo paciente e devidamente avaliados e registrados pelo médico. Tal conduta se justifica pela baixa acurácia dos métodos de diagnóstico laboratorial das deficiências hormonais, falhas de técnicas intrínsecas aos métodos, uso de metodologia inadequada na coleta da amostra de sangue, horário em que a amostra foi colhida, nível de hidratação do paciente no momento da coleta e limitações técnicas dos métodos laboratoriais. A coleta de uma amostra matinal de sangue para dosar um dado hormônio, expressa um retrato estático de um fenômeno intensamente dinâmico e complexo, que sofre influência de múltiplas variáveis, o que torna qualquer método diagnóstico potencialmente falho, limitado e pouco confiável, até que sejam desenvolvidas tecnologias e métodos mais eficazes. d. No momento da instituição da proposta terapêutica hormonal para a melatopausa, a SOBRAF recomenda que seus médicos associados estarão, concomitantemente, utilizem-se do termo de consentimento padrão adotado pela mesma e que deverá ser devidamente assinado pelo médico e pelo seu paciente. e. CONSENSO DA SOBRAF PARA O TRATAMENTO HORMONAL DA MELATOPAUSA Após criteriosa revisão da literatura científica, discussões com médicos representantes de todos os continentes e discussões entre médicos brasileiros, todos profissionais versados e adequadamente qualificados em utilizar e prescrever hormônios em seres humanos com a finalidade primária de promoção da saúde e, ainda, em total consonância com os preceitos e guidelines do Grupo Longevidade Saudável, da International Hormone Society e da World Society of AntiAging Medicine, nós, médicos membros do Grupo de Consenso do Grupo Longevidade Saudável, concluímos ter chegado o momento de considerar o tratamento da deficiência de melatonina em adultos. Até o presente momento, nenhuma sociedade médica convencional no mundo reconheceu a necessidade e a importância de tratar a deficiência da glândula pineal através da reposição de melatonina. Como é de costume quando se trata do assunto reposição hormonal, a controvérsia também não foge à regra na reposição de melatonina. Para algumas escolas constitui-se em um hormônio essencial, com importantes repercussões para a saúde humana. Já para outras escolas, não passa de um placebo sem qualquer importância clínica. Em contraste com esta controvérsia, existe uma unanimidade completa acerca da segurança e importância da reposição de melatonina entre pesquisadores renomados e médicos ao redor de todo o mundo que acumularam vasta experiência no uso e aplicações clínicas deste hormônio em seres humanos. A melatonina tem se mostrado tão segura, que até o presente momento não foi possível determinar os limites de doses tóxicas para humanos e para animais. Doses extremamente elevadas tem sido utilizadas em experimentos com animais com o intuito de estabelecer aqueles níveis, sem que se consiga produzir efeitos danosos ou mesmo a morte dos animais. Após exaustiva revisão da literatura e troca de experiências entre grupos versados no emprego clínico da melatonina, o que se pode concluir é que a sua reposição é capaz de produzir consistentes e significativos benefícios à saúde humana. Os efeitos mais notórios são observados na qualidade do sono, controle do Jet Lag, varredura de radicais livres, metabolismo da glicose, ossos, sistema cardiovascular, metabolismo cerebral, melhora do perfil lipídico e manutenção da ciclicidade e responsividade dos receptores celulares para hormônios anabólicos. Foram revistos mais de 350 estudos sobre o uso de melatonina e o sono, sendo que a quase totalidade dos mesmos (98,6%) deixa evidente uma notória melhora da qualidade do sono, por ser a melatonina capaz de encurtar o tempo de indução do sono, encurtar o início da fase REM do sono profundo e provocar um relaxamento muscular e nervoso através da estimulação do sistema parassimpático. O conjunto destas ações facilita o sono e melhora a sua qualidade, além de contribuir diretamente para o processo de reparo e recuperação metabólica ao longo do período de permanência no sono. Com base na literatura e experiência mundial atuais, inexistem quaisquer justificativas plausíveis de ordem científica ou médica que contraindiquem ou desestimulem o tratamento de reposição com melatonina. Sua segurança e eficácia clínica são motivos mais do que suficientes para ressegurar às autoridades de saúde a validade e aceitação do seu uso, desde de que tal seja feito sob criteriosa prescrição e supervisão médica. As doses de segurança são as chamadas doses fisiológicas, que devem ser seguidas e observadas pelos membros da sociedade. Lembramos que a melatonina pode reduzir a atividade do cortisol, de modo que, em casos de fadiga adrenal crônica devese iniciar o tratamento com doses menores e também corrigir a deficiência de cortisol de forma concomitante. Na opinião deste grupo, os seguintes argumentos dão suporte e fundamentam o tratamento de reposição de melatonina em adultos: Melatonina é uma substância natural ao organismo humano e sua presença é abundante, principalmente no período noturno. Melatonina está completamente adaptada ao corpo humano. Melatonina exerce uma multiplicidade de benefícios na manutenção da saúde física e mental, bem como contra o desenvolvimento das doenças degenerativas da velhice. Melatonina é segura. Melatonina tem custo acessível. O diagnóstico da deficiência de melatonina é baseado em critérios essencialmente clínicos. Pode-se, entretanto, em casos que se façam necessários, recorrer à dosagem da excreção em urina de 24 horas da 6sulfatoxi-melatonina, principal metabólito da melatonina, como parâmetro diagnóstico laboratorial. CONCLUSÃO DO CONSENSO: Com base na literatura científica atual, inexistem quaisquer justificativas plausíveis que contraindiquem ou desestimulem o tratamento de reposição com melatonina em adultos com baixos níveis. Ao contrário, uma vasta base de dados e evidências dão suporte e validam o seu emprego em indivíduos com deficiência e com baixos níveis, submetendo-os a um programa regular de acompanhamento médico. São Paulo, 12 de Novembro de 2012 Grupo de Consensos da SOBRAF 1. 2. 3. 4. 5. Professora Doutora Ana Cristina Vendramini, PhD Professora Doutora Andreia Conceição Milan B. Antoniolli, PhD Professora Doutora Andrea Thomaz Soccol, PhD Professor Doutor Eduardo Faria, PhD Professor Doutor Marcelo Alexandre de Mattos, PhD 6. Professor Doutor Marcos Renato Scholz, PhD 7. Dr. Ítalo Emmanuel Valeriano Rachid 8. ELETROPAUSA a. Quadro clínico i. Depressão, cansaço, adinamia, apatia, fragilidade imunológica, irritabilidade, déficit de memória, alterações do sono, alterações do humor e comprometimento da qualidade de vida. b. Quadro Laboratorial i. Dosagem do Sulfato de Pregnenolona no líquor ii. Sulfato de pregnenolona < 90 ng/mL. c. Observações complementares diagnóstico clínico-laboratorial: acerca do i. Quando o diagnóstico laboratorial mostrar-se coerente e compatível com o quadro clínico, este será considerado na confirmação do diagnóstico da eletropausa. Por outro lado, nas situações em que ocorrer clara discrepância, divergência ou distorções entre os dados clínicos e laboratoriais, o diagnóstico de eletropausa será confirmado tomando-se como referência as manifestações e o quadro clínico apresentados pelo paciente e devidamente avaliados e registrados pelo médico. Tal conduta se justifica pela baixa acurácia dos métodos de diagnóstico laboratorial das deficiências hormonais, falhas de técnicas intrínsecas aos métodos, uso de metodologia inadequada na coleta da amostra de sangue, horário em que a amostra foi colhida, nível de hidratação do paciente no momento da coleta e limitações técnicas dos métodos laboratoriais. A coleta de uma amostra matinal de sangue para dosar um dado hormônio, expressa um retrato estático de um fenômeno intensamente dinâmico e complexo, que sofre influência de múltiplas variáveis, o que torna qualquer método diagnóstico potencialmente falho, limitado e pouco confiável, até que sejam desenvolvidas tecnologias e métodos mais eficazes. d. No momento da instituição da proposta terapêutica hormonal para a eletropausa, a SOBRAF recomenda que seus médicos associados utilizem-se do termo de consentimento padrão adotado pela mesma e que deverá ser devidamente assinado pelo médico e pelo seu paciente. 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Effect of testosterone on bone in hypogonadal males. Maturitas. 1992 Aug;15(1):4751 5- Salamano G, Isaia GC, Pecchio F, Appendino S, Mussetta M, Molinatti GM. Effect on phospho-calcium metabolism of testosterone administration in hypogonadal males. Arch Ital Urol Nefrol Androl. 1990 Mar;62(1):149-53 6- Diamond T, Stiel D, Posen S. Effects of testosterone and venesection on spinal and peripheral bone mineral in six hypogonadal men with hemochromatosis. J Bone Miner Res. 1991 Jan;6(1):39-43 7- Kenny AM, Prestwood KM, Gruman CA, Marcello KM, Raisz LG. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels. J Gerontol A Biol Sci Med Sci. 2001 May;56(5):M266-72 8- Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A, Santanna J, Loh L, Lenrow DA, Holmes JH, Kapoor SC, Atkinson LE, Strom BL. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab. 2000 Aug;85(8):2670-7 9- Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Holmes JH, Dlewati A, Staley J, Santanna J, Kapoor SC, Attie MF, Haddad JG Jr, Strom BL. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab. 1999 Jun;84(6):1966-72 Fraturas do Quadril: A Associação Com Baixos Níveis de Testosterona 1- Leifke E, Wichers C, Gorenoi V, Lucke P, von zur Muhlen A, Brabant G. Low serum levels of testosterone in men with minimal traumatic hip fractures. Exp Clin Endocrinol Diabetes. 2005 Apr;113(4):208-13 - PREVENÇÃO DO CÂNCER E REDUÇÃO DO RISCO DE CÂNCER ATRAVÉS DA MODULAÇÃO HORMONAL 10 Proteção na MENOPAUSA: o Raghvendra K et al. Cardiovascular pharmacology of estradiol metabolites. Journal of Pharmacology and Experimental Therapeutics. 2004; 308-403-409. Replace E2 = presence of catecholestradiols and methoxyestradiols = not activation of the nuclear estrogen receptors = protection against cancer and other diseases o Liu ZJ et al. Selective insensitivity of ZR-75-1 human breast cancer cells to 2-methoxyestradiol: evidence for type II beta-ydroxisteroid dehydrogenase as the underlying cause. Cancer Res. 2005 Jul 1;65(13):5802-11 Metabolism of E2 after replacement by P450 produce 2ME2 and confer protection 2ME2 decreases tumor growth, angiogenesis and growth of cancer cells 2ME2 has strong antiproliferative, apoptotic and antiangiogenic action o Fournier A. et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort study. International Journal of Cancer .2005 Apr 10;114(3):448-54 Progesterone protects, progestins worsen cancer risk The risk was significantly greater ( p < 0.001) with HRT containing synthetic progestins than with HRT containing bioidentical Progesterone The RR respectively 1.4 and 0.8 20% decrease in risk with bioidentical progesterone o Fournier A. et al. Unequal risks for breast cancer associated with different hormone replacement thearpies: results of the E3N-EPIC cohort study. Breast Cancer Research Treat .2007 Feb 10;104(13):373-91 80.377 postmenopausal women No increase in breast cancer in women on E2 and Progesterone CEE+MPA had RR of 1.69 or 69% increase in risk of breast cancer These findings prove that bioidentical hormones are undoubtedly safer o Campagnoli C. et al. Progesterone and Progestins in relation to breast cancer risk. Journal of Steroid Biochemistry amd Molecular Biology.2005 441-450 Progesterone decreases breast cancer risk Synthetic progestins increase BC risk Higher P4 during menstrual cycle, 50% reduction risk Higher P4 HRT, 78% reduction in risk Proteção na ANDROPAUSA: o Morley, J. et al., “Testosterone replacement and the physiologic aspects of aging in men”, “ Mayo Clinic Proc 2000; 75(suppl):583-7 There is absolutelly no clinical evidence that the risk of either prostate cancer or BPH increases with transdermal testosterone replacement. o Stattin, P. et al., “High levels of circulating testosterone are not associated with increased prostate cancer risk: a pooled prospective study”, “ Intl J Cancer 2004 Jan 20; 108(3):418-24. Higher T less prostate cancer. Higher E2 more prostate câncer o Basaria, A. et al., “Anabolic androgenic steroid therapy in the treatment of chronic diseases”, “ The Journal of Clinical Endocrinology and Metabolism 2004; Vol 86. No. 11:5108-5117 The increase of prostate cancer is not increased by Testosterone administration o Rhoden, W. et al., “High levels of circulating testosterone are not associated with increased prostate cancer risk” . New England Journal of Medicine 2004 Mar; 163(3):824-7 No compelling evidence at present to suggest that men with higher testosterone levels are at great risk of prostate cancer or that treating men who have hipogonadism with exogenous androgens increases this risk. In fact, it should be recognized that prostate cancer becomes more prevalent exactly at the time of a man’s life when testosterone levels decline. o o TESTOSTERONE therapy in men with untreated PCa Morgentaler et al, J Urol 2011 All men experienced symptomatic benefit No increase in PSA No increase in prostate volume No definite cancer progression 54% of biopsies- no cancer seen! o Muller M, van der Schouw YT, Thijssen JH, Grobbee DE. Endogenous sex hormones and cardiovascular disease in men. J Clin Endocrinol Metab. 2003; 88 (11): 5076-86. A report in The Journal of Clinical Endocrinology and Metabolism (November 2003) sheds more light on the beneficial effects of testosterone supplementation in andropausal men. The study authors conducted a rigorous database search of testosterone’s effect on heart disease in men, and identified multiple studies showing that men with low testosterone levels had higher blood pressure, LDL cholesterol levels, triglyceride levels, and body mass index compared to men with optimal testosterone levels. Discussing the potential side effects of testosterone supplementation in elderly men, the authors noted, “the scientific basis for these concerns is scarce.”* HORMÔNIO DO CRESCIMENTO E CÂNCER: o Vance M, CJ. et al., “GH Therapy in Adults and Children. The New England Journal of Medicine. October 14, 2000 “No evidence that GH replacement therapy affects the risk of cancer” o Molitch ME. et al., “Diagnosis of GH deficiency in adults – how good the criteria need to be ? J Clin Endocrinol Metab 2002 Feb; 87(2):473-6 Although there has been concerns about an increased risk of cancer, reviews of existing well-maintained databases of treated patients have shown this theoretical risk to be nonexistent. o Fiebig HH et al. No evidence of tumor growth stimulation in human tumors in vitro following treatment with recombinant human growth hormone. Anticancer Drugs J 2000 Sep; 11(8):659-64 GH improves cancer cachexia No evidence of tumor growth stimulation o Growth Hormone Research Society. J Clin Endo Metab, May 2001. There is no data to suggest that IGF-1 and IGFBP 3 modulate cancer risk in GH treated patients. There is no data to support that active malignancy is a contraindication for GH supplementation. No evidence that GH increases cancer recurrence or de novo cancer or leukemia. o Swerdlow A. et al. Growth Hormone Treatment of Children with Brain Tumors and Risk of Tumor Recurrence. The Journal of Clinical Endocrinology and Metabolism Vol 85, No. 12, December 2000. Children with brain tumors 180 treated with GH 891 not treated with GH In treated patients Decreased risk of recurrence: 60% Decreased risk of mortality: 50% o Murray R.D. et al. GH-Deficient Survivors of Chidlhood Cancer: GH Replacement During Adult Life. The Journal of Clinical Endocrinology and Metabolism 2002 Jan;87(1):129-35 GH Replacement and Cancer Improved QOL “Importantly, during the 12-24 months of GH replacement therapy, there was absolutely no clinical suggestion of tumor reccurence. o Hong J et al. IGFBP 3 mutants that do not bind IGFs stimulate apoptosis in human cancer cells. Journal of Bio Chem 2002 Jan 9. IGFBP 3 Independent Anti-Cancer Actions IGFBP 3 triggers cell cycle and stimulates apoptosis. IGFBP 3 independent mechanisms are major contributors to IGFBP 3 induced apoptosis in cancer cells. IGFBP 3 plays a wider hole in the anti-proliferative and antitumorgenic actions. IGFBP 3 may be considered “The Guardian of the Genome”. o Kurek R et al. The significance of serum levels of insulin-like growth factor 1 in patients with prostate cancer. J Clin Endoc Metab, 2000 Jan;85(1):125-9. No association between IGF-1, GH and prostate cancer risk. Androgen decline or withdrawal did not change IGF-1. o Baffa R et al. Low serum insulin-like growth factor 1 : a significant association with prostate cancer. J Urology, 2000 Sep;6(3):236-239. Low IGF-1 Associated with Prostate Cancer IGF-1 considerably lower in Prostate CA patients than control. o No association of IGF-1, GH levels and PSA increase. IGF-1 decresed with age Prostate cancer risk increased with age . Finne P et Al IGf-1 Tumor Marker for cancer prostate ? . 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