D ISCUSSÃO SUCINTA E CONCLUSÕES GERAIS

1) A senescência levou ao desequilíbrio hormonal, causando desorganização estrutural na próstata, sobretudo no compartimento estromal, com hipertrofia dos elementos fibrilares e presença de células inflamatórias. Tais mudanças na senescência evidenciaram, especialmente, a potencialização da ação estrogênica no microambiente glandular.

2) A presente terapia hormonal não reverteu a hipertrofia e a ocorrência de células inflamatórias, bem como caracterizou alterações estruturais no compartimento epitelial, como o aparecimento de células com halo citoplasmático claro ao redor do núcleo. Tal fenótipo celular atípico sugeriu o desequilíbrio das sinalizações parácrinas prostáticas, indicando que a reposição de hormônios esteróides na senescência gerou um microambiente reativo propício ao desenvolvimento de lesões glandulares.

3) A terapia hormonal demonstrou-se capaz de elevar os níveis plasmáticos de hormônios esteróides em ratos senis, entretanto, considerando as alterações estruturais evidenciadas, sugere-se que estes não foram representativos das concentrações hormonais no tecido prostático.

4) A depleção androgênica na senescência provavelmente levou à redução dos níveis das DGs, comprometendo o equilíbrio da dinâmica molecular prostática e sugerindo o déficit da interação epitélio-estroma, com provável diminuição funcional do órgão. Por outro lado, a reposição hormonal, sobretudo com estradiol, promoveu aumento significativo dos níveis dessas moléculas de adesão, indicando aspecto positivo dessa terapia na restauração do equilíbrio glandular na senescência bem como o importante papel das vias estrogênicas nas sinalizações parácrinas da próstata.

5) As moléculas de IGFR-1 e MMP-9 apresentaram níveis protéicos aumentados tanto na reposição de hormônios esteróides como na depleção androgênica imposta pela castração durante o período de senescência, podendo-se concluir que o desequilíbrio do balanço hormonal entre andrógenos e estrógenos, e não somente a presença de um ou outro hormônio, resultou em perturbação da dinâmica molecular prostática.

6) Aumento de VEGF foi constatado na senescência, resultando em desequilíbrio entre esse fator pró-angiogênico e a endostatina, molécula inibidora da angiogênese, que apresentou redução de seus níveis, culminando em um microambiente prostático favorável à neovascularização.

7) A terapia hormonal não levou à reversão do aumento de VEGF verificado na senescência, sugerindo que a desordem do equilíbrio molecular glandular, caracterizada pelo aumento de IGFR-1 e MMP-9, possivelmente potencializou os níveis desse fator pró- angiogênico após a reposição de hormônios esteróides. Além disso, enquanto as vias ativadas por estrógenos sinalizaram positivamente a reatividade do VEGF no tecido prostático durante a senescência, a endostatina respondeu positivamente à reposição de testosterona.

8) A reposição de hormônios esteróides, apesar de seus efeitos positivos sobre as DGs, provavelmente acentuou o desequilíbrio hormonal entre andrógenos e estrógenos na próstata, levando à potencialização das alterações estruturais associadas à senescência e rompendo o equilíbrio da dinâmica molecular prostática. Assim, a terapia hormonal gerou microambiente prostático reativo, caracterizado por aumento de um fator mitogênico e da remodelação tecidual bem como por desequilíbrio da angiogênese, possivelmente comprometendo a função do órgão e predispondo-o a lesões glandulares.

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