Charakterisierung und Optimierung eines Tiermodells der Endometriose in Ratten

In the present work an in-vivo-model for endometriosis in rats was characterized and opti­mized with regards to the screening of new drugs for the therapy of endometriosis. For the first time, rat inbred strains were used for this purpose providing genetic conformity and unique characteristics within each strain and offering the possibility to identify a very sensitive strain for the endometriosis. Furthermore, an isogenic transplantation can be used to induce endometriosis in inbred animals and this should less harmful than the classical auto­transplantation of uterus fragments. The antagonistic GnRH-Analog Cetrorelix was used as test medication. Today GnRH-analogs are among the most effective therapeutic agents to treat endometriosis. The added-value of antagonists is their dose-dependent effect. In study 1A and 1B, 5 different rat strains were compared. Induction was performed by auto­transplantation and the animals were treated with 50µg/animal/d of the Cetrorelix acetate, control animals received 0,2ml of the vehicle mannitol (5%) for 3 weeks. Especially the BN rats but as well the BUF animals showed a high susceptibility towards induced endometriosis. They were characterized by a high transplant survival rate and a strong growth of the trans­plants. The animals of the BN strain also responded most strongly to the treatment with Cetrorelix acetate in high dosage. Obvious effects were reduction of the size and weight of the transplants, reduction of the weights of the uterus and ovary and increase in body weight. Serum estradiol concentratins decreased below detection limit. Immunhistochemichal detection of estrogen- and progesterone receptors reflected a physio­logical situation. The proliferative activity of glandular epithelial cells in the transplants was strongly reduced compared to the uterus. In study 2 the inbred strains with the lowest (F344) and with the highest (BN) susceptibility and the outbred strain SPRD were compared. The treatment group received once 156µg/250g body weight Cetrorelix pamoate (depot formulation), the control group received only vehicle. The treatment with Cetrorelix pamoate had similar effects as the treatment with Cetrorelix acetate, but only tendencies could be shown and there was no statistical significance. In the last study isogenic transplantation was performed in BN and F344 rats. The advantage of this method is, that the uterus of the recipient animal stays intact and more similarity to the human disease is achieved. In addition, the stress of the animals is reduced which is reflected by a shorter recovery rate after surgery. In this study, there was no pharmacological treatment. The mRNA expression analysis of a selection of potential endometriosis-related genes re­vealed that expression of some genes changes in the rat model in a comparable way as in hu­man endometriosis. Other genes appeared to be rat-specific. The treatment with Cetrorelix had significant effects on the mRNA expression in transplant and uterus and, in geneal the difference between the tissues was increased. With BN and BUF two inbred strains with specific genetic predisposition for endometriosis have been identified. An even better predictivity of the model is given by isogenic transplan­tation. This conclusion is supported by matches between pathological gene xpressions of endometriosis-related marker genes in humans and rats. Moreover, the efficacy of Cetrorelix was shown for the first time in an in vivo endometriosis model. This optimized model might open new possibilities to reveal predisposition factors and diagnostic markers and the testing of new endometriosis therapies in the future.