The progesterone antagonist onapristone retards the advanced endometrial transformation after gonadotropin stimulation in rabbits

Ovarian stimulation with gonadotropins (GN) during human in vitro fertiliza tion and embryo transfer (IVF/ET) therapy alters the ovarian steroid output , especially that of progesterone. As a consequence, endometrial transforma tion is advanced, and embryo implantation is hampered. This study used the rabbit model to determine if the application of the progesterone antagonist (PA) onapristone (ONA) could retard endometrial development after GN-stimu lation. Rabbits were GN-stimulated twice daily with 5 IU FSH and 5 IU LH on 3 consecutive days with a) hMG (n = 10) or b) with a mixture of recombinan t FSH and LH tit = 10). The animals were then mated, and hCG was injected i .v. to ensure ovulation. This day is designated as day 0 post coitum (d 0 p .c.). On day 2 p.c., five animals of each group were treated with 20 mg ONA /kg body weight and five with vehicle for control. On d 5 p.c. endometrial transformation was analyzed by morphology, uteroglobin (Ugl)-mRNA expressio n, and proliferation. Embryos were Bushed from the uteri. Their number and morphology was evaluated. The endometrium of GN-stimulated control animals demonstrated very long endometrial glands and narrow stromal septa. Ugl-mRN A expression was restricted to the cells at the bottom of the gland. 17.0 /- 4.6% (mean +/- SD) of glandular cells and 6.0 +/- 5.3% of luminal epithe lial cells proliferated. In ONA-treated animals, endometrial glands were si gnificantly shorter, and the pattern of arborization was less pronounced. E ndometrial gland cells and luminal epithelial cells expressed Ugl-mRNA. Fur thermore, glandular and luminal cells proliferated with high intensity (38. 6 +/- 6.8% and 36.4 +/- 9.3%, respectively). These results indicate that th e status of endometrial differentiation was retarded after ONA-treatment. N evertheless, the embryos of these ONA-treated animals were well developed. In conclusion, after ON-stimulation, ONA treatment retarded the advanced en dometrial transformation in rabbits. Therefore, postovulatory administratio n of a PA might be a possible strategy to modulate the advanced endometrial development in IVF-cycles. (C) 2000 Elsevier Science Inc. All rights reser ved.