Modification of endometrial cell biology using progesterone antagonists to manipulate the implantation window.
The preimplantation effects of progesterone antagonists on the cell biology of the endometrium, corpus luteum function and interactions between these two organs have been studied. The antagonists lilopristone (ZK 98.734) and onapristone (ZK 98.299) were initially given per os to rabbits early or late in pseudopregnancy in combination with human chorionic gonadotrophin (HCG). These protocols were then modified to include hysterectomy or luteotrophic support with 17 beta-oestradiol. Given alone, the antagonists gave rise to endometrial regression (inhibition of epithelial proliferation and differentiation, increase of apoptosis). The simultaneous addition of oestradiol did not alter these findings. A rapid luteolysis occurred when the antagonists were given in late pseudopregnancy, but not if combined with oestradiol or hysterectomy. The endometrium was capable of renewal and of sustaining implantation if the corpora lutea survived or oestradiol was administered, and transferred blastocysts displayed normal implantation and normal embryonic development. These events did not occur when the antagonists were given during late pseudopregnancy without any steroid supplement. Progesterone antagonists can evidently exert a direct inhibitory effect on the endometrium, possibly with a later indirect luteolytic effect via endometrial mediators. Simultaneous addition of a proper luteotrophic signal results in corpora lutea which are refractory to lysis, so revealing a potential functional dissociation between endometrium and corpus luteum. The endometrium has the capacity to differentiate normally after an interrupted transformation and becomes receptive and sustains normal pregnancy, due to an expanded lifespan of the corpora lutea and a transposition of the implantation window. Uterine secretions from patients undergoing in-vitro fertilization, collected at the onset of the luteal phase, were evaluated by SDS-PAGE densitometry. The protein profiles gave indications of an adequate luteal phase pattern and of a receptive preimplantation phase. These results open the prospect of manipulating the human implantation window.