MODIFICATION OF ENDOMETRIAL CELL BIOLOGY USING PROGESTERONE ANTAGONISTS TO MANIPULATE THE IMPLANTATION WINDOW

The preimplantation effects of progesterone antagonists on the cell bi ology of the endometrium, corpus luteum function and interactions betw een 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 cho rionic gonadotrophin (HCG). These protocols were then modified to incl ude hysterectomy or luteotrophic support with 17 beta-oestradiol. Give n alone, the antagonists gave rise to endometrial regression (inhibiti on of epithelial proliferation and differentiation, increase of apopto sis). The simultaneous addition of oestradiol did not alter these find ings. A rapid luteolysis occurred when the antagonists were given in l ate pseudopregnancy, but not if combined with oestradiol or hysterecto my. The endometrium was capable of renewal and of sustaining implantat ion if the corpora lutea survived or oestradiol was administered, and transferred blastocysts displayed normal implantation and normal embry onic development. These events did not occur when the antagonists were given during late pseudopregnancy without any steroid supplement. Pro gesterone antagonists can evidently exert a direct inhibitory effect o n the endometrium, possibly with a later indirect luteolytic effect vi a endometrial mediators. Simultaneous addition of a proper luteotrophi c signal results in corpora lutea which are refractory to lysis, so re vealing a potential functional dissociation between endometrium and co rpus luteum. The endometrium has the capacity to differentiate normall y after an interrupted transformation and becomes receptive and sustai ns normal pregnancy, due to an expanded lifespan of the corpora lutea and a transposition of the implantation window. Uterine secretions fro m patients undergoing in-vitro fertilization, collected at the onset o f the luteal phase, were evaluated by SDS-PAGE densitometry. The prote in profiles gave indications of an adequate luteal phase pattern and o f a receptive preimplantation phase. These results open the prospect o f manipulating the human implantation window.