Endometrial contraception: modulation of molecular determinants of uterinereceptivity

Modulation of endometrial receptivity is a promising approach for fertility regulation since it allows a contraceptive to act specifically at the endo metrium. This was corroborated by our previous observations that treatment with low doses of a pure progesterone antagonist (PA, antiprogestin), onapr istone (ZK 98299), in bonnet monkeys inhibited fertility by selectively ret arding endometrial development, without affecting the hypophyseal-hypothala mic function. In the present study, further investigations, undertaken to a nalyze the molecular repertoire of a nonreceptive primate endometrium, dete rmined expression of: steroid hormone receptors, i.e. progesterone receptor (PR) and estrogen receptor (ER); cytokines, i.e. leukemia inhibitory facto r (LIF): transforming growth factor beta (TGF beta) and its receptor (TGF b etaR); and cell adhesion molecules, i.e, integrins (alpha (v)beta (3), alph a (1)beta (1)). These studies were conducted during the different phases of the normal menstrual cycle and following treatment with different doses of onapristone (2.5 mg, 5 mg, or 10 mg every third day for one cycle) in bonn et monkeys. The molecules were analysed collectively to explore the possibi lity of a correlation between expression of these markers and endometrial r eceptivity and to investigate whether there exists a regulatory link betwee n expression of these molecules under in vivo conditions. Three types of ex pression patterns of endometrial factors were observed during the peri-impl antation period following onapristone treat-ment: 1) LIF, alpha (v)beta (3) , and alpha (1)beta (1) showed significant (P < 0.02) down regulation in gl andular epithelium of endometria in animals treated with all three doses of onapristone as compared to the control group. This was indicative of their critical role in the progesterone-driven cascade leading to implantation. 2) PR, TGF<beta>, and TGF betaR remained unaffected in the endometria from 2.5 mg treated animals and showed down regulation in animals treated with 5 and 10 mg onapristone as compared to the control group, thereby suggesting that the expression of these markers may not truely reflect endometrial re ceptivity per se. However, their facilitatory role in preparing the endomet rium for implantation can not be ruled out since continued perturbation in the expression of these molecules may affect endometrial growth, remodellin g, and differentiation, which in turn may render the endometrium nonrecepti ve; 3) ER remained unaltered in endometria of animals rendered infertile wi th 2.5, 5, and LO mg onapristone. This observation indirectly suggests that onapristone-induced endometrial changes are mediated via some specific mec hanisms. The present study clearly demonstrates that endometrial non-recept ivity induced at low doses of onapristone is associated with changes in the expression pattern of specific molecular markers. However, no direct corre lation was observed between in vivo expression of TGF beta, LIF, and integr ins, thereby lending support to the concept that there exists redundancy or multiple pathways which regulate implantation events. (C) 2000 Published b y Elsevier Science Inc.