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Endometrial tumor necrosis factor (TNF) is a likely mediator of early luteal phase mifepristone-mediated negative effector action on the preimplantation embryo

Department of Physiology, All India Institute of Medical Sciences, New Delhi-110029, India

Correspondence should be addressed to D Ghosh; Email: dghosh{at}aiims.ac.in

Cytokines and growth factors are important mediators of progesterone-regulated endometrial receptivity and embryo development. Early luteal phase administration of a potent antiprogestin-like mifepristone to the rhesus monkey results in endometrial desynchrony, loss of embryo viability and implantation failure. In the present study, administration of mifepristone (2 mg/kg body weight, s.c.) on day 2 after ovulation resulted in a significant increase (P < 0.01) in the level of tumor necrosis factor (TNF) in glandular and vascular compartments of endometrium, and in endometrial secretion and luminal fluid on day 6 after ovulation in the rhesus monkey. There was an associated lag in embryonic development, characterized by delayed mitochondrial maturity, poorly developed junctional complexes, a relative absence of intra-cytoplasmic filaments and a high degree of intra-cellular degenerative features. Exposure of TNF (0, 0.5, 5, 50 ng/ml) to preimplantation stage mouse embryos in vitro showed a dose-dependent arrest in growth and development at both morula and blastocyst stages along with ultra-structural features of degeneration similar to those observed in embryos collected from early luteal phase mifepristone-treated monkeys. The de novo synthesized and released proteins in terms of trichloroacetic acid precipitable ³⁵S by morulae and blastocysts in vitro showed a marked depression following exposure to TNF compared with control embryos. Based on the above observation and the fact that preimplantation stage embryos express receptors for TNF, we suggest that increased levels of TNF in endometrial and luminal compartments around the time of uterine receptivity following early luteal phase administration of mifepristone adversely affect the growth and viability of preimplantation stage embryos.

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