Endometrial tumor necrosis factor [alpha] (TNF[alpha]) is a likely mediator of early luteal phase mifepristone-mediated negative effector action on the preimplantation embryo
2005
Lalitkumar, PGL | Sengupta, J | Ghosh, D.
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 [alpha] (TNF[alpha]) 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[alpha] (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[alpha] compared with control embryos. Based on the above observation and the fact that preimplantation stage embryos express receptors for TNF[alpha], we suggest that increased levels of TNF[alpha] 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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