Effect of early luteal phase administration of mifepristone (RU486) on leukaemia inhibitory factor, transforming growth factor beta and vascular endothelial growth factor in the implantation stage endometrium of the rhesus monkey

Abstract

A single, low-dose administration of a potent antiprogesterone such as mifepristone (RU486) in the early luteal phase results in inhibition of blastocyst implantation in primates. The aim of the present study was to examine the status of leukaemia inhibitory factor (LIF), transforming growth factor beta (TGF beta) and vascular endothelial growth factor (VEGF) in day 6 gestational endometrium of rhesus monkeys with or without exposure to a single dose (2 mg/kg body weight, s.c.) of mifepristone on day 2 after ovulation. Densitometric analyses of immunoblots of endometrial spent media revealed an increase (P < 0.01) in TGF beta pan (TGF beta 1, 2, 3 and 5) and a decrease (P < 0.01) in VEGF secretion from RU486-exposed endometrial samples compared with control samples. Secretory profiles for LIF, TGF beta 1 and TGF beta 1 LAP (latency associated peptide) remained unchanged in the two treatment groups. Morphometric analyses of immunohistochemical staining showed altered cell-specific distribution. TGF beta 1 (P < 0.01) and TGF beta pan (P < 0.02) were higher, while VEGF declined (P < 0.05) in endometrial glands of RU486-exposed endometria compared with control tissue samples. Stromal cell staining patterns for all experimental cytokines studied remained unchanged. In blood vessels, VEGF was found to be low (P < 0.05), while LIF (P < 0.05) and TGF beta 1 (P < 0.01) were higher in mifepristone-exposed endometrial samples compared with control tissue samples. Increased TGF beta secretion together with elevated levels of TGF beta in glandular epithelia and in blood vessels with no apparent change in stromal levels of TGF beta or in levels of TGF beta LAP in any endometrial compartment in the two treatment groups suggest an altered paracrine involvement of this cytokine and an enhanced activation of latent TGF beta in endometrium following mifepristone treatment. Higher levels of TGF beta in gland cells may result in dysregulated growth control and degenerative morphology. Also, higher levels of LIF and TGF beta together with lower levels of VEGF in the vascular compartment in mifepristone-exposed endometrium suggest that endometrial vascular physiology is a target of this anti-progestin during the peri-implantation stage. It is thus plausible that LIF, TGF beta and VEGF in the glandular and vascular compartments of implantation stage endometrium play important roles in rendering the endometrium receptive, and that early luteal phase treatment with an anti-progestin such as mifepristone affects the involvement of these cytokines resulting in endometrial contraception.