Concentration of leukaemia inhibitory factor (LIF) in uterine flushing fluid is highly predictive of embryo implantation.

BACKGROUND: There is strong evidence that locally secreted cytokines control the implantation process and can cause implantation failure. Uterine flushing fluids were analysed to determine their concentrations of leukaemia inhibitory factor (LIF) and tumour necrosis factor (TNF). METHODS AND RESULTS: We began by flushing the uterine cavities of 33 infertile patients on day 26 of two consecutive cycles. The concentrations of LIF (by enzyme-linked immunosorbent assay) and TNF (by bioassay) were significantly correlated during these cycles (r = 0.762, P = 0.0001 and r = 0.822, P = 0.001 respectively) and hence reliable. Then, after a reference flushing of 30 infertile patients, we followed the outcome of their first consecutive cycle of ovarian stimulation, which preceded either IVF or intrauterine insemination. A total of 10 patients became pregnant. The median concentration of LIF was 0 pg/ml (range: 0-177) and of TNF was 0 U/ml (range: 0-6.17) among those who became pregnant, and 203 pg/ml (range: 0-1620) and 2.14 U/ml (range: 0-16) respectively among those who did not. The LIF concentration was significantly lower in the pregnant group (P = 0.0013). CONCLUSION: A low concentration of LIF in the uterine flushing fluid at day 26 was predictive of subsequent implantation. Use of this procedure should increase the number of IVF attempts yielding successful pregnancies and also lead to corrective therapies.

Follicular fluid concentration of leukaemia inhibitory factor is decreased among women with polycystic ovarian syndrome during assisted reproduction cycles.

BACKGROUND: The possibility that a specific cytokine profile could be detected in the ovaries of patients with polycystic ovarian syndrome (PCOS) was investigated. METHOD: Enzyme-linked immunosorbent assay (ELISA) or bioassays were used to assess the concentrations of leukaemia inhibitory factor (LIF), tumour necrosis factor, interleukin 11, gamma interferon, progesterone and oestradiol in follicular fluids from preovulatory follicles collected after ovarian stimulation from 15 PCOS patients, 15 infertile control patients with regular cycles, and 8 oocyte donors. RESULTS: LIF and progesterone concentrations were significantly lower in the follicular fluid of PCOS patients (LIF median: 265 pg/ml) compared with controls (LIF median: 816 pg/ml); LIF and progesterone follicular fluid concentrations were correlated (r = 0.720, P = 0.0001). The LH/FSH ratio was negatively correlated with LIF concentrations (r = - 0.714, P = 0.0075). Although the PCOS and control patients did not differ significantly in age, ovarian reserve or IVF indication, the implantation rate was significantly lower among the women with PCOS (IR = 9 versus 21%, P = < 0.01). CONCLUSION: The specific cytokine profile of the PCOS patients is probably related to the lower implantation rate since follicular fluid LIF appears to function as an embryotrophic agent.

Interleukin-6 levels in co-culture of human in vitro fertilization embryos with Vero cells are not predictive of future successful development.

PROBLEM: In an attempt to predict successful embryo transfer and implantation, we measured interleukin (IL)-6 levels in culture supernatants of co-cultured preimplantation human embryos. We tested whether all in vitro fertilized human embryos in co-cultures do secrete IL-6, and whether there was any difference in such production between embryos that successfully reached the blastocyst stage and blocked embryos. We also addressed the question of IL-6 secretion by co-culture support cells, namely Vero cells themselves. METHOD OF STUDY: Each fertilized oocyte was cultured individually and transferred in culture wells supplemented with a feeder layer of Vero cells at day 2. In vitro IL-6 production was measured by bioassay of the culture media. RESULTS: Because Vero cells themselves secrete IL-6, it became impossible, in co-culture, to quantify production of IL-6 by the sole embryos. On the other hand, the co-culture technique has shown us that embryos are likely to consume IL-6. There was no difference between blastocysts and blocked embryos. CONCLUSIONS: IL-6 levels in human embryo co-cultures do not correlate with future successful embryo transfer.

[Abnormal endometrial reactivity to colony stimulating factor 1 and leukemia inhibitory factor dependent female infertility]. / Réactivité anormale de l'endomètre au CSF-1 et stérilité féminine dépendante du LIF.

Maternal LIF is essential for embryo implantation in mice and it may also be the case in humans. We recently reported that endometrial LIF secretion from infertile women presenting repeated failures of embryonic implantation or unexplained sterility was significantly lower than the secretion of explants from fertile women. We now report on the modulation of the endometrial LIF secretion according to the obstetrical status. CSF-1 has little effect or increases LIF secretion from fertile women whereas it inhibits secretion from infertile women with repeated failures of embryonic implantation.