Endometrial Leukemia Inhibitory Factor (LIF) as a Possible Cause of Unexplained Infertility and Multiple Failures of Implantation

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Abstract
PROBLEM: The possible role of leukemia inhibiting factor (LIF) in unexplained infertility and multiple failures of implantation (MFI) was evaluated. METHOD OF STUDY: By a specific and sensitive enzyme‐linked immunosorbent assay (ELISA), the in vitro endometrial LIF secretion by explant cultures from women with unexplained infertility (n = 32) was examined. Endometrial samples were obtained on either days 8–11 of the proliferative phase or days 18–21 of the secretory phase. In some subjects (n = 11) an endometrial biopsy was performed twice, both in the proliferative and in the secretory phase of the cycle. The control group consisted of fertile women (n = 17). RESULTS: In fertile women the endometrial LIF secretion was 2.2 times higher in the secretory phase samples than in the proliferative phase samples (mean ± SEM, 3259 ± 314 pg in the proliferative phase vs. 7726 ± 1192 in the secretory phase; P < 0.05). In contrast, infertile women exhibited no such elevation of cytokine production. Moreover, in infertile women with MFI the level of LIF in the secretory phase demonstrated the tendency to decrease (mean ± SEM, 4953 ± 1125 pg Vs. 2162 ± 541 pg; P > 0.05). When the amount of cytokine secretion was compared on the same day of the cycle between the two groups of women, the LIF production in fertile women on days 18–21 of the menstrual cycle was 3.5 times greater than in the infertile women with MFI and 2.2 times greater than in women without MFI (P < 0.01 and P < 0.05, respectively). On days 8–11 of the cycle, the level of LIF in these groups did not differ significantly, however, in infertile women the range of distribution of cytokine was largely varied, demonstrating the highest amplitude of variations in subjects with MFI. Analyses of the data for women to whom LIF was examined in both phases of the cycle showed that some subjects (27%) exhibited an elevated amount of LIF in the secretory phase of the cycle. This suggests that in these cases the endometrial factor(s) may be irrelevant to infertility. CONCLUSIONS: In the majority of infertile women there is a deregulation of LIF production in the endometrium during both the proliferative and the secretory phases of the cycle. The dysfunction of cytokine production is more profound in patients with MFI. The deregulation of endometrial LIF secretion throughout the menstrual cycle may be a possible cause of unexplained infertility and repetitive failures of implantation.