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Objective: To document in the endometrium the correlation among the interleukin (IL)-12, -15, and -18 mRNA and the correlation between cytokine levels, vascular status, and endometrial natural killer (NK) cell count in the context of recurrent implantation failure., Design: A pilot study., Setting: Department of Reproductive Immunology., Patient(s): Women who failed to become pregnant after repeated IVF-embryo transfer and fertile control subjects., Intervention(s): Ultrasonic evaluation and endometrial biopsy in luteal phase., Main Outcome Measure(s): Uterine artery Doppler, count of uterine CD56 bright cells/field, and quantification by real-time polymerase chain reaction (PCR) to monitor IL-12 family (IL-12p40, IL-12p35, EBI3, IL-23), the IL-18 system (IL-18, IL-18R, IL18BP), and the IL-15 mRNA ratio., Result(s): The uterine artery Doppler and the CD56 bright cell counts were significantly different in fertile and infertile patients. The mean uterine artery pulsatility index correlated significantly negatively with the IL-18/actin ratio suggesting a defect of the cytokine-dependent vascular remodeling pathway. The number of uterine CD56 bright cells was significantly correlated with the IL-15/actin and IL-18/IL-18BP ratios. Thus, IL-18 and IL-15 seems to be involved in the local recruitment and the activation of uterine natural killer (uNK) cells. IL-18 was itself correlated with IL-15 and IL-12, suggesting a local control of uNK cells activation., Conclusion(s): The assessment of the tripod IL-12/-15/-18 shows distinct immune-related mechanisms that are involved in the broader context of inadequate uterine receptivity.

Objective: To investigate the endometrial immunohistochemical staining of interleukin (IL)-12 and IL-18 and to quantify the CD56 bright natural killer (NK) cells in relation to Doppler vascular disorders., Design: Controlled clinical study., Setting: Research unit of a university hospital. PATIENT(S)": Thirty-five women with repeated implantation failure after ET in IVF and 12 fertile control patients.Ultrasound evaluation and endometrial biopsy on day 20., Main Outcome Measure(s): The balance between IL-12 and IL-18, the number of NK cells, and the vascular status among fertile and implantation failure patients., Result(s): The control patients displayed normal vascular parameters, a weak anti-IL-12 staining, a consistent moderate stromal anti-IL-18 staining, and fewer than 15 NK cells/field. This pattern was observed among only 17% (6/35) of the implantation failure group. The remaining patients fit into one of two patterns: [1] 37% (13/35) had more than 40 NK cells/field with a strong anti-IL-12 and/or anti-IL-18 staining, and [2] the remaining 46% (16/35) had a marked local depletion of IL-18 and IL-12. Respectively, 85% and 31% of two groups displayed abnormal vascular parameters., Conclusion(s): Distinctions between the different local dysregulations of the cytokine network may provide clues for further exploration and treatment.

Objective: To assess intrauterine levels of leukemia inhibitory factor (LIF) by uterine flushing at the time of egg retrieval and to confirm that the procedure has no detrimental effect on pregnancy rates., Design: Prospective study., Setting: Assisted reproductive unit of a university hospital., Patient(s): Uterine flushing was performed in 148 IVF patients. The first 100 patients were compared with a matched control group., Intervention(s): Uterine flushing at the time of egg retrieval., Main Outcome Measure(s): IVP-ET results, pregnancy rates, and intrauterine LIF levels., Result(s): Pregnancy rates were not different in the group of patients with (27%) or without uterine flushing (28%). Leukemia inhibitory factor was detected in 60 patients (46%). Pregnancy rates did not differ between patients' detectable LIF and those in whom LIF was undetectable. Mean levels of LIF were 30.1 +/- 49.3 pg/mL and 28.6 +/- 51.2 pg/mL in pregnant and nonpregnant patients respectively., Conclusion(s): The flushing procedure at the time of egg retrieval did not adversely affect pregnancy rates. Leukemia inhibitory factor was detected in 46% of patients at the time of egg retrieval, but no correlation were observed with better pregnancy rates in patients with detectable LIF. Mean LIF levels did not differ in pregnant and nonpregnant women. Access to endoluminal secretions of the endometrium during IVF-ET may represent a new research in human implantation.

Introduction: To assess ultrasonic data in the context of repeated failure of implantation in assisted reproduction medicine., Materials and Methods: We reviewed ultrasonic data (uterine score at follicular and luteal phase). The same ultrasound exploration was repeated for two consecutive cycles to assess the changes in abnormalities observed and compare findings in 16 patients with repeated failure of implantation and in 14 controls. The controls were women who became pregnant within the three months following the exploration. We then introduced acetylsalicylic acid and prednisolone as first line treatment and nitroglycerin as second line treatment to measure the effects induced in 14 pathological uterine scores., Results: The score obtained under hormonal treatment was representative of other cycles (r = 0.812, p < 0.0014). The score was significantly lower and the luteal uterine artery pulsatility index was significantly higher in the repeated failure group than in the control group (p < 0.0001 and p = 0.008 respectively). For the 14 patients, treatment improved the uterine score in 8 with acetylsalicylic acid and prednisolone and in 4 with nitroglycerin. Two patients did not respond to treatment. Concerning the effect of therapy, of 14 patients, 8 had an improved uterine score with A + P, and with T; 2 patients did not respond to any treatment., Conclusion: The uterine score and luteal artery pulsatility index may be valuable tools for patients with implantation failure who all do not respond to the same therapy.

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.