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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. Intervention(s) 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) IVF-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.

Patients with a history of repeated and unexplained implantation failure after IVF-embryo transfer and a high uterine natural killer cell count during estrogen-progestin treatment may benefit from controlled natural IVF-ET.

To explore oocyte competence for subsequent birth. The modified natural IVF/intracytoplasmic sperm injection (ICSI) cycle was used as an experimental model by measuring levels of cytokines, chemokines, and growth factors in individual follicular fluids (FF).A retrospective blinded study.European network of research, Embryo Implantation Control (EMBIC).Single FF from 83 women were analyzed during a modified natural IVF/ICSI cycle, and reproducibility of follicular composition was evaluated over two cycles for 15 patients.Each FF sample was blindly tested to assess levels of 26 factors by bead-based immunoassays.Each mediator was evaluated as a potential biomarker of subsequent birth by multivariate regression analysis.A combination of both FF G-CSF and IL-15 was the optimal model to predict birth (AUC(ROC), 0.85). Birth rates per cycle were 48.9% (16/33) if two good-prognosis criteria were present (FF G-CSF12 pg/mL and IL-157 pg/mL) and 8% (3/36) and 0% (0/14) if, respectively, one or none were present. FF G-CSF was significantly correlated over two cycles (r=.71), suggesting a possible prognostic value of its documentation.Combined follicular G-CSF and IL-15 quantification appears as an efficient and noninvasive method to define oocyte competence for subsequent successful conception in modified natural IVF/ICSI cycles.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) could play a role in the regulation of interleukin (IL)-15 and IL-18, cytokines crucial for angiogenesis and uterine natural killer (uNK) cell recruitment during embryo implantation. We therefore confirmed the endometrial presence of TWEAK/fibroblast growth factor inducible-14 (Fn-14) and documented simultaneously the cytotoxic KIR receptor (NKp46) of uNK cells in the human endometrium while TWEAK, Fn-14, IL-15, and IL-18 mRNA were quantified by real-time polymerase chain reaction in relation to the recruitment of CD56+ cells among fertile control women and patients who had failed to implant after assisted reproduction treatment.

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 effects of tibolone and its main metabolites on breast homeostasis. Design: In vitro studies in primary cultures of normal breast cells and in breast cancer cell lines. Setting: Hospital-based academic research center. Patient(s): Human breast cells were obtained from women undergoing surgery for hypermastia. Breast cancer cell lines (MCF-7, T47-D, and ZR75-1) were routinely obtained from subcultures. Intervention(s): Cells were incubated with tibolone, its various metabolites, the pure pregnane Org 2058, and the androgen dihydrotestosterone. Main Outcome Measure(s): Proliferation was determined by using a morphometric growth index, apoptosis by using morphologic analysis and flow cytometry, and antiapoptotic proteins bcl-2 and bclx L by using Western blot assay. Activity of 17β-hydroxysteroid dehydrogenase was measured as an epithelial differentiation marker. Result(s): Tibolone and its δ 4 isomer were antiproliferative in normal breast cells. Tibolone and its δ 4 isomer increased apoptosis in breast cells. These proapoptotic effects were at least partially mediated through decreased expression of the antiapoptotic proteins bcl-2 and bclx L . An increase in HSD activity was observed after tibolone administration. Conclusion(s): Tibolone is antiproliferative and proapoptotic and induces differentiation in normal breast cells. It is also proapoptotic in breast cancer cell lines.