[Materno-foetal dialogue and human embryo implantation: some evolving concepts]. / Dialogue materno-foetal et implantation embryonnaire humaine: des concepts qui évoluent.

Multiple immunogical mechanisms allow fetal allograft tolerance. In this review, we first describe the maternal and embryological side in order to expose the dangers for the embryo enabling the development of materno-fetal strategies that will allow fetal survival and growth.

Detectable levels of interleukin-18 in uterine luminal secretions at oocyte retrieval predict failure of the embryo transfer.

BACKGROUND: Most implantation failures after successful in vitro fertilization-embryo transfer (IVF-ET) result from inadequate uterine receptivity. There is currently no way to predict this receptivity. METHODS: We investigated whether the detection of interleukin-(IL)18 by ELISA in uterine luminal secretions might predict implantation failure. Secretions of 133 patients enrolled in our IVF-ET program were sampled by uterine flushing immediately before oocyte retrieval. We assessed the following outcomes: pregnancy rate, multiple pregnancy rate, and implantation rate per embryo transferred. RESULTS: Interleukin-18 was detected in the flushing fluid of 38 patients (28.6%). Although the two groups were comparable for all other characteristics (age, etiology, ovarian reserve, number of embryos transferred, quality of embryos), all outcome variables differed significantly. The pregnancy rate was 37.9% in the IL-18 - ve group and 15% in the IL-18 + ve group, the multiple pregnancy rate 27.7% and 0%, and the implantation rate per embryo transferred 19.4% and 6.7% (all comparisons, P=0.02). Only embryos meeting good quality criteria were transferred to 65 patients: 50 IL-18 - ve and 15 IL-18 + ve. The pregnancy rate was 51% for the IL-18 - ve group and 20% for the IL-18 + ve group, the multiple pregnancy rate 36% and 0.0%, respectively, and the implantation rate 29% and 8.3% (P = 0.02). CONCLUSION: This non-invasive and simple method predicted inadequate uterine receptivity, independent of embryo quality.

[Secreted cytokines in the uterine lumina are predictive of subsequent implantation. Presence of IL18 in the uterine flushing]. / Prédiction de l'implantation par l'analyse des cytokines. Exemple du dosage de l'interleukine 18 (IL18) dans le flushing utérin.

The materno-foetal relationship is not simply maternal tolerance of a foreign tissue, but a series of intricate mutual cytokine interactions governing selective immune regulation and also control of the adhesion and vascularisation processes during this dialogue. There is strong evidence that locally secreted cytokines, such as interleukine 18 (IL18) control the implantation process and can cause implantation failure in case of absence or overactivation. Uterine flushing fluids may be analysed to determine the level of several cytokines. At the time of egg retrieval, the flushing procedure does not adversely affect pregnancy rates. We report a strong positive correlation between the presence of IL18 in the uterine flushing and bad implantation rates. The presence of IL18 in the lumina is the traduction of an overactivation of endometrial IL18 that should be diagnosed and treated. Moreover, endometrial biopsy could define which type of cytokinic dysregulation is implicated in repeated implantation failure and define which type of treatment need to be introduced.

[The impact of stress in the maternofetal relationship: an immunological approach]. / L'impact du stress dans le dialogue materno-foetal: une approche immunologique.

Pregnancy is controlled primarily, though not exclusively, by a delicate equilibrium between locally acting growth factors and cytokines, some under steroid control. The hypothesis considered here is that stress is able to influence the equilibrium between cytokines and thus lead to abortions or implantation failure. We thus detailed the studies on that topic in order to explore the psycho-neuro-immunological mechanisms concerned. The duration of stress, the patient's strategy for coping with this and the social context might be able to produce some opposite immunological effects. Thus, the link between stress and the immunological events induced is complex, and much care is needed for such patients.

Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme.

BACKGROUND: To evaluate the effect of an antifibrotic treatment by a combination of pentoxifylline (PTX) and tocopherol (vitamin E) in patients with a thin endometrium who were enrolled in an oocyte donation programme. METHODS: Eighteen oocyte recipients who failed to develop a pre-ovulatory endometrial thickness of at least 6 mm after receiving vaginal micronized estradiol were enrolled in the study. The patients received a combination of PTX (800 mg/day) and vitamin E (1000 IU/day) for 6 months. The main outcome measurements were the change in endometrial thickness and the pregnancy and delivery rates after treatment. RESULTS: Endometrial thickness increased significantly (P <0.001), with a mean of (+/-SD) 4.9 +/-0.6 mm before and 6.2 +/- 1.4 mm after treatment, with 72% (13/18) of patients being good responders. Five patients either did not respond to the treatment or responded only slightly. Three patients, of which two had received previous radiotherapy, became spontaneously pregnant, and two became pregnant after embryo transfer. Three patients did not have embryo transfer. A total of four babies were delivered. The pregnancy rate was thus 33% and the delivery rate 27%. CONCLUSION: Treatment by combination of PTX and vitamin E appears to improve the pregnancy rate in patients with a thin endometrium by increasing the endometrial thickness and improving ovarian function. This was especially noticeable in patients who had previously received total body irradiation.

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.

[Impact of systematically freezing embryos on ovum donation]. / Retentissement de la congélation embryonnaire systématique dans l'exercice du don d'ovocytes.

In France, all embryos obtained after ovum donation have to be frozen. We present a brief background on this policy and expose our results, then discuss the rationale of such a policy in order to upgrade knowledge on the mechanism of vertical HIV transmission.

[Contribution of diagnostic ultrasonography in cases of repeated embryonic implantation failure in fertilization in vitro]. / Apport du diagnostic échographique en cas d'échecs répétés d'implantation embryonnaire en fécondation in vitro.

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.