Recombinant human leukemia inhibitory factor does not improve implantation and pregnancy outcomes after assisted reproductive techniques in women with recurrent unexplained implantation failure

Brinsden, Peter; Alam, Verónica; Moustier, B de; Engrand, Patrick

doi:10.1016/j.fertnstert.2008.06.047

Cited by 81 publications

(59 citation statements)

References 14 publications

(14 reference statements)

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“…Although this study has focussed on the use of hLIF-05 for research purposes there is a clear therapeutic application. Clinical trials of recombinant hLIF (Emfilermin) used to improve implantation in women with recurrent implantation failure has been not successful (Brinsden et al 2009); however, a non-steroid based drug that inhibits implantation may have clinical relevance. In this context (White et al 2007), have demonstrated 100% reduction in implantation in mice by i.p.…”

Section: Discussionmentioning

confidence: 99%

Determining the LIF-sensitive period for implantation using a LIF-receptor antagonist

Mohamet

Heath²,

Kimber³

2009

Reproduction

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Uteri of Lif null mice do not support embryo implantation. Since deletion of some genes often prevents the survival of null mice to adulthood, we have used a proven inhibitor of leukaemia inhibitory factor (LIF) signalling to identify the precise window of time during which LIF is required in vivo, and assessed the cellular expression of several LIF-associated targets. On day 4 of pregnancy, mice were injected with hLIF-05 (inhibitor) into the uterine lumen, with corresponding volumes of PBS (vehicle) injected into the contralateral horn. On days 5 and 6, the number of implantation sites was recorded and the uteri processed for immunohistochemistry. Blockade of LIF on day 4 reduced embryo implantation by 50% (P%0.0001) and was effective maximally between 0930 and 1230 h. Antagonism of LIF signalling was evidenced by a lack of phosphorylated STAT3 in the luminal epithelium (LE). Amphiregulin was absent from the LE on day 4 evening and H-type-1 antigen expression was retained in the LE on day 5 in inhibited uteri. Interleukin-1a and oncostatin M expression were reduced in the stroma on day 6, following LIF inhibition. Unexpectedly, PTGS2 expression in stroma was unaffected by LIF inhibition in vivo, in contrast to Lif null mice. In summary, this suggests that LIF signalling is effective for implantation during a discrete time window on day 4 and antagonism of LIF signalling recapitulates many features exhibited in Lif null uteri. The data presented validates the use of antagonists to investigate tissue specific and temporal cytokine signalling in reproductive function.

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Section: Discussionmentioning

confidence: 99%

Determining the LIF-sensitive period for implantation using a LIF-receptor antagonist

Mohamet

Heath²,

Kimber³

2009

Reproduction

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“…Furthermore, it has been recently shown that biopsy treatment has a positive effect on spontaneous pregnancies as well (Brinsden et al 2009). …”

Section: Introductionmentioning

confidence: 99%

Biopsy-induced inflammatory conditions improve endometrial receptivity: the mechanism of action

Gnainsky¹,

Granot²,

Aldo³

et al. 2015

Reproduction

136

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A decade ago, we first reported that endometrial biopsy significantly improves the success of pregnancy in IVF patients with recurrent implantation failure, an observation that was later confirmed by others. Recently, we have demonstrated that this treatment elevated the levels of endometrial pro-inflammatory cytokines and increased the abundance of macrophages (Mac) and dendritic cells (DCs). We therefore hypothesised that the biopsy-related successful pregnancy is secondary to an inflammatory response, and aimed at deciphering its mechanism of action. Supporting our hypothesis, we found that the pro-inflammatory TNFa stimulated primary endometrial stromal cells to express cytokines that attracted monocytes and induced their differentiation into DCs. These monocytederived DCs stimulated endometrial epithelial cells to express the adhesive molecule SPP1 (osteopontin (OPN)) and its receptors ITGB3 and CD44, whereas MUC16, which interferes with adhesion, was downregulated. Other implantation-associated genes, such as CHST2, CCL4 (MIP1B) and GROA, were upregulated by monocyte-derived Mac. These findings suggest that uterine receptivity is mediated by the expression of molecules associated with inflammation. Such an inflammatory milieu is not generated in some IVF patients with recurrent implantation failure in the absence of local injury provoked by the biopsy treatment.Reproduction (2015) 149 75-85

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“…Aware that endometrial secretion of LIF might be low in patients with RIF [46], other investigators tested the systemic administration of LIF to patients with RIF. A multicenter, randomized, double-blinded, placebo-controlled study failed to demonstrate that r-hLIF administration after embryo transfer improved implantation and pregnancy rates compared with a placebo [17]. However, since in the latter studies, both hCG and LIF were administered systemically, their direct local effect on the endometrium is not clear.…”

Section: The Endometriummentioning

confidence: 99%

Assessment and treatment of repeated implantation failure (RIF)

Simon

Laufer

2012

J Assist Reprod Genet

211

161

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Repeated implantation failure (RIF) is determined when embryos of good quality fail to implant following several in vitro fertilization (IVF) treatment cycles. Implantation failure is related to either maternal factors or embryonic causes. Maternal factors include uterine anatomic abnormalities, thrombophilia, non-receptive endometrium and immunological factors. Failure of implantation due to embryonic causes is associated with either genetic abnormalities or other factors intrinsic to the embryo that impair its ability to develop in utero, to hatch and to implant. New methods of time-lapse imaging of embryos and assessment of their metabolic functions may improve selection of embryos for transfer, and subsequent outcomes for IVF patients, as well as for those diagnosed with RIF. This review discusses the various causes associated with RIF and addresses appropriate treatments.

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Recombinant human leukemia inhibitory factor does not improve implantation and pregnancy outcomes after assisted reproductive techniques in women with recurrent unexplained implantation failure

Cited by 81 publications

References 14 publications

Determining the LIF-sensitive period for implantation using a LIF-receptor antagonist

Determining the LIF-sensitive period for implantation using a LIF-receptor antagonist

Biopsy-induced inflammatory conditions improve endometrial receptivity: the mechanism of action

Assessment and treatment of repeated implantation failure (RIF)

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