Blocking LIF action in the uterus by using a PEGylated antagonist prevents implantation: A nonhormonal contraceptive strategy

White, Christine; Zhang, Jianguo; Salamonsen, Lois A.; Baca, Manuel; Fairlie, W. Douglas; Metcalf, Donald; Nicola, Nicos A.; Robb, Lorraine; Dimitriadis, Evdokia

doi:10.1073/pnas.0710110104

Cited by 90 publications

(86 citation statements)

References 39 publications

(45 reference statements)

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“…This may perhaps be a major, if not the sole, factor inhibiting implantation. This contention goes well with the earlier report that a highly potent LIF antagonist is 100% effective in blocking implantation (White et al 2007).…”

Section: Discussionsupporting

confidence: 77%

Puerarin, a selective oestrogen receptor modulator, disrupts pregnancy in rats at pre-implantation stage

Saha¹,

Saraswat²,

Chakraborty³

et al. 2012

Reproduction

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The tubers of Pueraria tuberosa have folkloric repute as emmenagogue. The n-BuOH fraction of the ethanolic extract of tubers exhibits significant antifertility activity in laboratory animals. The present investigation explored the active principle(s) of the tuber extract with reference to contragestive effects in rats and probed the possible mechanism of action. Bioactivity-guided fractionation identified puerarin as the major constituent that exerted pregnancy-terminating effects. Oral administration of puerarin at R300 mg/kg per day for days (D) 1-2 post-coitus resulted in complete implantation failure. Serum oestradiol levels during D2-D5 and progesterone (P 4 ) level on D5 remained unaffected, but the endometrial expression of oestrogen receptor a (ERa) and ERb was adversely modulated that disrupted the implantation-specific characteristic endometrial oestrogenic milieu. The eventual consequence was loss of endometrial receptivity characterised by down-regulation of the uterine expression of P 4 receptor (PR) and attenuation of endometrial expression of leukaemia inhibitory factor, vascular endothelial growth factor and cyclo-oxygenase-2, the three important signalling molecules involved in the process of implantation. Light microscopic examination of the embryos demonstrated no untoward effect of puerarin on the development of embryos until D4, but D5 blastocysts underwent gross morphological distortion. The findings taken together are interpreted to suggest that puerarin adversely impacts the uterine expression of ER and PR that disrupts the implantation-conducive uterine milieu and prevents implantation. In conclusion, puerarin may be envisaged as a prospective molecule that merits further exploration for the development of non-steroidal post-coital contraceptive for women.

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Section: Discussionsupporting

confidence: 77%

Puerarin, a selective oestrogen receptor modulator, disrupts pregnancy in rats at pre-implantation stage

Saha¹,

Saraswat²,

Chakraborty³

et al. 2012

Reproduction

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“…Our results confirm the localised activation of STAT3 in LE at the implantation site on day 4 of pregnancy as previously shown (Cheng et al 2001). This illustrates the rapid effect of such inhibitors, in agreement with a separate study in which p-STAT3 was shown to be downregulated within 2 h following injection of a different LIFR antagonist in vivo (White et al 2007). Since p-STAT3 expression in the LE 12 h post injection was absent in control and inhibited uteri, STAT3 activation is tightly regulated early on day 4.…”

Section: Discussionsupporting

confidence: 70%

“…Furthermore, the use of paired uterine horns from the same animal ensured that in each horn the endometrium was exposed to an identical ovarian steroid environment. The possibility of the inhibitor just affecting LIF signalling in the embryo is unlikely since a previous study using a LIF antagonist showed no differences in pre-implantation embryo development or blastocyst outgrowth capability between treated and control groups (White et al 2007). Furthermore, Lif-deficient embryos are viable and able to implant into pseudopregnant recipients (Stewart et al 1992) and embryos deficient in Lifr are also able to undergo successful implantation (Ware et al 1995).…”

Section: Discussionmentioning

confidence: 99%

“…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. injections of a polyethylene glycol tagged (PEGylated) LIFR antagonist and propose its use in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

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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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“…Leukemia inhibitory factor is a cytokine of pleiotropic action, involved in many physiological processes, including proliferation, differentiation and cell survivability, i.e., it exerts its impact on fecundity (Drogemüller et al, 2001;Rodriguez-Zas et al, 2006;White et al, 2007;Mihailov et al, 2014). Direct evidence of LIF expression in endometrium, being essential for implantation process, was obtained in experiments on mice using genetic engineering.…”

Section: Introductionmentioning

confidence: 99%

Leukemia Inhibitory Factor (<i>LIF</i>) Gene Polymorphism and its Impact on Reproductive Traits of Pigs

Леонова¹,

Getmantseva²,

Vasilenko³

et al. 2015

American Journal of Animal and Veterinary Sciences

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The purpose of this study was to determine the frequencies of alleles and genotypes of the Leukemia Inhibitory Factor (LIF) gene (ID: 399503) in Landrace, Large White and Duroc pigs in Russia and to evaluate the impact on productive traits of pigs. Polymorphism was genotyped using PCR-RFLP method. In the course of studies we observed a different distribution of allele and genotype frequencies of different breeds. In all breeds under study all three genotypes AA, AB, BB were determined. The results of this study suggest that the LIF gene promotes the reproductive traits of pigs. The AA genotype sows compared to BB genotype analogues have better Total Number of Born (TNB) and Number Born Alive (NBA) by 1.4 and 1.3 (p<0.01) in Landrace sows, 1.3 and 0.9 (p<0.05) in Large White and 2.0 and 3.3 (p<0.001) in Duroc, respectively. The AB genotype sows exhibit intermediate values, which testifies the concentration of a favorable A allele in the pig genotype of animals contributing to the fertility. Our research revealed a positive effect of A allele and AA genotype that indicates the possibility to use this polymorphism in improving reproduction traits of sows.

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Blocking LIF action in the uterus by using a PEGylated antagonist prevents implantation: A nonhormonal contraceptive strategy

Cited by 90 publications

References 39 publications

Puerarin, a selective oestrogen receptor modulator, disrupts pregnancy in rats at pre-implantation stage

Puerarin, a selective oestrogen receptor modulator, disrupts pregnancy in rats at pre-implantation stage

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

Leukemia Inhibitory Factor (<i>LIF</i>) Gene Polymorphism and its Impact on Reproductive Traits of Pigs

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