Implantation Failure in Female Kiss1−/− Mice Is Independent of Their Hypogonadic State and Can Be Partially Rescued by Leukemia Inhibitory Factor

Abstract

The hypothalamic kisspeptin signaling system is a major positive regulator of the reproductive neuroendocrine axis, and loss of Kiss1 in the mouse results in infertility, a condition generally attributed to its hypogonadotropic hypogonadism. We demonstrate that in Kiss1(-/-) female mice, acute replacement of gonadotropins and estradiol restores ovulation, mating, and fertilization; however, these mice are still unable to achieve pregnancy because embryos fail to implant. Progesterone treatment did not overcome this defect. Kiss1(+/-) embryos transferred to a wild-type female mouse can successfully implant, demonstrating the defect is due to maternal factors. Kisspeptin and its receptor are expressed in the mouse uterus, and we suggest that it is the absence of uterine kisspeptin signaling that underlies the implantation failure. This absence, however, does not prevent the closure of the uterine implantation chamber, proper alignment of the embryo, and the ability of the uterus to undergo decidualization. Instead, the loss of Kiss1 expression specifically disrupts embryo attachment to the uterus. We observed that on the day of implantation, leukemia inhibitory factor (Lif), a cytokine that is absolutely required for implantation in mice, is weakly expressed in Kiss1(-/-) uterine glands and that the administration of exogenous Lif to hormone-primed Kiss1(-/-) female mice is sufficient to partially rescue implantation. Taken together, our study reveals that uterine kisspeptin signaling regulates glandular Lif levels, thereby identifying a novel and critical role for kisspeptin in regulating embryo implantation in the mouse. This study provides compelling reasons to explore this role in other species, particularly livestock and humans.

Uterine and placental KISS1 regulate pregnancy: what we know and the challenges that lie ahead

“…We clearly demonstrated that while normal embryo apposition occurred, embryo adhesion and penetration did not (Calder et al 2014), fully supporting our hypothesis. Next, we demonstrated that Kiss1 C/K embryos, which failed to implant in the Kiss1 K/K uterus, implanted in the uterus of a WT recipient female; thus, the inability to implant was due to a maternal and not embryonic defect.…”

“…Initially, this infertility was thought to be the result of congenital hypogonadotropic hypogonadism, a disorder that originates at the level of the hypothalamus and/or pituitary and is characterized by the absence of spontaneous sexual maturation in the presence of low gonadotropin luteinizing hormone and follicle-stimulating hormone and sex steroids (estradiol (E 2 ) and testosterone) in the absence of anatomical or functional abnormalities of the hypothalamic-pituitary-gonadal axis. However, recent studies in the mouse strongly suggest that, independent of the hypothalamus and pituitary, a disruption of local KISS1 signaling in the ovary or uterus can also trigger infertility (Calder et al 2014. These important findings further strengthen human data that peripherally derived KISS1 regulates pregnancy (Janneau et al 2002, Horikoshi et al 2003, Bilban et al 2004, Taylor et al 2014.…”

Rola sygnalizacji kisspeptyny w osi podwzgórze–przysadka–nadnercza — aktualna perspektywa

“…Similar results were observed in indomethacintreated rats and photo-inhibited hamsters [155,157]. Additionally, recent studies on kiss1r heterozygous and knockout mice models further provide strong evidence in favour of the direct role of kisspeptins in the ovary by revealing that the loss of one kiss1r allele resulted in premature ovarian failure and loss of both kiss1r alleles blocked maturation of ovarian follicles and ovulation, which could not be rescued by gonadotrophins administration [159][160][161]. It has also been suggested that localised kisspeptin signalling is crucial for endometrial decidualisation and embryo implantation.…”

“…It has also been suggested that localised kisspeptin signalling is crucial for endometrial decidualisation and embryo implantation. It has been shown by studies in rats [160] that showed impaired embryo implan-…”

Kisspeptin across the human lifespan:evidence from animal studies and beyond

“…Calder and coworkers described that in Kiss1 -/-knockout mice, a failure of embryo implantation was observed due to a lack of adhesion and penetration (Calder et al 2014). This was found to be a function of uterine dysfunction, as evidenced by the fact that the Kiss1 +/-embryos created were able to be successfully implanted in wild-type female mice.…”