Potential roles for the kisspeptin/kisspeptin receptor system in implantation and placentation.

Kisspeptin (a 145-amino acid polypeptide) and its encoding gene KISS1 were originally identified as a human metastasis suppressor (and a gene) of malignant melanoma in Hershey, Pennsylvania, the USA, the hometown of the famous chocolate Hershey’s kisses ( Lee et al. , 1996 ). The name of KISS1 was derived from these sweets, with the terminology ‘SS’ in KISS1 indicating the ‘suppressor sequence’. In humans, the KISS1 gene that encodes kisspeptins is located on the long (q) arm of chromosome 1 at q32 ( West et al. , 1998 ). Initially, this gene encodes an intermediate 145-amino-acid prepropeptide, which is unstable and biologically inactive. The prepropeptide is then cleaved into four biologically active peptides distinguished by their number of amino acids: kisspeptin-10, 13, 14 and 54 (52 in rodent animals) (Figure 1 ). Sharing a common characteristic of the RF-amide signal peptide, all of these peptides have a C-terminal region that contains an Arg-Phe-NH2 motif, which allows these peptides to bind to and fully activate KISS1R. Because of the structural similarities and their common origin derived from the prepropeptide, the term ‘kisspeptins’ is now globally used to describe this family of peptides ( Kotani et al. , 2001 ; Gottsch et al. , 2009 ; Pinilla et al. , 2012 ). The major structure of kisspeptins in humans, the peptides encoded by the KISS1 gene . All kisspeptins are the products generated by the cleavage of a common precursor named prepro-kisspeptin. The prepro-kisspeptin is a 145-amino acid peptide, which is further cleaved into the following four peptides with lower molecular weights: KP-54, KP-14, KP-13 and KP-10. All kisspeptins contain the RF-amide motif that can bind and activate KISS1R. This figure is modified from Pinilla et al. (2012) ; Hu et al. (2017) . To acknowledge its metastasis inhibitory properties, kisspeptin-54 was initially termed ‘metastin’. This peptide was considered the major product of the human KISS1 gene, and it could be further cleaved into 14, 13 and 10 amino acid peptides ( Ohtaki et al. , 2001 ) (Figure 1 ). However, the largest proteolytic product of the kisspeptin precursor comprises 52 amino acids, and the terminal RF-amide signature is substituted by an Arg-Tyr-NH2 motif in rats and mice ( Pinilla et al. , 2012 ). In both humans and rats, the kisspeptin-54/52, -14, -13 and a shorter peptide kisspeptin-10 have the same affinity and binding efficacy onto their receptor, indicating that the C-terminal region of these peptides contributes to the high-affinity binding and the activation of KISS1R ( Kotani et al. , 2001 ). KISS1R belongs to the G-protein-coupled receptor family that was first identified as an orphan receptor in the rat brain. This seven-transmembrane receptor is structurally similar to the transmembrane region of galanin receptors, with ~40% sequence identity ( Lee et al. , 1999 ). Subsequently, the orthologue gene of KISS1R in humans was cloned and recognized as a putative receptor for KISS1 gene-derived peptides ( Muir et al. , 2001 ; Ohtaki et al. , 2001 ). In terms of nomenclature, KISS1R has different names, including KISS1R, AXOR12, GPR54, CPPB1, hOT7T175 and HH8 because various groups of researchers have independently identified its presence or studied its physiological roles ( Lee et al. , 1999 ; Kotani et al. , 2001 ; Muir et al. , 2001 ; Ohtaki et al. , 2001 ; Gottsch et al. , 2009 ).

The hypothalamic-pituitary-gonadal (HPG) axis plays a critical role in maintaining the normal function of the reproductive system in adolescents ( Knobil et al. , 1980 ). This axis is governed by the pulsatile secretion of gonadotropin-releasing hormone (GnRH) which, in turn, stimulates the secretion of gonadotropins (FSH and LH). The pulsatile secretion of GnRH/gonadotropins is modulated by feedback inhibition from the target gonadal hormones ( Herbison, 1998 ). During the periovulatory stage, the surge secretion of GnRH/gonadotropins is induced by the positive feedback of serum estrogen ( Goodman, 1978 ), which consequently triggers ovulation in female mammals ( Moenter et al. , 1992 ). Being the upstream regulator of pulsatile and surge GnRH release, kisspeptin has been much heralded in the past decade, with its fundamental roles in regulating female reproduction in several aspects, which include gonadotropin secretion, puberty onset, brain sex differentiation and ovulation ( Roa et al. , 2008 ; Pinilla et al. , 2012 ; Hu et al. , 2017 ). Kisspeptin neurons are located within two regions in the hypothalamus, the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC), which are responsible for mediating the positive and negative feedback effects of estrogen on GnRH/gonadotropin secretion, respectively ( Smith et al. , 2005 ; Tomikawa et al. , 2012 ). Specifically, estrogen binds to ERα on kisspeptin neurons in the ARC or infundibular nucleus, which further inhibit kisspeptin and subsequently the GnRH release ( Smith et al. , 2005 ). Additionally, estrogen exerts positive feedback (also mediated via ERα) on kisspeptin neurons in the AVPV nucleus, which accounts for the LH surge in the menstrual cycle ( Tomikawa et al. , 2012 ). In many mammals, kisspeptins function to stimulate the release of GnRH (and subsequently the secretion of FSH and LH) by binding to the kisspeptin receptor (KISS1R), which is a G-protein-coupled receptor. Notably, inactivating mutations of either KISS1 or KISS1R lead to the phenotype of hypogonadotropic hypogonadism in humans and mice ( Tena-Sempere, 2006 ; Tenenbaum-Rakover et al. , 2007 ; Roseweir and Millar, 2009 ; Nimri et al. , 2011 ; Topaloglu et al. , 2012 ). Additionally, recent studies have indicated the potential pathophysiological roles of extra-hypothalamic kisspeptins in the central and peripheral regulation of the activity of diverse systems ( Terao et al. , 2004 ; Pinto et al. , 2012 ; Laoharatchatathanin et al. , 2015 ; Comninos et al. , 2016 ; Uenoyama et al. , 2016 ). Outside the hypothalamic area, kisspeptins and their putative receptor KISS1R have been identified across different types of tissues, particularly those involved in reproductive and metabolic functions, including the hippocampus, forebrain, ovary, uterus, placenta, testis, adipose tissue, pancreas and liver ( Ohtaki et al. , 2001 ; Arai et al. , 2005 ; Castellano et al. , 2006 ; Cejudo Roman et al. , 2012 ; Pinto et al. , 2012 ; Xu et al. , 2012 ; Zhang et al. , 2014 ; Dudek et al. , 2016 ). Indeed, kisspeptins can exert several different physiological actions on various types of tissues in an autocrine/paracrine manner. During the processes of implantation and placentation, many studies have shown that the functional form of the kisspeptin/KISSR system is expressed at the maternal-fetal interface, including the endometrial and placental tissues of various species, including humans ( Shahed and Young, 2009 ; Cejudo Roman et al. , 2012 ; Zhang et al. , 2014 ). Furthermore, recent studies have indicated that locally expressed kisspeptin/KISS1R directly participates in various physiological and pathophysiological activities at the maternal-fetal interface. This review will mainly focus on the available literature related to the pathophysiological roles of the kisspeptin/KISS1R system in regulating the processes of implantation and placentation. We summarize our current knowledge regarding the underlying mechanisms by which kisspeptin exerts its cellular activities in the processes of implantation, embryo development and placentation. We will also mention the potential implications of kisspeptins in the prediction and diagnosis of early pregnancy-related disorders.

In humans, kisspeptin was initially implicated in the onset of puberty as two independent research groups reported KISS1R gene mutations in patients with idiopathic hypogonadotropic hypogonadism (IHH) ( de Roux et al. , 2003 ; Seminara et al. , 2003 ). Subsequently, heterozygous and homozygous KISS1 mutations have also been identified in patients with IHH ( Chan et al. , 2011 ; Topaloglu et al. , 2012 ). Interestingly, women with heterozygous KISS1 or KISS1R mutations were able to deliver their babies with homozygous KISS1 or KISS1R mutations ( Pallais et al. , 2006 ; Topaloglu et al. , 2012 ) (Table III ). These results suggested that carrying heterozygous mutations in KISS1 or KISS1R does not appear to limit subsequent uterine and placental function. Additionally, a case report showed that a woman with homozygous KISS1R mutations had a normal vaginal delivery of a healthy child with a normal birthweight ( Pallais et al. , 2006 ). Similarly, Kiss1 (+/ − ) and Kiss1r (+/ − ) female mice were able to carry the normal weight of fetus with homozygous KISS1 mutations and there was no significant harmful effect on placental function ( Herreboudt et al. , 2015 ). These results indicate that the functional role of the kisspeptin/KISS1R system in the placenta could be compensated by other factors during early pregnancy. However, global ablation of Kiss1 or Kiss1r led to dramatically suppressed uterine growth and almost entirely prevented adenogenesis ( Leon et al. , 2016 ) and caused subsequent infertility ( Funes et al. , 2003 ; Lapatto et al. , 2007 ), although Kiss1 (+/ − ) or Kiss1r (+/ − ) phenotypes were fertile ( Seminara et al. , 2003 ; Lapatto et al. , 2007 ; Gaytan et al. , 2014 ; Herreboudt et al. , 2015 ). Even though E2 treatment in Kiss1 ( − / − ) mice and/or genetic restoration of kisspeptin signaling in GnRH neurons in Kiss1r ( − / − ) mice fully rescued the uterine growth, functional adenogenesis in the endometrium was only partially restored ( Leon et al. , 2016 ). Therefore, while uterine growth is mainly contingent on E2-output via kisspeptin signaling in GnRH neurons, local kisspeptin signaling in the endometrium is essential for normal endometrial adenogenesis and functions. Furthermore, embryos failed to implant in maternal mice with homozygous Kiss1 mutations ( Calder et al. , 2014 ). These results seem to support the fundamental role of maternal kisspeptin/Kiss1r system in preparation for embryo implantation, at least in mice. Table III Summary of the effect of Kiss1/Kiss1r in genetically modified or mutant models (placental specific knockout or overall knockout) on fertility or placental function. Knockout model Species Fertility or placental function References Kiss1 +/− or Kiss1 −/−; Kiss1r +/− or Kiss1r −/− (fetus) Mouse Normal weight of fetus and placenta, normal nutrient transfer function of placenta at E15.5 days Herreboudt et al. (2015) Kiss1 +/− or Kiss1 r+/− (maternal) Mouse Fertile Herreboudt et al. (2015) Kiss1 −/− (maternal) Mouse Fail to implant and infertile Calder et al. (2014) Kiss1r −/− (maternal) Mouse Infertile Funes et al. (2003) Kiss1r +/− (maternal) Mouse Fertile Seminara et al. (2003) Kiss1r −/− (maternal) Mouse Infertile Seminara et al. (2003) Kiss1r +/− (maternal) Mouse Fertile before 48-week-old Infertile at 48-week-old Gaytan et al. (2014) Kiss1 +/− (maternal) Mouse Fertile Chan et al. (2011) Kiss1 +/− or Kiss1r +/− (maternal) Mouse Fertile Lapatto et al. (2007) Kiss1 −/− or Kiss1r −/− (maternal) Mouse Infertile Lapatto et al. (2007) Kiss1 −/− or Kiss1r −/− (maternal) Mouse Uterine growth suppressed and adenogenesis nearly stopped Leon et al. (2016) KISS1R +/− (maternal), KISS1R −/− (maternal) and KISS1R −/− (fetus) Human Fertile Pallais et al. (2006) KISS1 +/− (maternal) and KISS1 −/− (fetus) Human Fertile Topaloglu et al. (2012) Summary of the effect of Kiss1/Kiss1r in genetically modified or mutant models (placental specific knockout or overall knockout) on fertility or placental function.

Literature searches using either PubMed or Google Scholar were performed to review articles written in English focusing on the advancement of kisspeptins and KISS1R in embryo implantation, placentation and early pregnancy-related complications. The search included human and other mammalian studies starting from the initial identification of kisspeptin in 1996 until July 2018. Search terms included ‘kisspeptin’, ‘metastin’, ‘GPR54’ and ‘KISS1R’. We also combined the findings that best aligned with the themes of ‘implantation’, ‘uterus’, ‘pregnancy’, ‘placenta’, ‘miscarriage’ and ‘gestational trophoblastic neoplasia’. The search strategy and study selection for the references included in this review are presented in Supplemental Figure S1 .

Human placenta is a highly specialized organ that forms the interface between the mother and fetus, supplying the fetus with nutrients and excreting waste products from the fetus. The placenta releases metabolic products into the maternal and fetal circulations. In addition, the placenta releases hormones into both the maternal and fetal circulations to modulate multiple gestational functions, including metabolism, fetal growth, parturition and other pregnancy-related functions ( Gude et al. , 2004 ). Immediately following implantation, the trophoblast stem cells proliferate and differentiate into two main cell types described as villous and extravillous (for reviews, see Gude et al. , 2004 ; James et al. , 2012 ). Non-migratory, villous cytotrophoblast cells (vCTs) fuse to form the multinucleated villous syncytiotrophoblast cells (vSTs), which reside the outer epithelial layer of chorionic villi. As the fundamental functional unit of the placenta, the chorionic villus is responsible for all nutritional-waste exchange between the maternal and the fetal circulation, acting to protect the fetus and exert various endocrine functions (for reviews, see Gude et al. , 2004 ; James et al. , 2012 ). Extravillous trophoblast cells (EVTs) eventually differentiate into the placental bed (PB) and endovascular trophoblasts. The PB is responsible for the migration of the embryo into the decidua, and the endovascular trophoblasts are responsible for the uterine spiral artery remodeling ( Gude et al. , 2004 ) (Figure 3 ). However, it is important to note that the differentiation of the placenta in rodents (particularly in the mouse placenta) is quite different from that in humans. Following implantation in mice, the non-polar trophectoderm proliferates and then differentiates into primary trophoblast giant cells, while the polar trophectoderm proliferates and then forms the extraembryonic ectoderm, which further differentiates into the labyrinth and secondary trophoblast giant cells. The labyrinth, named for the intricate network between the mother and fetus, shares similar functions with chorionic villi, such as the transportation of nutrients and endocrine regulation. Both primary and secondary trophoblast giant cells are invasive cells that lead the placenta to attach to the uterus and remodel the uterine vasculature. Therefore, the activities of these cells are similar to those of the EVTs in humans (see reviews Cross et al. , 2002 ; James et al. , 2012 ) (Figure 3 ). Flow diagram demonstrating the different cell lineage pathways involved in murine and human trophoblast differentiation and function. KISS1 is mainly expressed in cells of the villous pathway, while KISS1R is expressed in cells of both the villous and extravillous pathways. Modified from James et al. (2012) . Using Northern blot analysis, a study demonstrated that the expression of KISS1 mRNA was very weak in the kidney and pancreas but extremely high in the placenta ( Lee et al. , 1996 ). However, the expression of KISS1 mRNA was undetectable in the normal heart, brain, liver, lung and skeletal muscle ( Lee et al. , 1996 ). In humans, KISS1R was highly expressed in endocrine tissues, including the placenta, pituitary, pancreas and brain, suggesting a role for the kisspeptin/KISS1R system in the regulation of the endocrine function ( Kotani et al. , 2001 ; Muir et al. , 2001 ). These early studies strongly suggested that the kisspeptin/KISS1R system may play a fundamental role in regulating the functions of the placenta. More recently, the expression of KISS1 and KISS1R in specific cells within the placenta has been identified, though some studies were inconsistent. In early pregnancy in humans, the KISS1 gene is mainly expressed in vCTs ( Janneau et al. , 2002 ; Horikoshi et al. , 2003 ; Park et al. , 2012 ; Matjila et al. , 2013 ; Wu et al. , 2014 ) but not in EVTs ( Bilban et al. , 2004 ). As the placenta matures, the expression of KISS1 is detected in vSTs as well as in the PB ( Horikoshi et al. , 2003 ; Matjila et al. , 2013 , 2016 ) (Table I ). Additionally, studies in rats suggested that Kiss1 is mainly expressed in trophoblast giant cells (similarly to vCTs in humans) and gradually decreases as the placenta matured ( Terao et al. , 2004 ; Mark et al. , 2013 ). Nevertheless, many inconsistencies need to be addressed. In humans, it was first identified that there was no significant difference in KISS1 expression in the placenta between term pregnancy and early pregnancy ( Janneau et al. , 2002 ). However, later studies indicated that KISS1 expression is much higher in the placenta in early pregnancy than that in term pregnancy ( Bilban et al. , 2004 ; Cartwright and Williams, 2012 ). Another study also suggested that KISS1 expression in the placenta is higher in preterm pregnancy than in term pregnancy ( Torricelli et al. , 2008 ), indicating that KISS1 expression gradually decreases as the placenta matured. Similarly, Kiss1 expression gradually decreases during the maturation of the placenta in rats ( Terao et al. , 2004 ) (Table I ). Interestingly, KISS1 expression in human term pregnancy shows a circadian rhythm, with two surges at 04:00 h and 12:00 h each day ( de Pedro et al. , 2015 ). Similar to the expression of the KISS1 gene in humans, KISS1R is also expressed in vCTs in early pregnancy ( Janneau et al. , 2002 ) and in vSTs during the maturation of the placenta ( Bilban et al. , 2004 ; Park et al. , 2012 ; Matjila et al. , 2013 ; Wu et al. , 2014 ) (Table I ). However, KISS1R is also located in EVTs ( Bilban et al. , 2004 ; Matjila et al. , 2013 ), the sites where KISS1 expression was not detected ( Bilban et al. , 2004 ). The expression level of KISS1R in the placenta was higher in the first trimester than in the term pregnancy, indicating that KISS1R expression gradually decreases as the placenta matured ( Janneau et al. , 2002 ; Bilban et al. , 2004 ; Cartwright and Williams, 2012 ). Additionally, KISS1R expression was not detected in PB ( Matjila et al. , 2013 ), and it showed a minimal expression level in human term pregnancy ( Matjila et al. , 2016 ). In combination with the expression pattern of KISS1 in the placenta, it may be speculated that the kisspeptin/KISS1R system in the placenta mainly functions in early pregnancy in humans in both autocrine and paracrine manners. However, the expression level of Kiss1r is very low in rats ( Terao et al. , 2004 ) and islower at Day 16 of pregnancy than at Day 22 of pregnancy Mark et al. (2013) . Notably, Kiss1r expression levels in canine placenta is higher in mid-gestation than in post-implantation ( Schafer-Somi et al. , 2017 ) (Table I ). These studies suggest that the role of the kisspeptin/KISS1R system in the placenta was not conserved in different species.

KISS1R is a G-protein-coupled receptor that belongs to the subgroup of typical Gq/11 protein-associated receptors. Following the stimulation of KISS1R by kisspeptin peptides, the phosphorylated Gq/11 protein activates phospholipase C (PLC)-β, leading to the activation or formation of various second messengers, including those involved in the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), the accumulation of inositol-(1,4,5)-triphosphate (IP3), diacylglycerol and protein kinase C (PKC) and the mobilization and release of intracellular Ca 2+ into the cytoplasm ( Ohtaki et al. , 2001 ; Stafford et al. , 2002 ; Jiang et al. , 2005 ) (Figure 2 ). Kisspeptin/KISS1R signaling and potential functions at a glance . KISS1R is a seven-transmembrane domain, Gq/11-coupled receptor. Upon binding of kisspeptin, the intracellular portion of KISS1R phosphorylates Gq/11. The α-subunit of Gq/11 activates PLC, which subsequently cleaves PIP2 into IP3 and DAG. IP3 promotes intracellular Ca 2+ release from the endoplasmic reticulum, while DAG activates a signaling cascade by phosphorylating PKC. PKC activation induces the phosphorylation of ERK1/2 and p38. In addition, activation of KISS1R recruits arrestin-1 and -2, which down-regulates and up-regulates phosphorylated ERK1/2 levels, respectively. The activation of KISS1R can also stimulate the phosphorylation of PI3K/Akt, and suppress the phosphorylation of PI3K/Akt by blocking the prometastatic chemokine receptor CXCR4 (the receptor for the chemokine stromal cell-derived factor 1) signaling. These signals act on downstream pathways, including NF-κB, MMPs and VEGF, to promote hormone secretion and apoptosis and inhibit metastasis, migration, angiogenesis and proliferation. DAG, diacylglycerol; ERK1/2, extracellular signal-regulated kinase; IP3, inositol 1,4,5-triphosphate; PI3K, phosphatidylinositol-3-kinase; MMPs, matrix metalloproteinases; NF-κB, nuclear factor κB; PIP2, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; VEGF, vascular endothelial growth factor. Apart from the PLC–PKC–Ca 2+ pathway, other intracellular transduction pathways are also activated in response to kisspeptin stimulation. In many cell types, the phosphorylation of ERK1/2 is thought to be the most conserved kinase signal. However, some cell types that show the activation of ERK1/2 do not have stable p38 MAPK and PI3K/Akt activation in response to kisspeptins ( Ringel et al. , 2002 ; Castano et al. , 2009 ; Peng et al. , 2013 ). For instance, treatment with kisspeptin-10 induces strong and sustained phosphorylation of ERK1/2 but very weak phosphorylation of p38 and no phosphorylation of stress-activated protein kinase/c-Jun NH 2 -terminal kinase in Chinese hamster ovary (CHO)-K1 cells ( Kotani et al. , 2001 ). Another example is that kisspeptin activates ERK1/2 signaling without significant effects on P38 phosphorylation in rat luteal cells ( Peng et al. , 2013 ). In many mammalian cells, the kisspeptin-induced activation of Kiss1r can recruit β-arrestin 1 and β-arrestin 2 to the plasma membrane, which further increases the intracellular level of phosphorylated ERK1/2. In particular, β-arrestin 2 potentiates Kiss1r signaling to ERK, but β-arrestin 1 inhibits it ( Pampillo et al. , 2009 ; Szereszewski et al. , 2010 ; Goertzen et al. , 2016 ). Additionally, activation of PKC is required to promote the ERK1/2 signaling cascade ( Woods and Johnson, 2007 ). Taking these data together, kisspeptin may activate the ERK1/2 signaling via the β-arrestin 1, β-arrestin 2 and PLC–PKC-ERK1/2 signaling pathways (Figure 2 ). The experimental results obtained from functional studies showed that kisspeptin activates the PI3K/Akt signaling pathway in a cell type-specific manner. Kisspeptin can induce the phosphorylation of PI3K/Akt in stably KISS1R -overexpressed thyroid cancer cells ( Stathatos et al. , 2005 ), but not in rat luteal cells ( Peng et al. , 2013 ). Similarly, previous studies demonstrated that kisspeptin-10 promotes the phosphorylation of PI3K/Akt in preoptic neurons ( Hanchate et al. , 2012 ), while kisspeptin-10 suppresses the phosphorylation of PI3K/Akt in tumor cells ( Navenot et al. , 2005 , 2009 ; Chen et al. , 2016 ). In fact, kisspeptin-10 does not directly inhibit the activation of PI3K/Akt signaling pathway in tumor cells. The suppressive effect of kisspeptin-10 on PI3K/Akt signaling is mediated by suppressing the capacity of the prometastatic chemokine receptor CXCR4 (the receptor for the chemokine stromal cell-derived factor 1) in response to stromal cell-derived factor 1, which subsequently abolishes the activation of PI3K/Akt signaling by CXCR4 in some tumor cells ( Navenot et al. , 2005 , 2009 ). In tumor cells, numerous studies have documented that kisspeptin inhibits the activity of matrix metalloproteinase-9 (MMP-9) and MMP-2 by blocking nuclear translocation of the nuclear factor κB (NF-κB), which subsequently reduces the capacity of NF-κB to bind to the MMP-9 promoter ( Yan et al. , 2001 ; Gao et al. , 2007 , 2008 ; Yoshioka et al. , 2008 ; Cho et al. , 2009a ; Takeda et al. , 2012 ). Studies have shown that the phosphorylation of ERK and PI3K/Akt is the upstream of NF-κB that regulates the NF-κB DNA-binding activity in tumor cells ( Dhawan and Richmond, 2002 ; Bai et al. , 2009 ; Lee et al. , 2012 ). Interestingly, the enhanced expression of MMP-9 and MMP-2 via the PI3K/Akt/NF-κB ( Cheng et al. , 2006 ) or ERK/NF-κB signaling pathways ( Birkenkamp et al. , 2000 ; Kang et al. , 2011 ) has also been identified in different cell types. Collectively, these findings suggest that ERK1/2 or PI3K/Akt signaling is involved in kisspeptin-induced regulation of NF-κB/MMP-9 or NF-κB/MMP-2 (Figure 2 ). Previous studies have also demonstrated that the administration of kisspeptin suppresses the expression of vascular endothelial growth factor (VEGF) via ERK1/2 signaling, to inhibit angiogenesis in tumors ( Cho et al. , 2009b ) and in trophoblast cells ( Francis et al. , 2014 ) (Figure 2 ). In the past couple of decades, studies have demonstrated the physiological role of kisspeptins and their receptor, KISS1R, in the neuroendocrine-reproductive axis ( de Roux et al. , 2003 ; Seminara et al. , 2003 ), which thereafter revolutionized the field of reproductive physiology. In the meantime, plasma concentrations of kisspeptin-54 were also identified in men and women (pregnant and non-pregnant) ( Horikoshi et al. , 2003 ). Interestingly, the plasma concentration of kisspeptin increased dramatically throughout the gestational period ( Horikoshi et al. , 2003 ). The clinical data together with the evidence that the KISS1 gene is greatly expressed in the placenta ( Lee et al. , 1999 ; Kotani et al. , 2001 ; Muir et al. , 2001 ; Ohtaki et al. , 2001 ) suggest that the plasma kisspeptin during pregnancy is mainly, if not completely, derived from the placental tissue. In the following sections, we gather the latest studies addressing the roles of kisspeptins in early pregnancy, including implantation and placentation, and discuss potential clinical applications.

Although the anti-invasive effect of kisspeptin and kisspeptin levels during early pregnancy have been thoroughly discussed in this review, many formidable questions remain to be addressed. The expression of KISS1 or KISS1R was increased in some tumors of advanced stage ( Ikeguchi et al. 2003 ; Schmid et al. , 2007 ; Kostakis et al. , 2015 , 2018 ; Savvidis et al. , 2015 ). It is likely that the kisspeptin/KISS1R system is increased to prevent further tumor invasiveness and the formation of local or distant metastasis. In support of this hypothesis, the expression of KISS1 or KISS1R in placental tissues was higher in early pregnancy when the invasion was higher than that in term pregnancy ( Janneau et al. , 2002 ; Bilban et al. , 2004 ; Torricelli et al. , 2008 ; Cartwright and Williams, 2012 ) (Table I ). Nevertheless, until now, no direct evidence has confirmed this hypothesis. Future studies are required to investigate whether overexpression of the kisspeptin/ KISS1R system can attenuate the metastasis and/or invasiveness of tumor cells as well as trophoblast cells. The concentrations of kisspeptin detected in serum samples are significantly lower than those detected in plasma ( Ramachandran et al. , 2008 ). Additionally, the collection tube type, processing time and storage condition of samples can also affect the kisspeptin concentrations examined. Therefore, a standardized sample collection method for the measurement of serum or plasma kisspeptin levels should be established if kisspeptin levels are to be used as markers for pregnancy or for other use. It remains possible that the plasma kisspeptin (kisspeptin-10 or kisspeptin-54) measured in pregnant patients is not, in fact, kisspeptin but several cross-reacting peptides, such as RFRP1, RFRP2, RFRP3, neuropeptide FF and neuropeptide AF. Furthermore, since all kisspeptins, including kisspeptin-54, kisspeptin-14, kisspeptin-13 and kisspeptin-10, have high-affinity binding and activation of KISS1R ( Kotani et al. , 2001 ; Ohtaki et al. , 2001 ), it is better to detect all these peptides rather than one single peptide. A measurement method of great sensitivity and specificity has been shown to detect kisspeptin levels, including kisspeptin-54, kisspeptin-14 and kisspeptin-10 ( Dhillo et al. , 2005 ; Jayasena et al. , 2014 ). In fact, kisspeptin-13 shares the C-terminal decapeptide motif with other isoforms of kisspeptin, which is most likely to have cross-reaction with kisspeptin-10. Future studies performed using mass spectrometry analyses or other proteomics to differentiate different kisspeptin isoforms will be of great interest. At present, the ratio of these kisspeptins in the blood is still unknown. Although plasma or serum kisspeptin levels are significantly increased in early pregnancy compared to non-pregnant controls ( Horikoshi et al. , 2003 ; Jayasena et al. , 2014 ; Sullivan-Pyke et al. , 2018 ), the time at which plasma or serum kisspeptin levels start to increase has not been investigated. It would be of great interest to compare the sensitivity and specificity of the diagnosis of early pregnancy between plasma or serum kisspeptin levels and serum β-hCG levels. It has been suggested that the urine kisspeptin:creatinine ratios are higher in pregnant women compared to non-pregnant women in the third trimester ( Jayasena et al. , 2015 ), indicating that kisspeptin could be released in the urine and be measured as a potential marker. Whether the urine kisspeptin:creatinine ratio is up-regulated in the early pregnancy has not been investigated. If it is true, could this ratio or kisspeptin levels be more specific and sensitive than the urine β-hCG levels to detect early pregnancy? Most likely, urine kisspeptin levels or urine kisspeptin:creatinine ratio may be used as a new screening method to detect early pregnancy. The incompatible change in plasma or serum kisspeptin levels and the expression of KISS1 in placental tissue during pregnancy in humans are still unexplained based on previous studies. It seems that the expression of KISS1 in the placenta may not necessarily reflect the plasma levels of kisspeptin, at least in humans. Most likely, the placenta-derived kisspeptins are not immediately secreted in the bloodstream after they are produced and modified within the cells in the placenta. It is also likely that the kisspeptins in the blood are derived from other organs or tissues during late pregnancy. More studies are needed to elucidate this interesting phenomenon in humans or other animals, if this phenomenon does exist. With regard to miscarriage and GTN, a prospective cohort study is necessary to explore the sensitivity and specificity of plasma kisspeptin levels in predicting these diseases or newborn health. A large-scale study to define the normal range of plasma and serum kisspeptin levels during early pregnancy will be greatly helpful. Furthermore, it is also necessary to compare the kisspeptin assay with other potential biomarkers, such as β-hCG, or their combination in predicting early pregnancy outcome. Additional studies should investigate the kisspeptin levels in other placenta-related diseases, such as placenta previa and placenta accreta/increta/percreta. Future studies focused on the kisspeptin levels in women with assisted reproduction will also be of great importance. To the best of our knowledge, the applicability of the serum or plasma kisspeptin assay in other pregnancy outcomes, such as multiple pregnancy and ectopic pregnancy, has not been investigated. Pre-eclampsia, a pregnancy-induced complication characterized by the de-novo development of concurrent hypertension and proteinuria, remains the second leading cause of maternal death ( Steegers et al. , 2010 ). Recent studies implicated a possible role of kisspeptin in predicting and diagnosing pre-eclampsia ( Adali et al. , 2012 ; Cetkovic et al. , 2012 ; Matjila et al. , 2016 ; Ziyaraa et al. , 2016 ). Plasma kisspeptin-10 levels were negatively correlated with the severity of disease ( Adali et al. , 2012 ), but the potential mechanism for kisspeptin signaling in this disease has not been fully investigated. The defect of placental angiogenesis has been thought to be involved in pre-eclampsia ( Liu et al. , 2015 ; Stevens et al. , 2015 ) and related to the severity of the disease as well as perinatal outcome ( Stevens et al. , 2013 , 2012 ). It is likely that the inhibition of new vessel sprouting from placental vessels by kisspeptin is involved in the pathogenesis of pre-eclampsia ( Ramaesh et al. , 2010 ; Francis et al. , 2014 ). Indeed, a clinical study showed that plasma kisspeptin-10 levels were lower in women with pre-eclampsia and inversely correlated with the severity of pre-eclampsia ( Ziyaraa et al. , 2016 ). The same study also showed that the maternal plasma kisspeptin-10 levels were correlated with the estimated fetal weight in the uterus during the second and the third trimesters ( Ziyaraa et al. , 2016 ). Furthermore, kisspeptin levels (16 weeks) in maternal plasma were positively correlated with the birthweight of fetuses in uncomplicated pregnancies ( Smets et al. , 2008 ; Logie et al. , 2012 ). These studies strongly suggested that plasma kisspeptin levels were an emerging biomarker for impaired utero-placental perfusion and intrauterine growth restriction.

Because kisspeptin is produced by trophoblasts and because trophoblast invasion is underway 5 days after blastocyst transplantation ( Norwitz et al. , 2001 ), plasma kisspeptin concentrations during the peri-implantation period may reflect early developmental events associated with pregnancy outcome. In humans, the plasma concentration of kisspeptin increases dramatically over the course of pregnancy, with a 900-fold increase in the first trimester and further increases to over 7000-fold in the third trimester compared to the non-pregnant women ( Horikoshi et al. , 2003 ). Intriguingly, previous studies in humans have suggested that KISS1 expression levels in the early placenta and the term placenta do not differ significantly ( Janneau et al. , 2002 ) or that they are much higher in the early placenta ( Bilban et al. , 2004 ; Cartwright and Williams, 2012 ). When taking these published data together, it seems that the expression levels of KISS1 in the placenta of humans may not necessarily reflect the plasma levels of kisspeptin. It is most likely that the increase in the total number of trophoblast cells throughout the course of gestation is responsible for the dramatic increase in serum kisspeptin levels examined. Interestingly, peripheral kisspeptin levels were found to be very low and did not increase during pregnancy in sheep, cows, pigs, rabbits, horses, rhesus monkeys and marmosets, suggesting that the increase in plasma kisspeptin levels during pregnancy may be unique to humans ( Babwah, 2015 ). However, by using the bovine-specific enzyme immunoassay, recent studies in cows suggested that plasma kisspeptin levels are consistently increased during pregnancy ( Mondal et al. , 2015 , 2016 ), indicating that the increase of plasma kisspeptin levels during pregnancy is conserved in cows. Therefore, we may speculate that the detection methods currently used are simply failing to identify kisspeptin proteins in the circulation of certain animals. Future studies performed using species-specific enzyme immunoassay or radioimmunoassay to detect the circulation levels of kisspeptin of related animals will be of great interest. It needs to be noted that kisspeptins are a series of peptides, including kisspeptin-54, kisspeptin-14, kisspeptin-13 and kisspeptin-10 ( Kotani et al. , 2001 ) (for reviews, see Pinilla et al. , 2012 ; Hu et al. , 2018). These studies seemed to detect only one kisspeptin peptide in the plasma, and the possibility that the antibody used in these studies cross-reacted with other RF amide related-peptides (RFRP), including prolactin-releasing peptide, RFRP1, RFRP2, RFRP3, neuropeptide FF and neuropeptide AF, could not be excluded ( Jayasena et al. , 2014 ). Nevertheless, a previous study using a more specific and sensitive antibody to detect the plasma kisspeptins (including human kisspeptin-54, kisspeptin-14 and kisspeptin-10, rather than one kind of kisspeptin) suggested that plasma kisspeptin levels significantly correlate with gestational age ( Jayasena et al. , 2014 ) (Table II ). Additionally, a very recent study that detected plasma kisspeptin-54 levels in pregnant women suggested the same results ( Sullivan-Pyke et al. , 2018 ) (Table II ). Therefore, the evidence for the increase in plasma kisspeptin levels during gestation in women seems convincing, at least in humans (Table II ). Future studies need to address the intriguing phenomenon of the increase in plasma kisspeptin levels and the decrease in placental KISS1 expression levels during gestation in humans. Table II Kisspeptin (KP) concentrations in human plasma or serum during early pregnancy. Pregnancy state Serum/plasma Kisspeptin (KP) Gestation age Concentration Reference UP Serum KP-54 6–10 Weeks ( n = 20) 1.50 (0.55–3.72) ng/ml Sullivan-Pyke et al. (2018) Plasma KP-54 6–10 Weeks ( n = 8) 3.52 (1.09–21.7) ng/ml SAB Serum KP-54 6–10 Weeks ( n = 20) 0.20 (0.07–0.37) ng/ml Plasma KP-54 6–10 Weeks ( n = 3) 2.7 (0.46–2.7) ng/ml UP Plasma KP-10 7–18 Weeks ( n = 20) 5783 (3168–9953) pg/ml Kavvasoglu et al. (2012) Miscarriage Plasma KP-10 7–18 Weeks ( n = 20) 391 (152–951) pg/ml UP Plasma KP-54, 14 and 10 11.3 ± 1.9 ( n = 899) 1.06 ± 0.42 pmol/ml Jayasena et al. (2014) Miscarriage Plasma KP-54, 14 and 10 9.8 ± 3.1 ( n = 50) 0.42 ± 0.39 pmol/ml UP (twin) Plasma KP-54, 14 and 10 10.7 ± 1.5 ( n = 20) 1.64 ± 0.54 pmol/ml Miscarriage of one fetus (twin) Plasma KP-54, 14 and 10 10.7 ± 1.5 ( n = 10) 1.15 ± 0.58 pmol/ml UP (triplet) Plasma KP-54, 14 and 10 10.7 ± 1.5 ( n = 2) 2.09 ± 0.26 pmol/ml UP Plasma KP-54, 14 and 10 9–12 Weeks ( n = 25) 4.51 ± 2.21 nmol/l Cetkovic et al. (2012) 21–25 Weeks ( n = 25) 10.33 ± 2.65 nmol/l 32–36 Weeks ( n = 25) 20.48 ± 7.60 nmol/l GD Plasma KP-54, 14 and 10 21–25 Weeks ( n = 20) 4.51 ± 3.18 nmol/l 32–36 Weeks ( n = 20) 11.643 ± 7.65 nmol/l Type 1 Plasma KP-54, 14 and 10 9–12 Weeks ( n = 16) 1.82 ± 1.47 nmol/l 21–25 Weeks ( n = 16) 7.12 ± 4.78 nmol/l 32–36 Weeks ( n = 16) 16.31 ± 12.10 nmol/l H Plasma KP-54, 14 and 10 9–12 Weeks ( n = 22) 1.18 ± 0.36 nmol/l 21–25 Weeks ( n = 22) 3.42 ± 1.04 nmol/l 32–36 Weeks ( n = 22) 14.14 ± 10.44 nmol/l GH Plasma KP-54, 14 and 10 21–25 Weeks ( n = 18) 8.46 ± 6.24 nmol/l 32–36 Weeks ( n = 18) 25.68 ± 9.23 nmol/l PE Plasma KP-54, 14 and 10 21–25 Weeks ( n = 28) 4.46 ± 3.73 nmol/l 32–36 Weeks ( n = 28) 16.03 ± 10.09 nmol/l UP Plasma KP-54, 14 and 10 FT (10.4 ± 0.5 Weeks) ( n = 13) 803 ± 125 pmol/l Dhillo et al. (2006) TT (38 ± 0.8 Weeks) ( n = 7) 2483 ± 302 pmol/l 15 d postpartum ( n = 7) <2 pmol/l Malignant GTN Plasma KP-54, 14 and 10 Pre-therapy ( n = 11) 1363 ± 1076 pmol/l Post-therapy ( n = 11) <2 pmol/l UP Plasma KP-54, 14 and 10 TT (34 ± 0.6) ( n = 49) 13 783 ± 864 pmol/l Jayasena et al. (2015) Salivary KP-54, 14 and 10 TT (34 ± 0.6) ( n = 49) 123 ± 34 pmol/l Urine KP-54, 14 and 10 TT (34 ± 0.6) ( n = 49) 301 ± 59 pmol/l UP Plasma KP-54 FT ( n = 11) 1230 ± 346 pmol/l Horikoshi et al. (2003) ST ( n = 16) 4590 ± 555 pmol/l TT ( n = 12) 9590 ± 1640 pmol/l 5 d postdelivery ( n = 10) 7.63 ± 1.33 pmol/l UP (singleton) Serum KP-54 11–14 Weeks ( n = 31) 1995 ± 375 pmol/l Madazli et al. (2012) PE (singleton) Serum KP-54 11–14 Weeks ( n = 30) 1554 ± 385 pmol/l UP (singleton) Plasma KP-54 TT ( n = 50) 9.69 ± 1.35 ng/ml Adali et al. (2012) Mild PE Plasma KP-54 TT ( n = 15) 2.61 ± 0.40 ng/ml Severe PE Plasma KP-54 TT ( n = 24) 1.17 ± 0.24 ng/ml UP (singleton) Plasma KP-10 16 Weeks ( n = 158) 1044 ± 621 pmol/l Logie et al. (2012) 28 Weeks ( n = 139) 1714 ± 1306 pmol/l 36 Weeks ( n = 99) 2441 ± 2123 pmol/l UP Serum KP-10 16–20 Weeks ( n = 317) 1188 (494–2298) pg/ml Armstrong et al. (2009) UP Serum KP-10 16–20 Weeks ( n = 118) 1164 (442–3903) pg/ml PE Serum KP-10 16–20 Weeks ( n = 57) 1109 (605–1935) pg/ml UP Serum KP-10 38.03 ± 0.06 ( n = 30) 1.66 ± 0.59 ng/ml Matjila et al. (2016) Cord serum 0.58 ± 0.39 ng/ml PE Serum KP-10 32.95 ± 0.53 ( n = 19) 2.03 ± 0.44 ng/ml Cord serum 1.78 ± 0.38 ng/ml UP Plasma KP-10 8–14 Weeks ( n = 31) 2035 ± 1260 pmol/l Smets et al. (2008) SGA Plasma KP-10 8–14 Weeks ( n = 31) 1376 ± 1317 pmol/l Abbreviations: UP, uncomplicated pregnancy; GD, gestational diabetes mellitus; type 1, pre-gestational insulin-dependent diabetes mellitus; H, chronic hypertension; GH, gestational hypertension; PE, pre-eclampsia; SGA, restriction small for gestational age; FT, the first trimester; ST, the second trimester; TT, the third trimester. Median ± SD or Median (quartile range) [range]. Kisspeptin (KP) concentrations in human plasma or serum during early pregnancy. Abbreviations: UP, uncomplicated pregnancy; GD, gestational diabetes mellitus; type 1, pre-gestational insulin-dependent diabetes mellitus; H, chronic hypertension; GH, gestational hypertension; PE, pre-eclampsia; SGA, restriction small for gestational age; FT, the first trimester; ST, the second trimester; TT, the third trimester. Median ± SD or Median (quartile range) [range].

We conducted literature reviews regarding the coordinated spatial and temporal expression patterns of kisspeptins and their functional receptors during embryo implantation and early human gestation. We also provided an overview of the available evidence, indicating a potential role of kisspeptin as an emerging marker in early pregnancy and a diagnostic or therapeutic target in pregnancy-related diseases. Admittedly, the conclusive demonstration of plasma, serum or urine kisspeptin levels as potential markers for early pregnancy-related diseases is still pending. In addition, the diagnostic utility and therapeutic target of kisspeptin in early pregnancy or placenta-related diseases have not been fully investigated. Thus, there are many unsolved problems that exist and are far from elucidated.

The highest KISS1 expression levels in the placenta were found during the first trimester in humans ( Bilban et al. , 2004 ; Cartwright and Williams, 2012 ) and during embryo Day 12.5 in rodents ( Terao et al. , 2004 ; Babwah, 2015 ). The expression pattern of KISS1 coincides with the time of peak trophoblast invasion when the regulation of this process is of critical importance ( Babwah, 2015 ). In humans, KISS1 is mainly expressed in the villous trophoblast and has an inhibitory role in trophoblast migration through a paracrine/autocrine mechanism within the placental tissue ( Bilban et al. , 2004 ; Roseweir et al. , 2012 ; Taylor et al. , 2014 ). Therefore, the change in the local expression of KISS1 in the placenta may be involved in some invasion-dysregulated diseases. Gestational trophoblastic neoplasia (GTN) is a spectrum of both benign and malignant gestational tumors, including complete mole, partial hydatidiform mole, invasive mole, choriocarcinoma, placental site trophoblastic tumor and epithelioid trophoblastic tumor ( Lurain, 2011 ; Biscaro et al. , 2015 ). Plasma β-hCG levels have been widely used to predict the prognosis of malignant GTN before, during or after chemotherapy ( Yang et al. , 2006 , 2008 ). Previous studies showed that the expression levels of KISS1 and KISS1R were significantly increased in molar pregnancies (a benign GTN), but the expression levels of KISS1 and KISS1R were decreased in choriocarcinoma cells (malignant GTN cells) ( Janneau et al. , 2002 ). These results strongly indicate that down-regulation of the placental expression of KISS1 is involved in the malignant invasion. Intriguingly, plasma kisspeptin levels (including kisspeptin-54, kisspeptin-14 and kisspeptin-10) in patients with malignant GTN were elevated ( Dhillo et al. , 2006 ). This study supported the notion that the expression levels of KISS1 in the placenta may not necessarily reflect the plasma levels of kisspeptin, and the increase in serum kisspeptin levels could be explained by the dramatic increase of malignant trophoblast cells. Additionally, plasma kisspeptin levels in GTN patients fell during and after treatment with chemotherapy ( Dhillo et al. , 2006 ), indicating that plasma kisspeptin levels could be used to predict the prognosis of malignant GTN during or after chemotherapy. Interestingly, the plasma kisspeptin levels strongly and positively correlated with plasma β-hCG levels ( r 2 = 0.99, P < 0.0001) in patients with malignant GTN before, during or after chemotherapy ( Dhillo et al. , 2006 ), suggesting that kisspeptin and β-hCG in the blood were derived from the same tissue and showed similar secretion pulses in cases of malignant GTN. It would be of great interest for future studies to compare plasma or serum kisspeptin levels with serum β-hCG levels regarding their sensitivity and specificity of predicting the prognosis of malignant GTN (before, during or after chemotherapy).

Previous studies have indicated that the expression of the kisspeptin/KISS1R system in ovarian cells is affected by the estrous/menstrual cycle ( Castellano et al. , 2006 ; Gaytan et al. , 2009 ; Cielesh et al. , 2017 ; Tanyapanyachon et al. , 2018 ) (for reviews, see Hu et al. , 2017 ). It is most likely that the expression of the kisspeptin/Kiss1r system in the endometrium shares the cycle-dependent changes in different kinds of species. In the human endometrium, a previous study showed that immunostaining of kisspeptin peptides and KISS1R was strong and limited to epithelial cells, with no detection in stromal cells ( Cejudo Roman et al. , 2012 ). Additionally, another study demonstrated that the expression of kisspeptin and KISS1R was present in epithelial cells, though at weak expression levels and was nearly absent in endometrial stromal cells during the proliferative and early secretory phases ( Baba et al. , 2015 ) (Table I ). However, the expression of kisspeptin was prominent in endometrial stromal cells in the late secretory phase ( Baba et al. , 2015 ), indicating that kisspeptin may function in the decidualized endometrium in preparation for adequate placentation. However, the endometrium showed no significant expression change in kisspeptin peptides and Kiss1r among different ovarian stages in domestic cats ( Tanyapanyachon et al. , 2018 ). Interestingly, it has been suggested that kisspeptin-10 expression is higher in the non-pregnant canine uterus compared to the gestational periods investigated ( Schafer-Somi et al. , 2017 ). The same study also suggested that the expression of Kiss1r is higher before embryo adhesion than during post-implantation and mid-gestation ( Schafer-Somi et al. , 2017 ), indicating a pregnancy-related down-regulation of the kisspeptin/Kiss1r system in the canine uterus. Additionally, no expression of kisspeptin or KISS1R was observed both in epithelial glands and stromal cells during the menopausal phase in humans ( Baba et al. , 2015 ), suggesting that the kisspeptin/KISS1R system may not have a fundamental role in the endometrium at this stage. Table I Expression of KISS1 and KISS1R at the utero-placental interface during mammalian pregnancy. Species Cells or tissues reported Trends across pregnancy References KISS1  Human vST, vCT, Decidua Decreased in RSA compared with abortion Wu et al. (2014)  Human vST, vCT Decreased in RSA compared with abortion Park et al. (2012)  Human vST; PB and DP (−) Not investigated Matjila et al. (2013)  Human vCT Not different between term pregnancy and early pregnancy Janneau et al. (2002)  Human Placenta (early and term pregnancy, PE) Early pregnancy > Term pregnancy > PE Cartwright and Williams (2012)  Human Placenta (term pregnancy, PE); PB and DP (minimal) Term pregnancy < PE Matjila et al. (2016)  Human Placenta (term pregnancy) Circadian rhythm (two surges, 04:00 h and 12:00 h, respectively). de Pedro et al. (2015)  Human vST Not investigated Horikoshi et al. (2003)  Rat Trophoblast giant cells Gradually decreased Terao et al. (2004)  Human vST, vCT; EVTs (−) First trimester > term pregnancy Bilban et al. (2004)  Rat Trophoblast giant cells (gestation Day 16 and Day 22) Day 22 > Day 16 Mark et al. (2013)  Human Placenta Preterm pregnancy > term pregnancy Torricelli et al. (2008)  Cat Luminal epithelial cells and uterine glands, stroma cells Not investigated Tanyapanyachon et al. (2018)  Dog Superficial uterine glands, Syncytiotrophoblast Not changed between pre-implantation and post-implantation Schafer-Somi et al. (2017)  Mouse Decidualizing stromal cells Increased dynamically from D5 onward Zhang et al. (2014)  Human Endometrium Glandular endometrium: ectopic > eutopic Kolioulis et al. (2017)  Human Epithelial cells (weak expression levels). ESCs (−) Proliferative stage and early secretory phase Baba et al. (2015) ESCs (prominent expression levels) Late secretory phase  Human Endometrium Glandular endometrium: Ectopic >eutopic, Stromal endometrium: no difference Timologou et al. (2016)  Human Luminal and glandular epithelial cells, stroma cells (−) Not investigated Cejudo Roman et al. (2012) KISS1R  Human vST, vCT Decreased in RSA compared with abortion Wu et al. (2014) Deciduas Not different between abortion and RSA  Human vST, vCT Not different between abortion and RSA Park et al. (2012)  Human vST, vCT, EVTs; PB and decidua basalis (−) Not investigated Matjila et al. (2013)  Human vCT (early pregnancy) First trimester > term pregnancy Janneau et al. (2002)  Human Placenta (early and term pregnancy, PE) Early pregnancy > PE > term pregnancy Cartwright and Williams (2012)  Human Placenta, PB and DP (term pregnancy, PE) Not different between term pregnancy and PE Matjila et al. (2016)  Rat Trophoblast giant cells Low expression level Terao et al. (2004)  Human vST, vCT, EVTs First trimester > term pregnancy Bilban et al. (2004)  Rat Placenta (gestation Day 16 and Day 22) Day 22 > Day 16 Mark et al. (2013)  Human Umbilical vein endothelial cells Not investigated Ramaesh et al. (2010)  Mouse Decidualizing stromal cells Increased from D5 onward Zhang et al. (2014)  Cat Luminal epithelial cells and uterine glands. ESCs (−) Not investigated Tanyapanyachon et al. (2018)  Dog Superficial and deep uterine glands Higher in pre-implantation than post-implantation Schafer-Somi et al. (2017)  Dog Syncytiotrophoblast cells Higher in mid-gestation than post-implantation Schafer-Somi et al. (2017)  Human Epithelial cells. ESCs (−) Week expression levels Baba et al. (2015)  Human Luminal and glandular epithelial cells. ESCs (−) Not investigated Cejudo Roman et al. (2012) Abbreviations: RSA, recurrent spontaneous abortion; vST, villous syncytiotrophoblasts; vCT, villous cytotrophoblasts; EVTs, extravillous trophoblast cells; ESCs, endometrial stroma cells; DP, decidua parietalis; PB, placental bed. Expression of KISS1 and KISS1R at the utero-placental interface during mammalian pregnancy. Abbreviations: RSA, recurrent spontaneous abortion; vST, villous syncytiotrophoblasts; vCT, villous cytotrophoblasts; EVTs, extravillous trophoblast cells; ESCs, endometrial stroma cells; DP, decidua parietalis; PB, placental bed. Endometriosis is considered a common benign gynecologic disease characterized by the ectopic presence of endometrial tissues (including glandular epithelium and stroma) outside the uterus. A previous study showed that the expression of KISS1 is significantly higher in the glandular endometrium of endometriosis lesions compared with the eutopic glandular endometrium in patients with or without endometriosis ( Timologou et al. , 2016 ). Interestingly, there was no significant difference in KISS1 expression in the stromal endometrium between patients with and patients without endometriosis ( Timologou et al. , 2016 ), indicating that kisspeptin, known as a suppressor of tumor metastasis, in the glandular endometrium, rather than the stromal endometrium, was potentially implicated in the pathogenesis or maintenance of endometriosis.

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