Reproductive functions of Kisspeptin/KISS1R Systems in the Periphery
Reproductive Biology and Endocrinology volume 17, Article number: 65 (2019)
Kisspeptin and its G protein-coupled receptor KISS1R play key roles in mammalian reproduction due to their involvement in the onset of puberty and control of the hypothalamic-pituitary-gonadal axis. However, recent studies have indicated a potential role of extra-hypothalamic kisspeptin in reproductive function. Here, we summarize recent advances in our understanding of the physiological significance of kisspeptin/KISS1R in the peripheral reproductive system (including the ovary, testis, uterus, and placenta) and the potential role of kisspeptin/KISS1R in reproductive diseases. A comprehensive understanding of the expression, function, and potential molecular mechanisms of kisspeptin/KISS1R in the peripheral reproductive system will contribute to the diagnosis, treatment and prevention of reproductive diseases.
Different species have evolved various survival strategies, but reproduction is an indispensable function of all species permanence. Reproductive function is driven by a complex neuro-hormonal system, with considerable contribution by the hypothalamic-pituitary-gonadal (HPG) axis. The HPG axis is divided into three main levels with the following regulatory signals: 1) hypothalamus: gonadotropin-releasing hormone (GnRH); 2) pituitary: gonadotropin, luteinizing hormone (LH) and follicle-stimulating hormone (FSH); and 3) gonads: sex steroids and peptides . In the regulation of the reproductive system, GnRH neurons are the main hub, and their regulation is complicated, as a wide range of cell types and signalling molecules directly or indirectly converge on the GnRH neuron network . Many regulators of GnRH neurons act through G protein-coupled receptors (GPCRs). KISS1R is one of the most important GPCRs in the neuroendocrine control of reproductive function, and its ligand kisspeptin has a significant effect on the hypothalamus . However, the expression of KISS1 and KISS1R in peripheral reproductive tissues led us to hypothesize that kisspeptin signalling is involved in the local regulation of reproduction within these tissues [4,5,6]. In particular, three recent reviews have discussed the role of KISS/KISSR signalling in the ovary, the reproductive axis, implantation and placentation [7,8,9]. In this review, we focus on the local expression and regulation of kisspeptin and its receptor KISS1R in the peripheral reproductive system, including in the ovary, testis, uterus, and placenta, and highlight the potential role of kisspeptin/KISS1R in reproductive diseases.
The role of kisspeptin in pubertal onset
Kisspeptin is an Arg-Phe-NH2 (RF-amide) peptide encoded by the KISS1 gene . The KISS1 gene was named after Hershey’s chocolate kisses because it was initially isolated from human non-metastatic pigment tumours in Hershey (Pennsylvania, USA), and the “SS” represents “suppressor sequence” . In humans, the KISS1 gene is located on chromosome 1q32.11 and encodes a 145-amino acid peptide that is cleaved into four shorter peptides: KP-54, KP-14, KP-13, and KP-10 of 54, 14, 13 and 10 amino acids, respectively. These forms all share a common C-terminal decapeptide (KP-10), which is required for binding with its receptor KISS1R (also known as GPR54) . In humans, kisspeptin is synthesized in two major sections of the hypothalamus: the arcuate nucleus and the anterior ventral periventricular nucleus . The binding of kisspeptin to KISS1R activates the phospholipase C pathway in hypothalamic cells, leading to changes in cellular activity . Current evidence suggests that the kisspeptin signalling pathway is essential for the onset of mammalian puberty. Loss of KISS1R function causes human hypogonadotropic hypogonadism (HH), and one manifestation of HH is the failure to establish puberty due to impaired gonadotropin secretion . The phenotype of human KISS1R mutation is mimicked in Kiss1r knockout mice . In addition, Kiss1 knockout rats lack the pulsing and proliferative patterns of gonadotropin and show puberty failure . Conversely, mutations that cause hyperactive KISS1R in humans lead to central precocious puberty [18, 19]. These results suggest that kisspeptin plays an integral role in the regulation of pubertal onset. However, emerging evidence indicates the involvement of extra-hypothalamic kisspeptin and the KISS1R system in peripheral reproductive functions.
Ovarian kisspeptin and KISS1R
Distribution in ovarian tissues
The expression of Kiss1 and Kiss1r was first demonstrated in the rodent ovary . To date, the expression of Kiss1/Kiss1r has been found in the ovaries of different animals, such as hamsters , mice , rats , chickens , cats , dogs , pigs , humans and marmoset primates . Because ovarian Kiss1 mRNA is mainly expressed in rat granulosa cells during proestrus, granulosa cells are likely the main site of kisspeptin synthesis . The LH surge may directly stimulate kisspeptin synthesis through LH receptors on granulosa cells , and prevention of the preovulatory gonadotropin surge can block the upregulation of ovarian Kiss1 expression . The expression of ovarian Kiss1 mRNA shows a distinctive cell- and stage-specific pattern under regulation of LH [22, 29, 30], whereas Kiss1r mRNA expression remains low and does not significantly fluctuate with the oestrous cycle or gonadotropin treatment in rats [28,29,30]. Interestingly, in both rodent and human growth follicles, kisspeptin is present in theca cells of the growing follicle; in preovulatory follicles, kisspeptin begins to appear in the basal cells of the granular layer; after ovulation, positive immunostaining can be observed in non-luteinized granulosa cells of newly ruptured ovulation follicles; and in the corpus luteum (CL), intense kisspeptin immunoreactivity can be detected in steroidogenic granulosa lutein cells, with a gradual increase with gradual maturation of the CL [22, 27]. These results demonstrate that kisspeptin and its receptor have a highly conserved expression pattern in rodent, monkey and human ovaries. The distribution of kisspeptin in the ovary has significant temporal and spatial specificity, suggesting that the kisspeptin/KISS1R system performs multiple functions at different physiological stages in the ovary.
The role in follicular development
The expression of ovarian Kiss1 mRNA gradually increases from infancy to adolescence . The immature ovary shows negligible Kiss1 expression , and there is no significant difference in ovarian weight between Kiss1/Kiss1r-deficient mice and normal mice before puberty . However, after puberty, the ovaries in Kiss1r−/− and Kiss1−/− mice shrink compared with those in control mice, likely due to the loss of kisspeptin-mediated regulation of follicular development, not defects in gonadotropin secretion because follicular development cannot be rescued by gonadotropin replacement . In fact, although the role of the HPG axis cannot be completely ruled out, follicles at all stages and the CL are present in mice with targeted removal of kisspeptin and Kiss1r neurons (> 90%), suggesting that local kisspeptin in the ovary plays a very important role in follicle development .
Under conditions of a healthy nutrient supply, the administration of kisspeptin in the ovary reduces the number of antral follicles and increases the number of preovulatory follicles, and these structural changes can be reversed by the administration of the kisspeptin antagonist peptide 234 (P234). Furthermore, kisspeptin administration increases plasma anti-Mullerian hormone (AMH) in 6- and 10-month-old rats. AMH, a marker of ovarian reserve, is mainly secreted by secondary and small sinus follicles and can inhibit the activation of primordial follicles by negative feedback; moreover, P234 administration reduces plasma AMH levels in rats . The FSH/follicle stimulating hormone receptor (FSHR) axis is responsible for follicular growth , but kisspeptin can block the increase in FSHR expression by isoproterenol (ISO, a β-adrenergic agonist). Collectively, kisspeptin negatively regulates the development of preantral follicles by inducing the production of AMH and reduces the sensitivity to FSH by inhibiting the induction of FSHR expression by sympathetic activators, thereby reducing the recruitment of primary follicles (Fig. 1a). In the future, an ovarian-specific Kiss1/Kiss1r knockout model will be established to further elucidate the role of kisspeptin in follicle development.
The role in oocyte maturation
The addition of kisspeptin to FSH-rich medium for porcine cumulus-oocyte complexes (COCs) promotes oocyte maturation, indicating a direct effect of kisspeptin on oocytes , and the mechanism may involve upregulating the expression of C-MOS, growth differentiation factor 9 (GDF 9) and bone morphogenetic protein 15 (BMP 15) . Even in the absence of cumulus cells, kisspeptin can increase the maturity of oocytes because Kiss1r is expressed in oocytes during in vitro maturation (IVM). Thus, kisspeptin may act continuously and directly on oocytes in an autocrine-paracrine manner. Interestingly, the absence of FSH results in failed oocyte maturation, even in IVM medium supplemented with kisspeptin, confirming a critical role of gonadotropins in the maturation of oocytes in vitro. Moreover, the addition of FSH to COCs induces a significant increase in Kiss1r expression, reflecting the permissive action of FSH on kisspeptin.
When a mouse oocyte acquires meiotic capacity, Kiss1 mRNA expression increases 82.2-fold . However, when the oocyte progresses through the first and second divisions of meiosis (MII), Kiss1 mRNA expression decreases by 5.4- and 12-fold, respectively . During the progression from germ-vesicle I to MII, the expression of Kiss1r remains stable. However, kisspeptin treatment fails to affect the percentage of MII eggs . Therefore, the upregulation of Kiss1 expression may be related to the ability to undergo meiosis and may affect the recovery of meiosis but not the progression of MII. Taken together, these data suggest that the effect of kisspeptin on oocyte maturation may be accomplished through the regulation of meiosis (Fig. 1b).
The role in ovulation
The LH peak plays a crucial role in ovulation by inducing the upregulation of COX-2 and prostaglandin production . The COX-2 inhibitor NS398 and the COX non-selective inhibitor indomethacin significantly inhibited Kiss1 mRNA expression in the rat ovary and decreased the efficiency of rat ovulation, suggesting that Kiss1 may be a downstream target of COX-2 (Fig. 1c). Furthermore, administration of prostaglandin E2 can reverse the antagonism of indomethacin on kiss1 expression. The anti-progestin RU486 ameliorates ovulation defects caused by indomethacin but cannot reverse the regulation of ovarian Kiss1 expression , implying the existence of other pathways that regulate ovulation. In fact, the indispensable role of ovarian kisspeptin in ovulation is suspect because gonadotropins can induce ovulation in Kiss1-deficient mice with mild hypogonadism and in women with homozygous KISS1R mutations .
The role in ovarian steroidogenesis
Kisspeptin stimulates progesterone secretion by rat luteal cells and by chicken and porcine granulosa cells. Our previous study showed that recombinant KP-10 significantly enhances basal and human chorionic gonadotropin (hCG)-induced progesterone levels in cultured rat luteal cells and upregulates the transcription of key steroidogenic enzymes (StAR, CYP11A, and 3β-HSD) . Moreover, KP-10 promotes the secretion of progesterone by cultured chicken follicular granulosa cells in vitro, accompanied by the upregulation of StAR, CYP11A, and 3β-HSD expression . In addition, KP-10 significantly enhances progesterone production and prevents the efflux of oestradiol from granulosa cells of porcine large follicles . Furthermore, KP-10 increases the phosphorylation of the mitogen-activated protein kinase Erk1/2 but not of P38 MAPK and Akt in cultured rat luteal cells, suggesting that kisspeptin may stimulate progesterone secretion via the Erk1/2 signalling pathway in these cells . However, treatment with KP-54 alone did not alter steroidogenesis or the expression of gonadotropin receptors , indicating that KP-54 may require gonadotropins to promote steroidogenesis  or that different kisspeptin isoforms (such as KP-10) may have different affinities for ovarian KISS1R .
Unlike progesterone, KP-10 does not promote the basal or hCG-induced secretion of oestrogen by rat luteal cells . Currently, the best data on the effects of kisspeptin on luteal cell function are from luteinized granulosa cell cultures. KP-54 significantly augments the expression of oestrogen receptors alpha and beta (ESR1 and ESR2) in human granulosa lutein cells, suggesting that kisspeptin may increase sensitivity to oestrogen .
Additional studies have indicated that serum kisspeptin levels are significantly higher in women with polycystic ovary syndrome (PCOS), which is characterized by hyperandrogenism and ovulatory dysfunction . Notably, serum levels of kisspeptin are negatively correlated with FSH but positively correlated with LH, testosterone and dehydroepiandrosterone (DHEA) . Mouse KP-10 and KP-52 can significantly increase serum testosterone levels in mice . Furthermore, ovary-derived kisspeptin has been shown to regulate the secretion of LH .
Testicular kisspeptin and KISS1R
Distribution in testicular tissues
There are not only significant differences in the distribution of testicular kisspeptin and KISS1R between mammals and non-mammalian species but also diverse distribution patterns in the same or similar species [5, 44,45,46,47,48] (summarized in Table 1). For example, a previous study reported kisspeptin and Kiss1r immunoreactivity in round spermatids in immature mice . However, another study showed kisspeptin immunoreactivity mainly in Leydig cells and sperm cells at different stages, not in only round sperm cells . Therefore, the different results in the same species may be related to the age of the experimental mice and largely influenced by experimental methods. For example, when the LacZ gene was inserted into the Kiss1 and Kiss1r alleles to allow β-galactosidase staining to detect gene expression, unique structural changes in sperm (deformation) resulted in inactivation of β-galactosidase after the round spermatid stage, making it impossible to determine whether kisspeptin is expressed in prolonged spermatid and spermatozoa .
The role in spermatogenesis
In non-mammalian species, subcutaneous injection of synthetic Kiss1 pentadecapeptide can speed up spermatogenesis in prepubertal male chub mackerel . In mammals, gene expression profiling revealed that the initiation of Kiss1/Kiss1r expression in mouse testis coincides with the formation of spermatozoa , suggesting a link between spermatogenesis and the testicular kisspeptin/Kiss1r system in mammals. In addition, kisspeptin exerts anti-metastatic effects by inhibiting cell chemotaxis and migration, which play important roles in the early stage of spermatogenesis . Furthermore, in the late stage of spermatogenesis, KP-13 can induce human sperm motility changes and hyperactivation, possibly caused by the increase in sperm intracellular Ca2+ concentration ([Ca2+]i) . The positive association between kisspeptin concentration in seminal plasma and semen quality supports the importance of the kisspeptin system in spermatogenesis . However, peripheral kisspeptin may not be essential for spermatogenesis in mammals. First, Kiss1 and Kiss1r mutant mice still show low levels of spermatogenesis on a phytoestrogen diet . Second, male patients with KISS1R mutations respond to exogenous hormonal therapy and successfully achieve fertility . Collectively, testicular kisspeptin may not be necessary for mammalian spermatogenesis but is an important regulator of this process.
The role in testicular steroidogenesis
Androgens (mainly testosterone) are steroid hormones secreted by Leydig cells in the testes of males. Thus far, there is no verdict as to whether peripheral kisspeptin has an effect on androgen production in Leydig cells. First, the interruption of Kiss1 expression is associated with decreased testosterone levels in rats , and the kisspeptin antagonist P234 reduces the production of hCG-activated testosterone in vitro , but local injection of P234 does not alter plasma testosterone levels in adult rhesus monkeys . Second, although the immortalized Leydig cell line MA-10 expresses Kiss1r, it does not respond to KP-10 stimulation . In addition, Sertoli cells respond to kisspeptin and stimulate the production of androgen-binding protein (ABP), indicating a potential role of kisspeptin in ABP production .
Roles in the uterus and placenta
The role in the uterus
In the human female genital tract, KISS1/KISS1R is mainly expressed in epithelial and stromal cells of the uterus but not of the myometrium . In mice, Kiss1 and Kiss1r mRNA expression levels are generally low from day 1 to 4 of pregnancy, which is the stage of zygote to blastocyst transformation (Fig. 2a). KISS1 and KISS1R proteins are mainly localized at low levels in the luminal and glandular epithelium. However, Kiss1 and Kiss1r mRNA expression level dramatically increase with the progression of uterine decidualization, and attenuated expression of Kiss1 can significantly inhibit the expression of stromal cell decidualization markers, indicating that the kisspeptin/kiss1r system plays an important role in the decidualization process . However, the underlying mechanism is unknown.
Calder et al. found that in kiss1 mutant mice, gonadotropin and oestradiol replacement could restore ovulation, mating, and fertilization but not lead to pregnancy; moreover, leukaemia inhibitory factor (Lif), a crucial cytokine required for implantation, is weakly expressed in these mice . Lif secreted by the uterine glands promotes embryo-uterine communication and contributes to embryo attachment and decidualization [58, 59]. Oestrogen upregulates Lif expression in the uterus, and supplementation with Lif restores implantation and decidualization in ovariectomized mice and mice lacking uterine oestrogen receptor expression [60, 61]. Furthermore, in Kiss1 knockout mice, exogenous administration of Lif, but not E2, partially rescues implantation failure , and our data demonstrated that E2 significantly increases the expression of uterine kiss1 mRNA in ovariectomized mice . These data suggest that kisspeptin signalling may act downstream of E2 to stimulate uterine Lif expression and is beneficial for promoting embryo implantation and decidualization in mice (Fig. 2b).
The role in pregnancy
There is evidence that the primary source of circulating kisspeptin is trophoblast cells of the placenta [12, 62]. In rat placental cells, Kiss1 expression is upregulated by GnRH and neurokinin B, and all of these neuropeptides can increase hCG expression . Serum KP-54 levels increase several thousand fold during pregnancy and return to normal within 15 days after delivery, suggesting that the placenta produces large quantities of kisspeptin during pregnancy [4, 62, 64]. Moreover, low circulating kisspeptin levels during pregnancy are associated with an increased risk of miscarriage. Therefore, plasma kisspeptin levels are a potential biomarker for miscarriage in the first and third trimesters [65, 66]. As one of the biomarkers of pregnancy, peripheral kisspeptin has multiple functions, including the regulation of placental invasion and migration (discussed in detail below) , the apoptosis of embryonic and placental cells, and foetal development [67, 68].
Kisspeptin administration increases the apoptosis of embryonic cells cultured in vitro by upregulating pro-apoptotic genes . The expression of the pro-apoptotic gene BAK1 in blastocysts increased 3.5-fold at 24 h after kisspeptin treatment, but no significant change was observed in the expression of the anti-apoptotic gene Bcl-2 . In addition, the apoptosis index (AI), the ratio of the pro-apoptotic protein BAX to the anti-apoptotic protein Bcl-2, determines whether the cell will initiate apoptosis . Interestingly, the AI and KISS1/KISS1R expression in the placenta are much higher in late pregnancy than at term delivery in humans . Furthermore, external administration of kisspeptin increases AI and induces apoptosis in placental explants in a dose-dependent manner . Taken together, these data indicate that kisspeptin may be a pro-apoptotic placental factor during pregnancy.
In addition, studies have indicated that the kisspeptin/KISS1R system in the embryo may affect human foetal adrenal function synergistically with adrenocorticotropic hormone and corticotropin-releasing hormone secretion by increasing the production of DHEA in mid to late gestation (Fig. 2c) [71, 72].
The role in placental migration and invasion
Kisspeptin was originally called metastin because it can inhibit tumour metastasis. Interestingly, the invasion processes of placental and tumour cells are markedly similar [73, 74]. The highest expression of Kiss1 and Kiss1r in gestational trophoblast cells is consistent with peak trophoblast invasion [62, 75]. Thus, kisspeptin is thought to inhibit trophoblast migration and invasion in the placenta. A series of studies demonstrated that kisspeptin can regulate trophoblast migration and invasion by a variety of mechanisms. First, kisspeptin stimulates Erk1/2 phosphorylation in trophoblast cells and inhibits the expression of matrix metalloproteinases (MMPs), such as MMP-2, thereby regulating placental invasion [74, 76]. Second, KP-10 inhibits the migration of HTR8SVneo cells by stimulating complex Erk1/2-GSK3β-FAK feedback interactions in vitro . Third, kisspeptin suppresses angiogenesis by downregulating vascular endothelial growth factor A (Fig. 2b) . In addition, the active kisspeptin/KISS1R system not only suppresses the migration of trophoblast cells but also inhibits their growth in placental explants .
Recently, kisspeptin analogues and KISS1R antagonists have been developed as modulators of the cascade upstream of GnRH, and most previous studies have focused on the central control of the kisspeptin/KISS1R system in the hypothalamus. However, as discussed in this review, the kisspeptin/KISS1R system plays a direct role in peripheral organs (including the ovary, testis, uterus, and placenta) and is implicated in reproductive diseases such as miscarriage and PCOS. A comprehensive understanding of the expression, function, and potential molecular mechanisms of kisspeptin/KISS1R in the peripheral reproductive system will contribute to the diagnosis, treatment and prevention of reproductive diseases.
Availability of data and materials
All data supporting the conclusion of this article are included in this published article.
Bone morphogenetic protein 15
Estrogen receptors alpha
Estrogen receptors beta
Follicle stimulating hormone
Follicle stimulating hormone receptor
Growth differentiation factor 9
G protein-coupled receptors
Human chorionic gonadotropin
- HPG axis:
Hypothalamic-pituitary-gonadal (HPG) axis
In vitro maturation
Gonadotropin, luteinizing hormone
Leukemia inhibitory factor
Second division of meiosis
Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev. 2012;92(3):1235–316.
Herbison AE. Control of puberty onset and fertility by gonadotropin-releasing hormone neurons. Nat Rev Endocrinol. 2016;12(8):452–66.
Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci U S A. 2005;102(6):2129–34.
Terao Y, Kumano S, Takatsu Y, Hattori M, Nishimura A, Ohtaki T, et al. Expression of KiSS-1, a metastasis suppressor gene, in trophoblast giant cells of the rat placenta. Biochim Biophys Acta. 2004;1678(2–3):102–10.
Mei H, Doran J, Kyle V, Yeo SH, Colledge WH. Does Kisspeptin signaling have a role in the testes? Front Endocrinol (Lausanne). 2013;4:198.
Cejudo Roman A, Pinto FM, Dorta I, Almeida TA, Hernandez M, Illanes M, et al. Analysis of the expression of neurokinin B, kisspeptin, and their cognate receptors NK3R and KISS1R in the human female genital tract. Fertil Steril. 2012;97(5):1213–9.
Hu KL, Zhao H, Chang HM, Yu Y, Qiao J. Kisspeptin/Kisspeptin receptor system in the ovary. Front Endocrinol (Lausanne). 2017;8:365.
Franssen D, Tena-Sempere M. The kisspeptin receptor: a key G-protein-coupled receptor in the control of the reproductive axis. Best Pract Res Clin Endocrinol Metab. 2018;32(2):107–23.
Hu KL, Chang HM, Zhao HC, Yu Y, Li R, Qiao J. Potential roles for the kisspeptin/kisspeptin receptor system in implantation and placentation. Hum Reprod Update. 2019;25(3):326–43.
Tsutsui K, Bentley GE, Kriegsfeld LJ, Osugi T, Seong JY, Vaudry H. Discovery and evolutionary history of gonadotrophin-inhibitory hormone and kisspeptin: new key neuropeptides controlling reproduction. J Neuroendocrinol. 2010;22(7):716–27.
Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE, et al. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst. 1996;88(23):1731–7.
Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem. 2001;276(37):34631–6.
Marraudino M, Martini M, Trova S, Farinetti A, Ponti G, Gotti S, et al. Kisspeptin system in ovariectomized mice: estradiol and progesterone regulation. Brain Res. 2018;1688:8–14.
Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, et al. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci U S A. 2005;102(5):1761–6.
de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A. 2003;100(19):10972–6.
Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349(17):1614–27.
Uenoyama Y, Nakamura S, Hayakawa Y, Ikegami K, Watanabe Y, Deura C, et al. Lack of pulse and surge modes and glutamatergic stimulation of luteinising hormone release in Kiss1 knockout rats. J Neuroendocrinol. 2015;27(3):187–97.
Oh YJ, Rhie YJ, Nam HK, Kim HR, Lee KH. Genetic variations of the KISS1R gene in Korean girls with central precocious puberty. J Korean Med Sci. 2017;32(1):108–14.
Silveira LG, Noel SD, Silveira-Neto AP, Abreu AP, Brito VN, Santos MG, et al. Mutations of the KISS1 gene in disorders of puberty. J Clin Endocrinol Metab. 2010;95(5):2276–80.
Shahed A, Young KA. Differential ovarian expression of KiSS-1 and GPR-54 during the estrous cycle and photoperiod induced recrudescence in Siberian hamsters (Phodopus sungorus). Mol Reprod Dev. 2009;76(5):444–52.
Merhi Z, Thornton K, Bonney E, Cipolla MJ, Charron MJ, Buyuk E. Ovarian kisspeptin expression is related to age and to monocyte chemoattractant protein-1. J Assist Reprod Genet. 2016;33(4):535–43.
Castellano JM, Gaytan M, Roa J, Vigo E, Navarro VM, Bellido C, et al. Expression of KiSS-1 in rat ovary: putative local regulator of ovulation? Endocrinology. 2006;147(10):4852–62.
Xiao Y, Ni Y, Huang Y, Wu J, Grossmann R, Zhao R. Effects of kisspeptin-10 on progesterone secretion in cultured chicken ovarian granulosa cells from preovulatory (F1-F3) follicles. Peptides. 2011;32(10):2091–7.
Tanyapanyachon P, Amelkina O, Chatdarong K. The expression of kisspeptin and its receptor in the domestic cat ovary and uterus in different stages of the ovarian cycle. Theriogenology. 2018;117:40–8.
Cielesh ME, McGrath BM, Scott CJ, Norman ST, Stephen CP. The localization of kisspeptin and kisspeptin receptor in the canine ovary during different stages of the reproductive cycle. Reprod Domest Anim. 2017;52(Suppl 2):24–8.
Basini G, Grasselli F, Bussolati S, Ciccimarra R, Maranesi M, Bufalari A, et al. Presence and function of kisspeptin/KISS1R system in swine ovarian follicles. Theriogenology. 2018;115:1–8.
Gaytan F, Gaytan M, Castellano JM, Romero M, Roa J, Aparicio B, et al. KiSS-1 in the mammalian ovary: distribution of kisspeptin in human and marmoset and alterations in KiSS-1 mRNA levels in a rat model of ovulatory dysfunction. Am J Physiol Endocrinol Metab. 2009;296(3):E520–31.
Ricu MA, Ramirez VD, Paredes AH, Lara HE. Evidence for a celiac ganglion-ovarian kisspeptin neural network in the rat: intraovarian anti-kisspeptin delays vaginal opening and alters estrous cyclicity. Endocrinology. 2012;153(10):4966–77.
Laoharatchatathanin T, Terashima R, Yonezawa T, Kurusu S, Kawaminami M. Augmentation of Metastin/Kisspeptin mRNA expression by the Proestrous luteinizing hormone surge in Granulosa cells of rats: implications for Luteinization. Biol Reprod. 2015;93(1):15.
Peng J, Tang M, Zhang BP, Zhang P, Zhong T, Zong T, et al. Kisspeptin stimulates progesterone secretion via the Erk1/2 mitogen-activated protein kinase signaling pathway in rat luteal cells. Fertil Steril. 2013;99(5):1436–43.e1.
Garcia-Galiano D, van Ingen Schenau D, Leon S, Krajnc-Franken MA, Manfredi-Lozano M, Romero-Ruiz A, et al. Kisspeptin signaling is indispensable for neurokinin B, but not glutamate, stimulation of gonadotropin secretion in mice. Endocrinology. 2012;153(1):316–28.
Gaytan F, Garcia-Galiano D, Dorfman MD, Manfredi-Lozano M, Castellano JM, Dissen GA, et al. Kisspeptin receptor haplo-insufficiency causes premature ovarian failure despite preserved gonadotropin secretion. Endocrinology. 2014;155(8):3088–97.
Baarends WM, Uilenbroek JT, Kramer P, Hoogerbrugge JW, van Leeuwen EC, Themmen AP, et al. Anti-mullerian hormone and anti-mullerian hormone type II receptor messenger ribonucleic acid expression in rat ovaries during postnatal development, the estrous cycle, and gonadotropin-induced follicle growth. Endocrinology. 1995;136(11):4951–62.
Fernandois D, Na E, Cuevas F, Cruz G, Lara HE, Paredes AH. Kisspeptin is involved in ovarian follicular development during aging in rats. J Endocrinol. 2016;228(3):161–70.
Saadeldin IM, Koo OJ, Kang JT, Kwon DK, Park SJ, Kim SJ, et al. Paradoxical effects of kisspeptin: it enhances oocyte in vitro maturation but has an adverse impact on hatched blastocysts during in vitro culture. Reprod Fertil Dev. 2012;24(5):656–68.
Rocha AM, Ding J, Lehman M, Smith GD. Kisspeptin and kisspeptin receptor are expressed in mouse oocytes and participate in meiosis resumption. Fertil Steril. 2012;98(3):S22.
Sirois J, Sayasith K, Brown KA, Stock AE, Bouchard N, Dore M. Cyclooxygenase-2 and its role in ovulation: a 2004 account. Hum Reprod Update. 2004;10(5):373–85.
Pallais JC, Bo-Abbas Y, Pitteloud N, Crowley WF Jr, Seminara SB. Neuroendocrine, gonadal, placental, and obstetric phenotypes in patients with IHH and mutations in the G-protein coupled receptor, GPR54. Mol Cell Endocrinol. 2006;254-255:70–7.
Owens LA, Abbara A, Lerner A, O'Floinn S, Christopoulos G, Khanjani S, et al. The direct and indirect effects of kisspeptin-54 on granulosa lutein cell function. Hum Reprod. 2018;33(2):292–302.
Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet (London, England). 2007;370(9588):685–97.
Gorkem U, Togrul C, Arslan E, Sargin Oruc A, Buyukkayaci Duman N. Is there a role for kisspeptin in pathogenesis of polycystic ovary syndrome? Gynecol Endocrinol. 2018;34(2):157–60.
Mikkelsen JD, Bentsen AH, Ansel L, Simonneaux V, Juul A. Comparison of the effects of peripherally administered kisspeptins. Regul Pept. 2009;152(1–3):95–100.
Balasch J, Fabregues F, Carmona F, Casamitjana R, Tena-Sempere M. Ovarian luteinizing hormone priming preceding follicle-stimulating hormone stimulation: clinical and endocrine effects in women with long-term hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2009;94(7):2367–73.
Chianese R, Ciaramella V, Fasano S, Pierantoni R, Meccariello R. Kisspeptin regulates steroidogenesis and spermiation in anuran amphibian. Reproduction. 2017;154(4):403–14.
Pinto FM, Cejudo-Roman A, Ravina CG, Fernandez-Sanchez M, Martin-Lozano D, Illanes M, et al. Characterization of the kisspeptin system in human spermatozoa. Int J Androl. 2012;35(1):63–73.
Irfan S, Ehmcke J, Shahab M, Wistuba J, Schlatt S. Immunocytochemical localization of kisspeptin and kisspeptin receptor in the primate testis. J Med Primatol. 2016;45(3):105–11.
Anjum S, Krishna A, Sridaran R, Tsutsui K. Localization of gonadotropin-releasing hormone (GnRH), gonadotropin-inhibitory hormone (GnIH), kisspeptin and GnRH receptor and their possible roles in testicular activities from birth to senescence in mice. J Exp Zool A Ecol Genet Physiol. 2012;317(10):630–44.
Meccariello R, Chianese R, Chioccarelli T, Ciaramella V, Fasano S, Pierantoni R, et al. Intra-testicular signals regulate germ cell progression and production of qualitatively mature spermatozoa in vertebrates. Front Endocrinol (Lausanne). 2014;5:69.
Harms JF, Welch DR, Miele ME. KISS1 metastasis suppression and emergent pathways. Clin Exp Metastasis. 2003;20(1):11–8.
Zou P, Wang X, Chen Q, Yang H, Zhou N, Sun L, et al. Kisspeptin protein in seminal plasma is positively associated with semen quality: results from the MARHCS study in Chongqing, China. Biomed Res Int. 2019;2019:5129263.
Mei H, Walters C, Carter R, Colledge WH. Gpr54−/− mice show more pronounced defects in spermatogenesis than Kiss1−/− mice and improved spermatogenesis with age when exposed to dietary phytoestrogens. Reproduction. 2011;141(3):357–66.
Wahab F, Quinton R, Seminara SB. The kisspeptin signaling pathway and its role in human isolated GnRH deficiency. Mol Cell Endocrinol. 2011;346(1–2):29–36.
Ayturk N, Firat T, Kukner A, Ozogul C, Tore F, Kandirali IE, et al. The effect of kisspeptin on spermatogenesis and apoptosis in rats. Turk J Med Sci. 2017;47(1):334–42.
Samir H, Nagaoka K, Watanabe G. Effect of kisspeptin antagonist on goat in vitro Leydig cell steroidogenesis. Theriogenology. 2018;121:134–40.
Huma T, Ulla F, Hanif F, Rizak JD, Shahab M. Peripheral administration of kisspeptin antagonist does not alter basal plasma testosterone but decreases plasma adiponectin levels in adult male rhesus macaques. Turk J Biol. 2014;38:450–6.
Zhang P, Tang M, Zhong T, Lin Y, Zong T, Zhong C, et al. Expression and function of kisspeptin during mouse decidualization. PLoS One. 2014;9(5):e97647.
Calder M, Chan YM, Raj R, Pampillo M, Elbert A, Noonan M, et al. Implantation failure in female Kiss1−/− mice is independent of their hypogonadic state and can be partially rescued by leukemia inhibitory factor. Endocrinology. 2014;155(8):3065–78.
Kelleher AM, Milano-Foster J, Behura SK, Spencer TE. Uterine glands coordinate on-time embryo implantation and impact endometrial decidualization for pregnancy success. Nat Commun. 2018;9(1):2435.
Stewart CL, Kaspar P, Brunet LJ, Bhatt H, Gadi I, Kontgen F, et al. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature. 1992;359(6390):76–9.
Pawar S, Laws MJ, Bagchi IC, Bagchi MK. Uterine epithelial estrogen receptor-alpha controls Decidualization via a paracrine mechanism. Mol Endocrinol. 2015;29(9):1362–74.
Chen JR, Cheng JG, Shatzer T, Sewell L, Hernandez L, Stewart CL. Leukemia inhibitory factor can substitute for nidatory estrogen and is essential to inducing a receptive uterus for implantation but is not essential for subsequent embryogenesis. Endocrinology. 2000;141(12):4365–72.
Bilban M, Ghaffari-Tabrizi N, Hintermann E, Bauer S, Molzer S, Zoratti C, et al. Kisspeptin-10, a KiSS-1/metastin-derived decapeptide, is a physiological invasion inhibitor of primary human trophoblasts. J Cell Sci. 2004;117(Pt 8):1319–28.
Oride A, Kanasaki H, Mijiddorj T, Sukhbaatar U, Ishihara T, Kyo S. Regulation of kisspeptin and gonadotropin-releasing hormone expression in rat placenta: study using primary cultures of rat placental cells. Reprod Biol Endocrinol. 2015;13:90.
Horikoshi Y, Matsumoto H, Takatsu Y, Ohtaki T, Kitada C, Usuki S, et al. Dramatic elevation of plasma metastin concentrations in human pregnancy: metastin as a novel placenta-derived hormone in humans. J Clin Endocrinol Metab. 2003;88(2):914–9.
Jayasena CN, Abbara A, Izzi-Engbeaya C, Comninos AN, Harvey RA, Gonzalez Maffe J, et al. Reduced levels of plasma kisspeptin during the antenatal booking visit are associated with increased risk of miscarriage. J Clin Endocrinol Metab. 2014;99(12):E2652–60.
Sullivan-Pyke C, Haisenleder DJ, Senapati S, Nicolais O, Eisenberg E, Sammel MD, et al. Kisspeptin as a new serum biomarker to discriminate miscarriage from viable intrauterine pregnancy. Fertil Steril. 2018;109(1):137–41.e2.
Katugampola H, King PJ, Chatterjee S, Meso M, Duncan AJ, Achermann JC, et al. Kisspeptin is a novel regulator of human fetal adrenocortical development and function: a finding with important implications for the human Fetoplacental unit. J Clin Endocrinol Metab. 2017;102(9):3349–59.
Torricelli M, Novembri R, Conti N, De Falco G, De Bonis M, Petraglia F. Correlation with placental kisspeptin in postterm pregnancy and apoptosis. Reprod Sci. 2012;19(10):1133–7.
Brown D, Yu BD, Joza N, Benit P, Meneses J, Firpo M, et al. Loss of Aif function causes cell death in the mouse embryo, but the temporal progression of patterning is normal. Proc Natl Acad Sci U S A. 2006;103(26):9918–23.
Athapathu H, Jayawardana MA, Senanayaka L. A study of the incidence of apoptosis in the human placental cells in the last weeks of pregnancy. J Obstet Gynaecol. 2003;23(5):515–7.
Ishimoto H, Jaffe RB. Development and function of the human fetal adrenal cortex: a key component in the feto-placental unit. Endocr Rev. 2011;32(3):317–55.
Nakamura Y, Aoki S, Xing Y, Sasano H, Rainey WE. Metastin stimulates aldosterone synthesis in human adrenal cells. Reprod Sci. 2007;14(8):836–45.
Yoshioka K, Ohno Y, Horiguchi Y, Ozu C, Namiki K, Tachibana M. Effects of a KiSS-1 peptide, a metastasis suppressor gene, on the invasive ability of renal cell carcinoma cells through a modulation of a matrix metalloproteinase 2 expression. Life Sci. 2008;83(9–10):332–8.
Cohen M, Bischof P. Factors regulating trophoblast invasion. Gynecol Obstet Investig. 2007;64(3):126–30.
Hiden U, Bilban M, Knofler M, Desoye G. Kisspeptins and the placenta: regulation of trophoblast invasion. Rev Endocr Metab Disord. 2007;8(1):31–9.
Francis VA, Abera AB, Matjila M, Millar RP, Katz AA. Kisspeptin regulation of genes involved in cell invasion and angiogenesis in first trimester human trophoblast cells. PLoS One. 2014;9(6):e99680.
Roseweir AK, Katz AA, Millar RP. Kisspeptin-10 inhibits cell migration in vitro via a receptor-GSK3 beta-FAK feedback loop in HTR8SVneo cells. Placenta. 2012;33(5):408–15.
Ramaesh T, Logie JJ, Roseweir AK, Millar RP, Walker BR, Hadoke PW, et al. Kisspeptin-10 inhibits angiogenesis in human placental vessels ex vivo and endothelial cells in vitro. Endocrinology. 2010;151(12):5927–34.
We acknowledge the American Journal Experts (AJE) for their editing and polishing to improve the manuscript.
This study was financially supported by the National Natural Science Foundation of China (81860283 and 81671486) and the 555 Project of Jiangxi Province Gan Po Excellence. The funders had no role in study design, data collection and analysis, interpretation of data, decision to publish, or preparation of the manuscript.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Cao, Y., Li, Z., Jiang, W. et al. Reproductive functions of Kisspeptin/KISS1R Systems in the Periphery. Reprod Biol Endocrinol 17, 65 (2019). https://doi.org/10.1186/s12958-019-0511-x