REPRODUCTION

REVIEW

A role for kisspeptins in pregnancy: facts and speculations

Rebecca M Reynolds1, James J Logie2, Antonia K Roseweir3, Angus J McKnight2
and Robert P Millar3,4
1
Endocrinology Unit, Centre for Cardiovascular Sciences, 2Jennifer Brown Research Laboratory and 3MRC Human
Reproductive Sciences Unit, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent,
Edinburgh EH16 4TJ, UK and 4Receptor Biology Group, Division of Medical Biochemistry, University of Cape Town,
Cape Town 7925, South Africa
Correspondence should be addressed to R M Reynolds; Email: [email protected]

Abstract
Kisspeptin is a neuropeptide that was originally discovered in 1996 from a metastasis tumour suppressor gene, KISS1 and was
appropriately named metastin. More recently, the discovery of inactivating mutations in the receptor for kisspeptin, a G protein-coupled
receptor, GPR54 (KISS1R), have been shown to result in a failure to progress through puberty in man. These findings have led to the
kisspeptin/KISS1R system being described as an essential gatekeeper of reproductive function. Recent studies have suggested additional
roles of kisspeptin, other than in the central control of the gonadotropic axis including placentation and pregnancy, energy
homeostasis and cardiovascular function. Therefore, kisspeptin–KISS1R signalling potentially plays diverse roles in human physiology.
Here, we review the literature regarding the role and physiological significance of kisspeptin in pregnancy and highlight some of the key
questions that require addressing.
Reproduction (2009) 138 1–7

Introduction Kisspeptins and KISS1R

Kisspeptin is a neuropeptide that was originally Discovery and nomenclature
discovered in 1996 from a metastasis tumour suppres-
Kisspeptins comprise a family of peptides derived from
sor gene, KISS1 (Lee et al. 1996) and was appropriately the primary translation product of the KISS1 gene,
named metastin. More recently, the discovery of localized to chromosome 1, which were identified
inactivating mutations in the receptor for kisspeptin, a more than a decade ago (Lee et al. 1996). These
G-protein-coupled receptor, KISS1R, have been shown peptides were discovered as the result of a systematic
to result in a failure to progress through puberty in man bioinformatics search for processed peptides encoded
(de Roux et al. 2003, Seminara et al. 2003, Lanfranco by the human genome (Ohtaki et al. 2001), and
et al. 2005, Semple et al. 2005). These findings have simultaneously by the isolation of a biological activity
led to the kisspeptin/KISS1R system being described as from human placenta and its identification by mass
an essential gatekeeper of reproductive function spectrometry (Kotani et al. 2001). Proteolytic proces-
(Seminara et al. 2003). Recent studies have suggested sing of the full-length 145 amino acid kisspeptin
additional roles of kisspeptin, other than in the central protein results in shorter fragments of the carboxyl
control of the gonadotrophic axis including placentation (C)-terminus region of the molecule with 54 (KP-54;
and pregnancy, energy homeostasis and cardio- previously designated metastin), 14 (KP14), 13 (KP-13)
vascular function (Bilban et al. 2004, Tena-Sempere or 10 (KP-10) amino acids (Kotani et al. 2001, Ohtaki
2006, Crown et al. 2007, Hiden et al. 2007, Mead et al. 2001). Initially, the largest cleavage product,
et al. 2007b). Therefore, kisspeptin–KISS1R signalling KP-54 was identified for its ability to suppress
potentially plays diverse roles in human physiology. the metastatic potential of malignant melanoma cells
Here, we review the literature regarding the role and (Lee et al. 1996, Lee & Welch 1997) and it was
physiological significance of kisspeptin in pregnancy therefore termed ‘metastin’ (Ohtaki et al. 2001).
and highlight some of the key questions that require Interestingly, the naming of the gene KISS1 and its
addressing. product, kisspeptin (aka metastin), was made by the
q 2009 Society for Reproduction and Fertility DOI: 10.1530/REP-09-0026
ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org
2 R M Reynolds and others

team of scientists who discovered the gene in the town Finally, it has been suggested that kisspeptin may
of Hershey, Pennsylvania, famous for its chocolate suppress metastasis by induction of apoptosis in cells
‘kisses’, with inclusion of the terminology ‘SS’ also since metastatic spread is dependent on cell growth
indicating a suppressor sequence. The term ‘kisspep- (Harms et al. 2003), but there have been conflicting
tins’ is now widely employed to collectively describe reports in the literature. Culturing recombinant CHO
this family of peptides that show an Arg–Phe–NH2 cells with 1 mM KP-10 resulted in a strong anti-
motif at the C-terminus, characteristic of the extensive proliferative effect, while no evidence of apoptosis
RF-amide peptide superfamily (Roa et al. 2008). was detected (concentration used not disclosed; Kotani
et al. 2001). By contrast, in a more recent study using
human mammary carcinoma cells and a cDNA
Intracellular signalling microarray, stimulation of KISS1R by 500 nM KP-10
The mechanism(s) of action of kisspeptins are only caused upregulation of several genes involved in cell
partially elaborated. Kisspeptins are endogenous ligands cycle progression (including CDKN1A, GADD45A,
for a G-protein-coupled receptor named GPR54 (in rat), GADD45B, and HIF1A-responsive DDIT4), cell cycle
hOT7T175, AXOR12 (the human homologues), or arrest and apoptosis (Becker et al. 2005).
alternatively, KISS1R (Lee et al. 1999, Muir et al.
2001). KISS1R was originally cloned from rat brain Tissue distribution
tissue as an orphan receptor with a sequence similar
(28–39% protein homology) to the galanin receptors Tissue distribution of KISS1R and KISS1 often coincides.
(Lee et al. 1999) although it is unresponsive to galanin Distribution has been best described in the rodent
ligands. In 2001, kisspeptins were shown to be the where expression of both receptor and ligand are the
endogenous ligands for KISS1R (Kotani et al. 2001, Muir highest in placenta, with additional wide distribution
et al. 2001, Ohtaki et al. 2001). All kisspeptins are able throughout the CN (the highest levels in hypothalamus
to bind KISS1R, with KP-10 having maximal activity at and pituitary but also in cerebellum, cortex and
the receptor level (Kotani et al. 2001). Indeed, KP-10 is brainstem; Lee et al. 1996, Kotani et al. 2001, Muir
et al. 2001). There are also some reports of variable
highly conserved between human, sheep, mouse and rat,
expression in rodent adipose tissue, pancreas, liver,
with only one amino acid difference in the sequence
small intestine, peripheral blood lymphocytes, testes,
between species. The major intracellular signalling
lymph nodes, and in human aorta, coronary artery and
system recruited by KISS1R is the Gq pathway, which
umbilical vein, although the cellular distribution is not
activates phospholipase C to hydrolyse phosphatidyl-
always well described (Muir et al. 2001, Ohtaki et al.
inositol bisphosphate to inositol trisphosphate and diacyl
2001, Hauge-Evans et al. 2006, Mead et al. 2007a).
glycerol, which mobilize intracellular Ca2C mobili-
Moreover, the specificity of antiserum used in some of
zation and activate protein kinase C respectively (Muir these studies has yet to be fully confirmed. This is
et al. 2001, Becker et al. 2005). This subsequently causes crucial in view of the large number of peptides with the
downstream activation of MAPK3/1 and MAPK14 MAP RF.NH2 motif at their carboxyl termini. The cellular
kinases in a variety of cell types including KISS1R- distribution in the placenta will be described in more
transfected Chinese hamster ovary (CHO) cells (Kotani detail below.
et al. 2001) and trophoblast cells (Bilban et al. 2004,
Castellano et al. 2006).
Kisspeptin has also been shown to signal to a variety of Kisspeptin and reproduction
factors involved in cell migration, which have been
hypothesized to be important in both trophoblast and Puberty
metastasis inhibition. For example, kisspeptin can The connection between the kisspeptin/KISS1R system
induce focal adhesion and stress fibre formation (Kotani and pubertal development was revealed in 2003 when
et al. 2001, Ohtaki et al. 2001). Kisspeptin can also two groups independently reported the presence of
phosphorylate focal adhesion kinase and paxillin, the inactivating mutations of KISS1R in patients with
intracellular signals needed for these events, which hypogonadotrophic hypogonadism (de Roux et al. 2003,
may associate with integrins to inhibit migration (Ohtaki Seminara et al. 2003), a condition characterized by the
et al. 2001). Kisspeptin has also been shown to diminish absence of sexual maturation and decreased levels of sex
matrix metalloprotease (MMP)9 expression by reduced hormones and gonadotrophins. Numerous and extensive
NFKB binding to the MMP9 promoter, to cause an studies provide cogent arguments for a crucial role for
inhibition of cell migration (Yan et al. 2001). This may kisspeptin in development, puberty and adult function of
also prove to be important in placentation but additional the hypothalamic–pituitary–gonadal axis (see reviews by
work will be necessary to determine which factors Colledge 2004, Crown et al. 2007, Roa et al. 2008). The
are involved in the activation of the NFKB pathway link between kisspeptin activation and onset of puberty
by KISS1R. was confirmed following the description of the
Reproduction (2009) 138 1–7 www.reproduction-online.org
 Kisspeptin and pregnancy 3

phenotype of Kiss1r-knockout mice which closely gestational trophoblastic neoplasia and fall during and
paralleled that of human hypogonadotrophic hypogo- after treatment with chemotherapy (Dhillo et al. 2006).
nadism (Funes et al. 2003, Seminara et al. 2003). Mice The circulating levels of kisspeptin are considerably
lacking the KISS1R receptor failed to undergo puberty higher than the levels of kisspeptin achieved after
and mutant males were sterile with very small genitalia exogenous administration, which have been shown to
and lacked secondary sexual characteristics (Funes et al. potently stimulate LH (Dhillo et al. 2006). However, LH
2003, Seminara et al. 2003). Similarly, mutant female is not elevated in pregnancy. There are several possible
mice also failed to undergo sexual maturation; the explanations for this apparent discrepancy. For example,
uterine horns from mutants were thread-like and the KISS1R receptor in GNRH1 neurons may be
the ovaries significantly smaller than normal. In addition, desensitized as has been demonstrated in rhesus
the ovaries contained primary and secondary follicles but monkeys (Plant & Ramaswamy 2009). Alternatively,
large antral (Graafian) follicles or corpora lutea were other factors in pregnancy such as elevated progesterone
never found. The phenotype of Kiss1r-null mice was prevent the GNRH1 neurone from responding to
consistent with a lack of sex steroid production and kisspeptin. In addition, there may be species differences
serum testosterone and oestradiol levels were lower than in responses, as for example, in the rodent, despite
normal in these animals (Seminara et al. 2003). It has also suppression of LH levels during pregnancy, LH responses
been reported that mice lacking the Kiss1 gene exhibited to high (1 nmol) doses of kisspeptin were preserved
abnormal timing of puberty (d’Anglemont de Tassigny during gestation (Roa et al. 2006). Moreover, significant
et al. 2007, Lapatto et al. 2007), although their LH responses were observed after central injection of
reproductive phenotypes were not as severe as the doses as low as 0.1 pmol, suggesting preserved (if not
Kiss1r-knockout mice. These animals also have impaired enhanced) sensitivity to kisspeptin during gestation (Roa
sexual maturation, low gonadotrophin levels and et al. 2006). Finally, it remains possible that the
abnormal gametogenesis, but the phenotype of Kiss1- kisspeptin immunoreactivity measured in pregnancy
knockout mice appears to be more variable, with some plasma is not in fact kisspeptin but a cross-reacting
animals being less severely affected, and indeed, some peptide/s. Thus, the physiological role of circulating
females having larger gonadal weight and persistent kisspeptin during pregnancy remains uncertain.
vaginal cornification (Lapatto et al. 2007). This may Kisspeptin has a prime location at the foeto-maternal
suggest different thresholds for sexual maturation or that interface, being abundant in the syncytiotrophoblast of
other RF.NH2 peptides may be able to substitute for the both normal human placenta (Bilban et al. 2004) and
kisspeptins. in molar pregnancies (Janneau et al. 2002). The outer
In support of a role for kisspeptin as a gatekeeper of syncytiotrophoblasts lie adjacent to blood vessels
puberty, a gain-of-function mutation that activates allowing easy passage of kisspeptin into the maternal
KISS1R signalling has recently been described in an blood (Fig. 1). KISS1R has been identified in both the
8-year old girl who presented with idiopathic central villous and invasive extravillous human cytotrophoblasts
precocious (premature) puberty (Teles et al. 2008). (Janneau et al. 2002, Bilban et al. 2004). Intriguingly,
In vitro studies demonstrated that the substitution of levels of expression of both KISS1 and KISS1R mRNA are
proline for arginine at amino acid 386 (Arg386Pro) leads higher in first trimester placentae than in term placentae
to prolonged activation of intracellular signalling (Bilban et al. 2004), apparently contrasting with higher
pathways in response to kisspeptin (Teles et al. 2008). circulating kisspeptin levels reported during pregnancy
Consequently, KISS1R agonists have therapeutic (Horikoshi et al. 2003). Although the human and rat
potential in initiating puberty in cases of pubertal delay differ in regard to length of gestation and placental
and kisspeptin antagonists or desensitization with structure, the spatial and temporal expression of KISS1
agonists may find application in precocious puberty. and KISS1R are similar. KISS1 mRNA is expressed in the
trophoblast giant cells of the rodent placenta (Terao et al.
2004), which are responsible for early invasion as they
Pregnancy and placenta
invade the spiral arteries and replace the endovascu-
Circulating kisspeptin levels are low in males and non- lature. These cells are thus considered as having the
pregnant females (!2 pmol/l) but dramatically increase same functional phenotype as the human extravillous
in pregnancy (Horikoshi et al. 2003). In the first reported trophoblasts. As in the human, levels of KISS1 and
study of 10 pregnant women and 12 non-pregnant its receptor gradually decline during placental
controls, kisspeptin levels increased by 940-fold in the maturation and are not detectable at embryonic (e) day
first trimester and further increased to some w7000-fold 18.5 (Terao et al. 2004).
higher in the third trimester. Circulating kisspeptin levels The finding of the highest expression levels of KISS1
fell again 5 days post delivery to comparable concen- and KISS1R mRNAs in trophoblast cells during the first
trations prior to pregnancy, implicating a placental trimester in humans and at e12.5 in rodents coincides
source of the peptide. In support of a placental origin, with the time of peak trophoblast invasion when
plasma kisspeptin levels are increased in patients with regulation of this process is of critical importance.
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4 R M Reynolds and others

Figure 1 Schematic demonstrating trophoblast

invasion of the maternal blood vessels. Location
of kisspeptin and its receptor at the foeto-maternal
interface. Figure demonstrates outer syncytiotro-
phoblasts (ST) lying adjacent to blood vessels
allowing easy passage of kisspeptin into maternal
blood. KISS1 is expressed in ST (Bilban et al.
2004), while both KISS1 and KISS1R have been
identified in both villous and invasive cytotro-
phoblasts (CT). EC, endothelial cell; SMC, smooth
muscle cell.

In vitro, KP10 inhibits the migration and invasion of Cellular and molecular mechanisms of kisspeptin
trophoblast cells (Bilban et al. 2004) and thus it is actions in the placenta
postulated that kisspeptin plays a key role in restraining
The mechanisms by which kisspeptin may regulate
trophoblast invasion and regulating implantation and
invasion of the trophoblast into the decidua have not
subsequent development. To investigate this hypothesis,
been studied in detail (Bilban et al. 2004) but are
circulating levels of kisspeptin have been measured in
likely to involve processes that are emerging in other
plasma and serum from women with pregnancies
tissues, such as in tumour biology. For example,
associated with poor placentation. A recent study on a
kisspeptin has been shown to inhibit MMP expression
small number of subjects has reported that circulating
and activity in vitro (Yan et al. 2001, Yoshioka et al.
levels of kisspeptin measured early in pregnancy
2008), and MMPs are critically involved in events
(between 8 and 14 weeks gestation) were lower in
taking place at the cell–extracellular membrane
women who later had small for gestational age neonates
interface such as cell division, migration and
(Smets et al. 2008). Likewise, lower kisspeptin levels
were found in early second trimester (w16-week morphogenesis and ultimately regulate cell behaviour
gestation) serum samples from women who sub- (Mott & Werb 2004). There are striking similarities
sequently developed pre-eclampsia and/or delivered between the behaviour of invasive placental cells
offspring with intrauterine growth retardation and of invasive cancer cells. Angiogenesis, the
(RA Armstrong, RM Reynolds, R Leask, CH Shearing, formation of new blood vessels from pre-existing
AA Calder & SC Riley, 2008, personal communication). vascular beds, is a common feature of both
These findings appear to be contrary to a role of implantation and cancer spread (Murray & Lessey
kisspeptin in inhibiting invasion. One hypothesis to 1999) and is of vital importance in establishing the
explain the findings of lower circulating kisspeptin levels placenta. Kisspeptin and KISS1R expression have
in these pregnancies, where reduced invasive capacity been reported in human aorta, coronary artery and
would be expected, is that low expression of kisspeptin umbilical vein and kisspeptin acts as a vasoconstric-
within the placenta signals low invasive capacity (Smets tor (a crucial phase in angiogenesis) in isolated
et al. 2008). Alternatively, development of smaller, less coronary arteries (Mead et al. 2007a), suggesting a
invasive placentas occur first and these produce less role in the vascular system. A potential angiostatic
kisspeptin. However, another study reported higher effect of kisspeptin may also explain, at least in part,
KISS1 mRNA and protein, in association lower MMP9 the anti-metastatic potential of this peptide given that
mRNA and protein expression in trophoblasts from angiogenesis is intimately involved in this process.
women with pre-eclampsia compared with controls Indeed, a very recent gene expression profiling study
and an inverse correlation of KISS1 mRNA expression has emerged to support this hypothesis. In metastatic
levels with birth weight (Qiao et al. 2005; Fig. 2). To brain tumours, there was upregulation of genes
date, all data regarding circulating kisspeptin, KISS1 involved in angiogenesis (vascular endothelial growth
expression and pre-eclampsia are correlative and so factor and placental growth factor), cell adhesion and
whether altered kisspeptin levels are a cause or migration (including integrins, and extracellular
consequence of the disease cannot be determined from matrices collagen and laminin) and marked
these studies. A possible role for kisspeptin in the downregulation of genes involved in apoptosis,
prevention of ectopic pregnancy has also been specu- neuroprotection and suppression of angiogenesis
lated upon following the finding of Kiss1 mRNA in (including KISS1; Zohrabian et al. 2007). Detailed
mouse fallopian tube (Gaytan et al. 2007), and a in vitro and in vivo studies to investigate the
potential role in parturition suggested (Torricelli et al. potential angiostatic effects and to determine the
2008), but clearly more studies are required to test these molecular mechanisms underpinning such effects of
hypotheses. kisspeptin are required.

Reproduction (2009) 138 1–7 www.reproduction-online.org

 Kisspeptin and pregnancy 5

Figure 2 Expression of KISS1 and MMP9 mRNA

in trophoblasts from patients with pre-eclampsia
and uncomplicated term pregnancies. mRNA
and protein measured by RT-PCR and western
blot analyses in trophoblasts from 40 patients
with pre-eclampsia (mild (nZ15); severe
(nZ25) and 20 cases of term pregnancy
(normal)). Figure demonstrates higher KISS1
mRNA and protein, in association lower MMP9
mRNA and protein expression in trophoblasts
from women with pre-eclampsia. *P!0.01
compared with control. Data redrawn from
Qiao et al. (2005).

Facts and speculation (as suggested by an earlier study in rodents whereby

oxytocin production was stimulated by kisspeptin
Interestingly, species-specific differences may exist in the
administration (Kotani et al. 2001)). In addition, the
importance of the kisspeptin/KISS1R system because, in
ability of the patient with a KISS1R mutation to
Kiss1r-knockout mice, males and females were incap-
able of reproducing when paired with fertile littermates breastfeed suggests that KISS1R is not critical for
(Funes et al. 2003) whereas successful pregnancies have lactation (Pallais et al. 2006). Other putative, but little
been reported in human females carrying a KISS1R tested, roles for kisspeptin in pregnancy have included a
mutation (Seminara et al. 2003). Of note, the knockout role in aldosterone production and fluid balance
mice have null mutations whereas human mutations are (Nakamura et al. 2007). Kisspeptin is also thought to
mainly non-sense mutations. Indeed, the physiological have a central role in the metabolic regulation of
relevance of kisspeptin actions in human placental reproductive function (Tena-Sempere 2006). Mounting
function is challenged by a lack of gross abnormalities evidence now supports the hypothesis that peripheral,
in placental formation and/or function in humans and adipocyte-derived leptin modulates the functioning of
mice carrying null mutations in the Kiss1r gene the reproductive axis, at least in part, via regulation of
(Seminara et al. 2003, Pallais et al. 2006). Nevertheless, the kisspeptin/KISS1R system. To date, this role for
this does not exclude a role for kisspeptin in the fine kisspeptin has principally been explored in relation to
tuning of aspects of placental function and physiology. puberty but it may also be important in metabolic
A potential role that KISS1R activation may have in regulation during pregnancy. Finally, whether kisspeptin
regulating maternal physiology during pregnancy and functions to downregulate the hypothalamic–pituitary–
the postpartum period was provided by evaluating gonadal axis in human pregnancy is not known.
pregnancy outcomes in a female patient bearing the Measurements of circulating kisspeptin levels during
homozygote leucine to serine mutation at amino acid pregnancy should be interpreted with caution. In the
148 (L148S) within the third intracellular loop of KISS1R published studies of kisspeptin in pregnancy, there are
(Pallais et al. 2006). All patients carrying homozygous or significantly different concentrations of circulating
compound heterozygous mutations in Kiss1r are living kisspeptin (Horikoshi et al. 2003, Dhillo et al. 2006)
proof of their ability to establish functioning placentas reported, which may, in part, be attributable to
during early gestation. A female homozygote for L148S differences in pre-analytical variables, such as collection
had a normal vaginal delivery of a healthy child of a tube type, processing times, and storage conditions
normal birth weight, after induction of ovulation, (Ramachandran et al. 2008), but may also reflect
demonstrating that KISS1R signalling in the mother is problems and/or lack of specificity of different assays
not critical for placental function and uterine contraction used. For example, of the published data in human
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6 R M Reynolds and others

pregnancy, the assays used include an in-house two-site Funding

enzyme immunoassay in which the authors confirmed
J J L was a Jennifer Brown/PiggyBankKids research fellow; A M
the presence of metastin immunoreactivity by detection was supported by a Jennifer Brown/PiggyBankKids summer
of a single peak for metastin on reverse phase HPLC studentship. A R and R P M were supported by grants from the
(Horikoshi et al. 2003). Others have used RIAs although Medical Research Council.
the antibodies and methods used differ including both an
in-house assay (antibody sourced from Bachem, UK,
Merseyside, UK; Dhillo et al. 2006) and a commercially Acknowledgements
available RIA from Phoenix Pharmaceuticals, Inc.
(Blemont, CA, USA; Smets et al. 2008). To date, there We thank Dr P Hadoke for his helpful comments on the
are no studies reporting levels of kisspeptin in rodent, or manuscript.
other species, pregnancies. Indeed, most of the data
gathered on kisspeptin and placental function are based
on correlations of changes in gene expression during References
pregnancy and immunocytochemical and immunoassay
Becker JA, Mirjolet JF, Bernard J, Burgeon E, Simons MJ, Vassart G,
of undefined specificity. The conclusions that kisspeptin/ Parmentier M & Libert F 2005 Activation of GPR54 promotes cell cycle
KISS1R may not play a significant role in implantation arrest and apoptosis of human tumor cells through a specific
and pregnancy derive from successful pregnancy after transcriptional program not shared by other Gq-coupled receptors.
induction of ovulation in women with KISS1R mutations. Biochemical and Biophysical Research Communications 326 677–686.
Bilban M, Ghaffari-Tabrizi N, Hintermann E, Bauer S, Molzer S, Zoratti C,
However, since kisspeptin is proposed to have a Malli R, Sharabi A, Hiden U, Graier W et al. 2004 Kisspeptin-10, a KiSS-
restraining influence on excessive or premature implan- 1/metastin-derived decapeptide, is a physiological invasion inhibitor of
tation, the phenotype may not be obvious and excessive primary human trophoblasts. Journal of Cell Science 117 1319–1328.
Castellano JM, Navarro VM, Fernandez-Fernandez R, Castano JP,
kisspeptin may be more likely to cause a clear
Malagon MM, Aguilar E, Dieguez C, Magni P, Pinilla L &
pathological phenotype. Tena-Sempere M 2006 Ontogeny and mechanisms of action for the
stimulatory effect of kisspeptin on gonadotropin-releasing hormone
system of the rat. Molecular and Cellular Endocrinology 257–258 75–83.
Colledge WH 2004 GPR54 and puberty. Trends in Endocrinology and
Conclusions Metabolism 15 448–453.
Crown A, Clifton DK & Steiner RA 2007 Neuropeptide signaling in the
Since the discovery of kisspeptin in 1996, there has been integration of metabolism and reproduction. Neuroendocrinology 86
175–182.
a rapidly developing field unravelling the potential d’Anglemont de Tassigny X, Fagg LA, Dixon JP, Day K, Leitch HG,
physiological roles of this peptide. There remain many Hendrick AG, Zahn D, Franceschini I, Caraty A, Carlton MB et al. 2007
unanswered questions concerning its function in Hypogonadotropic hypogonadism in mice lacking a functional Kiss1
pregnancy. Kisspeptins do appear to be regulators of gene. PNAS 104 10714–10719.
Dhillo WS, Savage P, Murphy KG, Chaudhri OB, Patterson M, Nijher GM,
invasion both in pathological conditions (tumours) and Foggo VM, Dancey GS, Mitchell H, Seckl MJ et al. 2006
also in physiological situations including trophoblast Plasma kisspeptin is raised in patients with gestational trophoblastic
invasion in pregnancy. However, the significance of the neoplasia and falls during treatment. American Journal of Physiology.
Endocrinology and Metabolism 291 E878–E884.
dramatic rise in circulating levels of kisspeptin during Funes S, Hedrick JA, Vassileva G, Markowitz L, Abbondanzo S, Golovko A,
pregnancy remains unknown (Horikoshi et al. 2003). Yang S, Monsma FJ & Gustafson EL 2003 The KiSS-1 receptor GPR54
It has been suggested that measurement of circulating is essential for the development of the murine reproductive system.
levels may be useful as a marker for gestational Biochemical and Biophysical Research Communications 312
1357–1363.
trophoblastic neoplasia (Dhillo et al. 2006). Further Gaytan M, Castellano JM, Roa J, Sanchez-Criado JE, Tena-Sempere M &
studies are also required to see whether kisspeptin levels Gaytan F 2007 Expression of KiSS-1 in rat oviduct: possible involvement
measured in pregnancy may be useful as a marker in prevention of ectopic implantation? Cell and Tissue Research 329
for predicting pregnancies associated with poor 571–579.
Harms JF, Welch DR & Miele ME 2003 KISS1 metastasis suppression and
placentation such as intrauterine growth retardation or emergent pathways. Clinical & Experimental Metastasis 20 11–18.
pre-eclampsia. The potential role of kisspeptin in reg- Hauge-Evans AC, Richardson CC, Milne HM, Christie MR, Persaud SJ &
ulating angiogenesis is exciting and may have Jones PM 2006 A role for kisspeptin in islet function. Diabetologia 49
2131–2135.
important implications for physiological processes Hiden U, Bilban M, Knöfler M & Desoye G 2007 Kisspeptins and the
requiring tightly regulated angiogenesis including men- placenta:regulation of trophoblast invasion. Reviews in Endocrine and
struation and pregnancy. Metabolic Disorders 8 31–39.
Horikoshi Y, Matsumoto H, Takatsu Y, Ohtaki T, Kitada C, Usuki S &
Fujino M 2003 Dramatic elevation of plasma metastin concentrations in
human pregnancy: metastin as a novel placenta-derived hormone in
humans. Journal of Clinical Endocrinology and Metabolism 88 914–919.
Declaration of interest Janneau JL, Maldonado-Estrada J, Tachdjian G, Miran I, Motte N,
Saulnier P, Sabourin JC, Cote JF, Simon B, Frydman R et al. 2002
The authors declare that there is no conflict of interest Transcriptional expression of genes involved in cell invasion and
that could be perceived as prejudicing the impartiality of migration by normal and tumoral trophoblast cells. Journal of Clinical
this review. Endocrinology and Metabolism 87 5336–5339.

Reproduction (2009) 138 1–7 www.reproduction-online.org

 Kisspeptin and pregnancy 7

Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Ramachandran R, Patterson M, Murphy KG, Dhillo WS, Patel S,
Le PE, Brezillon S, Tyldesley R, Suarez-Huerta N, Vandeput F et al. 2001 Kazarian A, Ghatei MA & Bloom SR 2008 Preanalytical factors affecting
The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural RIA measurement of plasma kisspeptin. Clinical Chemistry 54 615–617.
ligands of the orphan G protein-coupled receptor GPR54. Journal of Roa J, Vigo J, Castellano JM, Navarro VM, Fernández-Fernández R,
Biological Chemistry 276 34631–34636. Casanueva FF, Dieguez C, Aguilar E, Pinilla L & Tena-Sempere M 2006
Lanfranco F, Gromoll J, von ES, Herding EM, Nieschlag E & Simoni M 2005 Hypothalamic expression of KiSS-1 system and gonadotropin-releasing
Role of sequence variations of the GnRH receptor and G protein-coupled effects of kisspeptin in different reproductive states of the female rat.
receptor 54 gene in male idiopathic hypogonadotropic hypogonadism. Endocrinology 147 2864–2878.
European Journal of Endocrinology 153 845–852. Roa J, Aguilar E, Dieguez C, Pinilla L & Tena-Sempere M 2008 New
Lapatto R, Pallais JC, Zhang D, Chan YM, Mahan A, Cerrato F, Le WW, frontiers in kisspeptin/GPR54 physiology as fundamental gatekeepers of
Hoffman GE & Seminara SB 2007 Kiss1K/K mice exhibit more variable reproductive function. Frontiers in Neuroendocrinology 29 48–69.
hypogonadism than Gpr54K/K mice. Endocrinology 148 4927–4936. de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL & Milgrom E 2003
Lee JH & Welch DR 1997 Suppression of metastasis in human breast Hypogonadotropic hypogonadism due to loss of function of the KiSS1-
carcinoma MDA-MB-435 cells after transfection with the metastasis derived peptide receptor GPR54. PNAS 100 10972–10976.
suppressor gene, KiSS-1. Cancer Research 57 2384–2387. Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr,
Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE & Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG et al.
Welch DR 1996 KiSS-1, a novel human malignant melanoma metastasis- 2003 The GPR54 gene as a regulator of puberty. New England Journal of
suppressor gene. Journal of the National Cancer Institute 88 1731–1737. Medicine 349 1614–1627.
Lee DK, Nguyen T, O’Neill GP, Cheng R, Liu Y, Howard AD, Coulombe N, Semple RK, Achermann JC, Ellery J, Farooqi IS, Karet FE, Stanhope RG,
Tan CP, Tang-Nguyen AT, George SR et al. 1999 Discovery of a receptor O’Rahilly S & Aparicio SA 2005 Two novel missense mutations in g
related to the galanin receptors. FEBS Letters 446 103–107. protein-coupled receptor 54 in a patient with hypogonadotropic
Mead EJ, Maguire JJ, Kuc RE & Davenport AP 2007a Kisspeptins are novel hypogonadism. Journal of Clinical Endocrinology and Metabolism 90
potent vasoconstrictors in humans, with a discrete localization of their 1849–1855.
receptor, G protein-coupled receptor 54, to atherosclerosis-prone Smets EM, Deurloo KL, Go AT, van Vugt JM, Blankenstein MA &
vessels. Endocrinology 148 140–147. Oudejans CB 2008 Decreased plasma levels of metastin in early
Mead EJ, Maguire JJ, Kuc RE & Davenport AP 2007b Kisspeptins: a pregnancy are associated with small for gestational age neonates.
multifunctional peptide system with a role in reproduction, cancer and Prenatal Diagnosis 28 299–303.
the cardiovascular system. British Journal of Pharmacology 151 Teles MG, Bianco SD, Brito VN, Trarbach EB, Kuohung W, Xu S,
1143–1153. Seminara SB, Mendonca BB, Kaiser UB & Latronico AC 2008
Mott JD & Werb Z 2004 Regulation of matrix biology by matrix A GPR54-activating mutation in a patient with central precocious
metalloproteinases. Current Opinion in Cell Biology 16 558–564. puberty. New England Journal of Medicine 358 709–715.
Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Tena-Sempere M 2006 KiSS-1 and reproduction: focus on its role in the
metabolic regulation of fertility. Neuroendocrinology 83 275–281.
Calamari A, Szekeres PG, Sarau HM, Chambers JK, Murdock P et al.
Terao Y, Kumano S, Takatsu Y, Hattori M, Nishimura A, Ohtaki T &
2001 AXOR12, a novel human G protein-coupled receptor, activated by
Shintani Y 2004 Expression of KiSS-1, a metastasis suppressor gene, in
the peptide KiSS-1. Journal of Biological Chemistry 276 28969–28975.
trophoblast giant cells of the rat placenta. Biochimica et Biophysica Acta
Murray MJ & Lessey BA 1999 Embryo implantation and tumor metastasis:
1678 102–110.
common pathways of invasion and angiogenesis. Seminars in
Torricelli M, Galleri L, Voltolini C, Biliotti G, Florio P, De BM & Petraglia F
Reproductive Endocrinology 17 275–290.
2008 Changes of placental Kiss-1 mRNA expression and maternal/cord
Nakamura Y, Aoki S, Xing Y, Sasano H & Rainey WE 2007 Metastin
kisspeptin levels at preterm delivery. Reproductive Sciences 15 779–784.
stimulates aldosterone synthesis in human adrenal cells. Reproductive
Yan C, Wang H & Boyd DD 2001 KiSS-1 represses 92-kDa type IV
Sciences 14 836–845.
collagenase expression by down-regulating NF-kappa B binding to the
Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y,
promoter as a consequence of Ikappa Balpha -induced block of p65/p50
Kumano S, Takatsu Y, Masuda Y et al. 2001 Metastasis suppressor gene
nuclear translocation. Journal of Biological Chemistry 276 1164–1172.
KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature
Yoshioka K, Ohno Y, Horiguchi Y, Ozu C, Namiki K & Tachibana M 2008
411 613–617. Effects of a KiSS-1 peptide, a metastasis suppressor gene, on the invasive
Pallais JC, Bo-Abbas Y, Pitteloud N, Crowley WF Jr & Seminara SB 2006 ability of renal cell carcinoma cells through a modulation of a matrix
Neuroendocrine, gonadal, placental, and obstetric phenotypes in metalloproteinase 2 expression. Life Sciences 83 332–338.
patients with IHH and mutations in the G-protein coupled receptor, Zohrabian VM, Nandu H, Gulati N, Khitrov G, Zhao C, Mohan A,
GPR54. Molecular and Cellular Endocrinology 254–255 70–77. Demattia J, Braun A, Das K, Murali R et al. 2007 Gene expression
Plant TM & Ramaswamy S 2009 Kisspeptin and the regulation of the profiling of metastatic brain cancer. Oncology Reports 18 321–328.
hypothalamic–pituitary–gonadal axis in the rhesus monkey (Macaca
mulatta). Peptides 30 67–75.
Qiao C, Wang CH, Shang T & Lin QD 2005 Clinical significance of KiSS-1
Received 27 January 2009
and matrix metalloproteinase-9 expression in trophoblasts of women
with preeclampsia and their relation to perinatal outcome of neonates. First decision 2 March 2009
Zhonghua Fu Chan Ke Za Zhi 40 585–590. Accepted 31 March 2009

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