Cao et al.

Reproductive Biology and Endocrinology (2019) 17:65

https://doi.org/10.1186/s12958-019-0511-x

REVIEW Open Access

Reproductive functions of Kisspeptin/

KISS1R Systems in the Periphery
Yubin Cao1,2, Zeping Li1,2, Wenyu Jiang1,2, Yan Ling3 and Haibin Kuang1,4*

Abstract
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.
Keywords: Kisspeptin, KISS1R, Ovary, Testis, Uterus, Placenta

Introduction KISS1R in peripheral reproductive tissues led us to

Different species have evolved various survival strategies, hypothesize that kisspeptin signalling is involved in the
but reproduction is an indispensable function of all spe- local regulation of reproduction within these tissues [4–6].
cies permanence. Reproductive function is driven by a In particular, three recent reviews have discussed the role
complex neuro-hormonal system, with considerable con- of KISS/KISSR signalling in the ovary, the reproductive
tribution by the hypothalamic-pituitary-gonadal (HPG) axis, implantation and placentation [7–9]. In this review,
axis. The HPG axis is divided into three main levels with we focus on the local expression and regulation of kis-
the following regulatory signals: 1) hypothalamus: go- speptin and its receptor KISS1R in the peripheral repro-
nadotropin-releasing hormone (GnRH); 2) pituitary: go- ductive system, including in the ovary, testis, uterus, and
nadotropin, luteinizing hormone (LH) and follicle- placenta, and highlight the potential role of kisspeptin/
stimulating hormone (FSH); and 3) gonads: sex steroids KISS1R in reproductive diseases.
and peptides [1]. 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 The role of kisspeptin in pubertal onset
and signalling molecules directly or indirectly converge Kisspeptin is an Arg-Phe-NH2 (RF-amide) peptide
on the GnRH neuron network [2]. Many regulators of encoded by the KISS1 gene [10]. The KISS1 gene was
GnRH neurons act through G protein-coupled receptors named after Hershey’s chocolate kisses because it was
(GPCRs). KISS1R is one of the most important GPCRs initially isolated from human non-metastatic pigment
in the neuroendocrine control of reproductive function, tumours in Hershey (Pennsylvania, USA), and the “SS”
and its ligand kisspeptin has a significant effect on the represents “suppressor sequence” [11]. In humans, the
hypothalamus [3]. However, the expression of KISS1 and 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
* Correspondence: [email protected]
1
Department of Physiology, Basic Medical College, Nanchang University, of 54, 14, 13 and 10 amino acids, respectively. These
Nanchang, Jiangxi 330006, People’s Republic of China forms all share a common C-terminal decapeptide (KP-
4
Jiangxi Provincial Key Laboratory of Reproductive Physiology and Pathology, 10), which is required for binding with its receptor
Medical Experimental Teaching Center, Nanchang University, Nanchang,
Jiangxi 330006, People’s Republic of China KISS1R (also known as GPR54) [12]. In humans,
Full list of author information is available at the end of the article kisspeptin is synthesized in two major sections of the
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
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Cao et al. Reproductive Biology and Endocrinology (2019) 17:65 Page 2 of 9

hypothalamus: the arcuate nucleus and the anterior kisspeptin in the ovary has significant temporal and
ventral periventricular nucleus [13]. The binding of spatial specificity, suggesting that the kisspeptin/
kisspeptin to KISS1R activates the phospholipase C KISS1R system performs multiple functions at differ-
pathway in hypothalamic cells, leading to changes in ent physiological stages in the ovary.
cellular activity [14]. Current evidence suggests that the
kisspeptin signalling pathway is essential for the onset of The role in follicular development
mammalian puberty. Loss of KISS1R function causes hu- The expression of ovarian Kiss1 mRNA gradually
man hypogonadotropic hypogonadism (HH), and one increases from infancy to adolescence [28]. The imma-
manifestation of HH is the failure to establish puberty ture ovary shows negligible Kiss1 expression [22], and
due to impaired gonadotropin secretion [15]. The there is no significant difference in ovarian weight
phenotype of human KISS1R mutation is mimicked in between Kiss1/Kiss1r-deficient mice and normal mice
Kiss1r knockout mice [16]. In addition, Kiss1 knockout before puberty [31]. However, after puberty, the ovaries
rats lack the pulsing and proliferative patterns of in Kiss1r−/− and Kiss1−/− mice shrink compared with
gonadotropin and show puberty failure [17]. Conversely, those in control mice, likely due to the loss of kisspep-
mutations that cause hyperactive KISS1R in humans lead tin-mediated regulation of follicular development, not
to central precocious puberty [18, 19]. These results defects in gonadotropin secretion because follicular de-
suggest that kisspeptin plays an integral role in the regu- velopment cannot be rescued by gonadotropin
lation of pubertal onset. However, emerging evidence replacement [32]. In fact, although the role of the HPG
indicates the involvement of extra-hypothalamic kisspep- axis cannot be completely ruled out, follicles at all stages
tin and the KISS1R system in peripheral reproductive and the CL are present in mice with targeted removal of
functions. kisspeptin and Kiss1r neurons (> 90%), suggesting that
local kisspeptin in the ovary plays a very important role
Ovarian kisspeptin and KISS1R in follicle development [1].
Distribution in ovarian tissues Under conditions of a healthy nutrient supply, the
The expression of Kiss1 and Kiss1r was first demon- administration of kisspeptin in the ovary reduces the
strated in the rodent ovary [4]. To date, the expression number of antral follicles and increases the number of
of Kiss1/Kiss1r has been found in the ovaries of different preovulatory follicles, and these structural changes can
animals, such as hamsters [20], mice [21], rats [22], be reversed by the administration of the kisspeptin
chickens [23], cats [24], dogs [25], pigs [26], humans and antagonist peptide 234 (P234). Furthermore, kisspeptin
marmoset primates [27]. Because ovarian Kiss1 mRNA is administration increases plasma anti-Mullerian hormone
mainly expressed in rat granulosa cells during proestrus, (AMH) in 6- and 10-month-old rats. AMH, a marker of
granulosa cells are likely the main site of kisspeptin syn- ovarian reserve, is mainly secreted by secondary and
thesis [28]. The LH surge may directly stimulate kisspep- small sinus follicles and can inhibit the activation of
tin synthesis through LH receptors on granulosa cells primordial follicles by negative feedback; moreover, P234
[29], and prevention of the preovulatory gonadotropin administration reduces plasma AMH levels in rats [33].
surge can block the upregulation of ovarian Kiss1 The FSH/follicle stimulating hormone receptor (FSHR)
expression [22]. The expression of ovarian Kiss1 mRNA axis is responsible for follicular growth [34], but kisspep-
shows a distinctive cell- and stage-specific pattern under tin can block the increase in FSHR expression by
regulation of LH [22, 29, 30], whereas Kiss1r mRNA isoproterenol (ISO, a β-adrenergic agonist). Collectively,
expression remains low and does not significantly fluctu- kisspeptin negatively regulates the development of
ate with the oestrous cycle or gonadotropin treatment in preantral follicles by inducing the production of AMH
rats [28–30]. Interestingly, in both rodent and human and reduces the sensitivity to FSH by inhibiting the in-
growth follicles, kisspeptin is present in theca cells of duction of FSHR expression by sympathetic activators,
the growing follicle; in preovulatory follicles, kisspeptin thereby reducing the recruitment of primary follicles
begins to appear in the basal cells of the granular layer; (Fig. 1a). In the future, an ovarian-specific Kiss1/Kiss1r
after ovulation, positive immunostaining can be knockout model will be established to further elucidate
observed in non-luteinized granulosa cells of newly the role of kisspeptin in follicle development.
ruptured ovulation follicles; and in the corpus luteum
(CL), intense kisspeptin immunoreactivity can be detected The role in oocyte maturation
in steroidogenic granulosa lutein cells, with a gradual in- The addition of kisspeptin to FSH-rich medium for
crease with gradual maturation of the CL [22, 27]. These porcine cumulus-oocyte complexes (COCs) promotes
results demonstrate that kisspeptin and its receptor oocyte maturation, indicating a direct effect of kisspeptin
have a highly conserved expression pattern in rodent, on oocytes [35], and the mechanism may involve upreg-
monkey and human ovaries. The distribution of ulating the expression of C-MOS, growth differentiation
Cao et al. Reproductive Biology and Endocrinology (2019) 17:65 Page 3 of 9

Fig. 1 The role of kisspeptin/KISS1R system in the ovary. Ovarian-derived kisspeptin regulates follicular development, oocyte maturation, and
ovulation in autocrine or paracrine manner. a The possible role and mechanisms of kisspeptin in follicular development. b The possible role and
mechanisms of kisspeptin in oocyte maturation. c The role and mechanisms of kisspeptin in ovulation. AMH, anti-Mullerian hormone; BDNF,
brain-derived neurotrophic factor; BMP15, bone morphogenetic protein 15; COX-2, Cyclooxygenase-2; FSH, follicle stimulating hormone; FSHR,
follicle stimulating hormone receptor; GDF9, growth differentiation factor 9; LH, luteinizing hormone; NA, noradrenaline; NTRK2, neurotrophic
tyrosine kinase receptor type 2; PKC, protein kinase C

factor 9 (GDF 9) and bone morphogenetic protein 15 oocyte maturation may be accomplished through the
(BMP 15) [36]. Even in the absence of cumulus cells, kis- regulation of meiosis (Fig. 1b).
speptin can increase the maturity of oocytes because
Kiss1r is expressed in oocytes during in vitro maturation The role in ovulation
(IVM). Thus, kisspeptin may act continuously and dir- The LH peak plays a crucial role in ovulation by indu-
ectly on oocytes in an autocrine-paracrine manner. cing the upregulation of COX-2 and prostaglandin pro-
Interestingly, the absence of FSH results in failed oocyte duction [37]. The COX-2 inhibitor NS398 and the COX
maturation, even in IVM medium supplemented with non-selective inhibitor indomethacin significantly inhib-
kisspeptin, confirming a critical role of gonadotropins in ited Kiss1 mRNA expression in the rat ovary and
the maturation of oocytes in vitro. Moreover, the decreased the efficiency of rat ovulation, suggesting that
addition of FSH to COCs induces a significant increase Kiss1 may be a downstream target of COX-2 (Fig. 1c).
in Kiss1r expression, reflecting the permissive action of Furthermore, administration of prostaglandin E2 can
FSH on kisspeptin. reverse the antagonism of indomethacin on kiss1 expres-
When a mouse oocyte acquires meiotic capacity, Kiss1 sion. The anti-progestin RU486 ameliorates ovulation
mRNA expression increases 82.2-fold [36]. However, defects caused by indomethacin but cannot reverse the
when the oocyte progresses through the first and second regulation of ovarian Kiss1 expression [27], implying the
divisions of meiosis (MII), Kiss1 mRNA expression de- existence of other pathways that regulate ovulation. In
creases by 5.4- and 12-fold, respectively [36]. During the fact, the indispensable role of ovarian kisspeptin in ovu-
progression from germ-vesicle I to MII, the expression lation is suspect because gonadotropins can induce ovu-
of Kiss1r remains stable. However, kisspeptin treatment lation in Kiss1-deficient mice with mild hypogonadism
fails to affect the percentage of MII eggs [36]. Therefore, and in women with homozygous KISS1R mutations [38].
the upregulation of Kiss1 expression may be related to
the ability to undergo meiosis and may affect the recov- The role in ovarian steroidogenesis
ery of meiosis but not the progression of MII. Taken to- Kisspeptin stimulates progesterone secretion by rat luteal
gether, these data suggest that the effect of kisspeptin on cells and by chicken and porcine granulosa cells. Our
Cao et al. Reproductive Biology and Endocrinology (2019) 17:65 Page 4 of 9

previous study showed that recombinant KP-10 signifi- 10 and KP-52 can significantly increase serum testos-
cantly enhances basal and human chorionic gonadotropin terone levels in mice [42]. Furthermore, ovary-derived
(hCG)-induced progesterone levels in cultured rat luteal kisspeptin has been shown to regulate the secretion of
cells and upregulates the transcription of key steroido- LH [43].
genic enzymes (StAR, CYP11A, and 3β-HSD) [30]. More-
over, KP-10 promotes the secretion of progesterone by Testicular kisspeptin and KISS1R
cultured chicken follicular granulosa cells in vitro, accom- Distribution in testicular tissues
panied by the upregulation of StAR, CYP11A, and 3β-HSD There are not only significant differences in the distribution
expression [23]. In addition, KP-10 significantly enhances of testicular kisspeptin and KISS1R between mammals and
progesterone production and prevents the efflux of non-mammalian species but also diverse distribution
oestradiol from granulosa cells of porcine large follicles patterns in the same or similar species [5, 44–48] (summa-
[23]. Furthermore, KP-10 increases the phosphorylation of rized in Table 1). For example, a previous study reported
the mitogen-activated protein kinase Erk1/2 but not of kisspeptin and Kiss1r immunoreactivity in round sperma-
P38 MAPK and Akt in cultured rat luteal cells, suggesting tids in immature mice [5]. However, another study showed
that kisspeptin may stimulate progesterone secretion via kisspeptin immunoreactivity mainly in Leydig cells and
the Erk1/2 signalling pathway in these cells [30]. However, sperm cells at different stages, not in only round sperm
treatment with KP-54 alone did not alter steroidogenesis cells [47]. Therefore, the different results in the same spe-
or the expression of gonadotropin receptors [39], indicat- cies may be related to the age of the experimental mice and
ing that KP-54 may require gonadotropins to promote ste- largely influenced by experimental methods. For example,
roidogenesis [30] or that different kisspeptin isoforms when the LacZ gene was inserted into the Kiss1 and Kiss1r
(such as KP-10) may have different affinities for ovarian alleles to allow β-galactosidase staining to detect gene
KISS1R [23]. expression, unique structural changes in sperm (deform-
Unlike progesterone, KP-10 does not promote the ation) resulted in inactivation of β-galactosidase after the
basal or hCG-induced secretion of oestrogen by rat lu- round spermatid stage, making it impossible to determine
teal cells [30]. Currently, the best data on the effects of whether kisspeptin is expressed in prolonged spermatid
kisspeptin on luteal cell function are from luteinized and spermatozoa [5].
granulosa cell cultures. KP-54 significantly augments
the expression of oestrogen receptors alpha and beta The role in spermatogenesis
(ESR1 and ESR2) in human granulosa lutein cells, sug- In non-mammalian species, subcutaneous injection of
gesting that kisspeptin may increase sensitivity to synthetic Kiss1 pentadecapeptide can speed up sperm-
oestrogen [39]. atogenesis in prepubertal male chub mackerel [47]. In
Additional studies have indicated that serum kisspep- mammals, gene expression profiling revealed that the
tin levels are significantly higher in women with polycys- initiation of Kiss1/Kiss1r expression in mouse testis coin-
tic ovary syndrome (PCOS), which is characterized by cides with the formation of spermatozoa [5], suggesting
hyperandrogenism and ovulatory dysfunction [40]. Not- a link between spermatogenesis and the testicular
ably, serum levels of kisspeptin are negatively correlated kisspeptin/Kiss1r system in mammals. In addition, kis-
with FSH but positively correlated with LH, testosterone speptin exerts anti-metastatic effects by inhibiting cell
and dehydroepiandrosterone (DHEA) [41]. Mouse KP- chemotaxis and migration, which play important roles in

Table 1 The expression of of kisspeptin/KISS1R system in the testis

Reference kisspeptin KISS1R methods species
Mei et al. [5] Round SPT Round SPT, LCs (−) X-GAL staining Mouse
and IHC
Pinto et al. [45] SPZ SPZ IF, WB Human
Irfan et al. [46] Interstitial SCs ICC Monkey
Anjum et al. Interstitial, LCs, Primordial GCs, elongated GCs, No data IHC Mouse
[47] Degenerated GCs
Chianese et al. Interstitial Interstitial, PMCs, SCs, ISPG, IISPG, ISPC, IISPC, SPT, IHC Frog
[44] SPZ
Meccariello et al. No data Interstitial, ISPG, IISPG, PMCs ISH Frog
[6]
SPT, spermatids; LCs, Leydig cells; SPZ, spermatozoa; SCs, Sertoli cells; GCs, germ cells; PMCs, peritubular myoid cells; ISPG, primary spermatogonia; IISPG,
secondary spermatogonia; ISPC, primary spermatocytes; IISPC, secondary spermatocytes;
IHC, immunohistochemistry; IF, immunofluorescence; WB, western blot; ICC, Immunocytochemistry; ISH, In situ hybridization
Cao et al. Reproductive Biology and Endocrinology (2019) 17:65 Page 5 of 9

the early stage of spermatogenesis [49]. Furthermore, in adult rhesus monkeys [55]. Second, although the immor-
the late stage of spermatogenesis, KP-13 can induce hu- talized Leydig cell line MA-10 expresses Kiss1r, it does
man sperm motility changes and hyperactivation, pos- not respond to KP-10 stimulation [5]. In addition, Sertoli
sibly caused by the increase in sperm intracellular Ca2+ cells respond to kisspeptin and stimulate the production
concentration ([Ca2+]i) [45]. The positive association be- of androgen-binding protein (ABP), indicating a poten-
tween kisspeptin concentration in seminal plasma and tial role of kisspeptin in ABP production [46].
semen quality supports the importance of the kisspeptin
system in spermatogenesis [50]. However, peripheral kis- Roles in the uterus and placenta
speptin may not be essential for spermatogenesis in The role in the uterus
mammals. First, Kiss1 and Kiss1r mutant mice still show In the human female genital tract, KISS1/KISS1R is
low levels of spermatogenesis on a phytoestrogen diet mainly expressed in epithelial and stromal cells of the
[51]. Second, male patients with KISS1R mutations re- uterus but not of the myometrium [6]. In mice, Kiss1
spond to exogenous hormonal therapy and successfully and Kiss1r mRNA expression levels are generally low
achieve fertility [52]. Collectively, testicular kisspeptin from day 1 to 4 of pregnancy, which is the stage of zyg-
may not be necessary for mammalian spermatogenesis ote to blastocyst transformation (Fig. 2a). KISS1 and
but is an important regulator of this process. KISS1R proteins are mainly localized at low levels in the
luminal and glandular epithelium. However, Kiss1 and
The role in testicular steroidogenesis Kiss1r mRNA expression level dramatically increase with
Androgens (mainly testosterone) are steroid hormones the progression of uterine decidualization, and attenu-
secreted by Leydig cells in the testes of males. Thus far, ated expression of Kiss1 can significantly inhibit the
there is no verdict as to whether peripheral kisspeptin expression of stromal cell decidualization markers, indi-
has an effect on androgen production in Leydig cells. cating that the kisspeptin/kiss1r system plays an import-
First, the interruption of Kiss1 expression is associated ant role in the decidualization process [56]. However,
with decreased testosterone levels in rats [53], and the the underlying mechanism is unknown.
kisspeptin antagonist P234 reduces the production of Calder et al. found that in kiss1 mutant mice, gonado-
hCG-activated testosterone in vitro [54], but local injec- tropin and oestradiol replacement could restore ovula-
tion of P234 does not alter plasma testosterone levels in tion, mating, and fertilization but not lead to pregnancy;

Fig. 2 The potential role of kisspeptin/KISS1R system in the pregnancy. a A schematic diagram of zygote development, embryo implantation and
fetal development in the uterus. b The known and potential mechanisms of locally produced kisspeptin in embryo implantation. c The known
and potential mechanisms of peripheral kisspeptin in fetal development. HFA, human fetal adrenal; MMPs, matrix metalloproteinases; LIF,
leukemia inhibitory factor; VEGFA, vascular endothelial growth factor A
Cao et al. Reproductive Biology and Endocrinology (2019) 17:65 Page 6 of 9

moreover, leukaemia inhibitory factor (Lif ), a crucial In addition, studies have indicated that the kisspeptin/
cytokine required for implantation, is weakly expressed KISS1R system in the embryo may affect human foetal
in these mice [57]. Lif secreted by the uterine glands adrenal function synergistically with adrenocorticotropic
promotes embryo-uterine communication and contrib- hormone and corticotropin-releasing hormone secretion
utes to embryo attachment and decidualization [58, 59]. by increasing the production of DHEA in mid to late
Oestrogen upregulates Lif expression in the uterus, and gestation (Fig. 2c) [71, 72].
supplementation with Lif restores implantation and
decidualization in ovariectomized mice and mice lacking The role in placental migration and invasion
uterine oestrogen receptor expression [60, 61]. Further- Kisspeptin was originally called metastin because it can in-
more, in Kiss1 knockout mice, exogenous administration hibit tumour metastasis. Interestingly, the invasion pro-
of Lif, but not E2, partially rescues implantation failure cesses of placental and tumour cells are markedly similar
[57], and our data demonstrated that E2 significantly in- [73, 74]. The highest expression of Kiss1 and Kiss1r in ges-
creases the expression of uterine kiss1 mRNA in ovariec- tational trophoblast cells is consistent with peak tropho-
tomized mice [56]. These data suggest that kisspeptin blast invasion [62, 75]. Thus, kisspeptin is thought to
signalling may act downstream of E2 to stimulate uterine inhibit trophoblast migration and invasion in the placenta.
Lif expression and is beneficial for promoting embryo A series of studies demonstrated that kisspeptin can regu-
implantation and decidualization in mice (Fig. 2b). late trophoblast migration and invasion by a variety of
mechanisms. First, kisspeptin stimulates Erk1/2 phosphor-
The role in pregnancy ylation in trophoblast cells and inhibits the expression of
There is evidence that the primary source of circulating matrix metalloproteinases (MMPs), such as MMP-2,
kisspeptin is trophoblast cells of the placenta [12, 62]. In thereby regulating placental invasion [74, 76]. Second, KP-
rat placental cells, Kiss1 expression is upregulated by 10 inhibits the migration of HTR8SVneo cells by stimulat-
GnRH and neurokinin B, and all of these neuropeptides ing complex Erk1/2-GSK3β-FAK feedback interactions in
can increase hCG expression [63]. Serum KP-54 levels vitro [77]. Third, kisspeptin suppresses angiogenesis by
increase several thousand fold during pregnancy and re- downregulating vascular endothelial growth factor A (Fig.
turn to normal within 15 days after delivery, suggesting 2b) [78]. In addition, the active kisspeptin/KISS1R system
that the placenta produces large quantities of kisspeptin not only suppresses the migration of trophoblast cells but
during pregnancy [4, 62, 64]. Moreover, low circulating also inhibits their growth in placental explants [35].
kisspeptin levels during pregnancy are associated with
an increased risk of miscarriage. Therefore, plasma kis- Conclusion
speptin levels are a potential biomarker for miscarriage Recently, kisspeptin analogues and KISS1R antagonists
in the first and third trimesters [65, 66]. As one of the have been developed as modulators of the cascade
biomarkers of pregnancy, peripheral kisspeptin has mul- upstream of GnRH, and most previous studies have
tiple functions, including the regulation of placental in- focused on the central control of the kisspeptin/KISS1R
vasion and migration (discussed in detail below) [62], system in the hypothalamus. However, as discussed in this
the apoptosis of embryonic and placental cells, and review, the kisspeptin/KISS1R system plays a direct role in
foetal development [67, 68]. peripheral organs (including the ovary, testis, uterus, and
Kisspeptin administration increases the apoptosis of placenta) and is implicated in reproductive diseases such
embryonic cells cultured in vitro by upregulating pro- as miscarriage and PCOS. A comprehensive understand-
apoptotic genes [69]. The expression of the pro-apop- ing of the expression, function, and potential molecular
totic gene BAK1 in blastocysts increased 3.5-fold at 24 h mechanisms of kisspeptin/KISS1R in the peripheral repro-
after kisspeptin treatment, but no significant change was ductive system will contribute to the diagnosis, treatment
observed in the expression of the anti-apoptotic gene and prevention of reproductive diseases.
Bcl-2 [35]. In addition, the apoptosis index (AI), the ratio
of the pro-apoptotic protein BAX to the anti-apoptotic Abbreviations
protein Bcl-2, determines whether the cell will initiate ABP: Androgen-binding protein; AI: Apoptosis index; AMH: Anti-Mullerian
hormone; BMP15: Bone morphogenetic protein 15; CL: Corpus luteum;
apoptosis [70]. Interestingly, the AI and KISS1/KISS1R COCs: Cumulus-oocyte complexes; DHEA: Dehydroepiandrosterone;
expression in the placenta are much higher in late preg- ESR1: Estrogen receptors alpha; ESR2: Estrogen receptors beta; FSH: Follicle
nancy than at term delivery in humans [68]. Further- stimulating hormone; FSHR: Follicle stimulating hormone receptor;
GDF9: Growth differentiation factor 9; GnRH: Gonadotropin-releasing
more, external administration of kisspeptin increases AI hormone; GPCRs: G protein-coupled receptors; hCG: Human chorionic
and induces apoptosis in placental explants in a dose- gonadotropin; HH: Hypogonadotropic hypogonadism; HPG
dependent manner [68]. Taken together, these data indi- axis: Hypothalamic-pituitary-gonadal (HPG) axis;
IBMX: Isobutylmethylxanthine; ISO: Isoproterenol; IVM: In vitro maturation;
cate that kisspeptin may be a pro-apoptotic placental LH: Gonadotropin, luteinizing hormone; Lif: Leukemia inhibitory factor;
factor during pregnancy. MII: Second division of meiosis; P234: Peptide 234
Cao et al. Reproductive Biology and Endocrinology (2019) 17:65 Page 7 of 9

Acknowledgments 9. Hu KL, Chang HM, Zhao HC, Yu Y, Li R, Qiao J. Potential roles for the
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