Kisspeptin has recently emerged as a

key regulator of the mammalian

reproductive axis.

It is known that kisspeptin is acting

centrally via the kisspeptin receptor,
stimulates secretion of (GnRH).
Clarke H et al., 2015
 Introduction

Loss of kisspeptin signaling causes hypo

gonadotrophic hypogonadism in humans.

Kisspeptin interacts with other neuropeptides such as

neurokinin B and dynorphin, to regulate GnRH pulse
generation.

kisspeptin signaling is regulated by nutritional status

and stress .

Clarke H et al., 2015

 Kisspeptin is a novel potential therapeutic target in
the treatment of fertility disorders.

Peripheral exogenous kisspeptin administration

stimulates gonadotrophin release in healthy
adults and in patients with certain forms of
infertility.
Tng EL et al., 2015
Kisspeptin was first discovered in 1996 as a
metastasis inhibitor in melanoma cell lines.

The first gene member of the family (KISS 1) was

discovered by a group working in Hershey,
Pennsylvania.

It is named after the city’s chocolate ‘Kisses’,

which are made in Hershey.
Clarke H et al., 2015
The early literature of the gene, its receptor orphan
G protein-coupled receptor 54 (GPR54;
subsequently re-named kisspeptin receptor) and
protein product (first named metastin, now
renamed kisspeptin).
Clarke H et al., 2015
The KISS1 gene encodes a number of peptide
products, now collectively known as
kisspeptins, which activate the kisspeptin
receptor.
The initial polypeptide synthesized is 145 amino acids
in length and is then cleaved to active shorter lengths.

Tng EL et al., 2015

The nomenclature represents the number of amino acids
included in the four main types [ kisspeptin 54, 14, 13 and
10] and all of them share the same C-terminal
decapeptide sequence.

Kisspeptin-54 is the most abundant circulating isoform in

humans. Moreover, both kisspeptin 10 and 54 have been shown
to be potent stimulators of endogenous gonadotropin hormone
secretion.

Clarke H et al., 2015

The kisspeptin receptor was discovered in 2000, and was
originally known as GPR54.

It is a member of the rhodopsin family of G-protein-

coupled receptors and is structurally similar to the
galanin receptor.

The kisspeptin receptor has been shown to be

present in the human placenta and brain.
Tng EL et al., 2015
Kisspeptin expression was demonstrated in high levels
in the placenta, testis , ovary, pancreas, small intestine

and various parts of the nervous system.

Kisspeptin neurons were identified in the hypothalamus,

basal ganglia and periventricular region,

while KISS1R was localized to the hypothalamus, basal

ganglia, amygdala, substantia nigra, hippocampus and
spinal cord.
Clarke H et al., 2015
Kiss1 mRNA :
• Hypothalamus :
• Basal ganglia
• Anteroperiventricular nucleus

GPR54 mRNA :
• Hypothalamus : basal
ganglia,)
• Limbic system :
• Amygdala
• Hippocampus
• Spinal cord

M. Tena- Sempere, Handbook of biologically active peptides (2013)

Kisspeptin stimulates GnRH neurons leading to
GnRH release in both in vitro and in vivo
studies , an effect which is inhibited by the
administration of GnRH antagonists.

Pinilla L et al., 2012

These act on testes and ovaries to produce the
sex hormones testosterone and estradiol,
which cause the physical and emotional
changes that are well recognized during
puberty.

Dhillo et al .,2005
 In 2003 De Roux et al. and Seminara et al. discovered a
number of mutations in the kisspeptin receptor gene in
humans with congenital hypogonadotropic
hypogonadism (CHH).

Polymorphisms in the kisspeptin receptor gene have

been associated with congenital precocious puberty
(CPP).

Tng EL et al., 2015

 Kisspeptin,
Puberty

Puberty
?
GnRH • ↑ LH & FSH
•Bone age +
Critical fat mass • More and more • ↑ Sex-steroids
•Leptin receptors sensitive

Kisspeptin Puberty

Tng EL et al., 2015

 Precocious Puberty
Development of
secondary sexual
characters, before
the age of 7 for girls
and 9 for boys.

•Immature bone age

GnRH •↑ LH & FSH
•Immature critical fat •↑ Sex-steroids
•GnRH pulses
mass • No menarches
•BUT activating
mutation

Kisspeptin Puberty

Tng EL et al., 2015

• Prevalence : Hypogonadotropic
1/100000 Hypogonadism.
Congenital
• 1/3 idiopathic
• 2003 
mutation
discovered
Ø GnRH
• ↓ LH & FSH
• KISS1R  • ↓ Sex-
decrease of steroids
signalling
pathway Sexual
Ø Kisspeptin
maturation

- Absence of
spontaneous
sexual maturation
- Low blood levels of
De Roux et al ., 2003 steroids
 In 2007, two other neuropeptides have come under the
spotlight for their role in regulating reproduction: NKB
and DYN. NKB is known for its role in steroid feedback
control of GnRH release.

Recently discovered that mutations in the gene

encoding NKB, tachykinin 3 (TAC3), or its receptor
(TACR3) leads to hypogonadism in humans, like
kisspeptin.

Prague JK ., 2015
 A subpopulation of kisspeptin neurons (‘KNDy
neurons’) in the infundibular/arcuate nucleus have
been described as co-localizing neurokinin B (NKB)
and dynorphin (Dyn).

These neurons are present in close contact with

GnRH-secreting neurons in humans.

Prague JK ., 2015
 DYN is an endogenous opioid peptide, which
acts primarily through the K-Opioid Receptor
(KOR) and NKB (acting via the NK3 receptor)
both influence LH secretion.

DYN is known to regulate progesterone-

mediated negative feedback on GnRH
release.

Prague JK ., 2015
 It is known that kisspeptin stimulates LH
release via GnRH neurons, whereas DYN
inhibits GnRH pulse frequency.

Current models suggest that kisspeptin may

trigger GnRH pulses, and DYN may terminate
GnRH pulses .

Prague JK ., 2015
 The highest levels of peripheral kisspeptin expression in
the body have been found in the syncytiotrophoblast
cells of the placenta .

Circulating levels of kisspeptin have been shown

increase with gestation in humans, with levels in late
pregnancy rising to up to 7,000 times greater than in
non-pregnant controls.

Jamil Z et al ., 2017
 Levels of kisspeptin receptor expression are increased
in placental tissue with GTD when compared with
normal placental tissue .

The precise function of kisspeptin in these instances

is unclear, although it has been speculated that it may
act to regulate trophoblast cell invasion .

Thus, studies have proceeded to investigate the

potential link between kisspeptin levels and placental
dysfunction such as pre-eclampsia , and IUGR .

Jamil Z et al ., 2017
 It is well known that body weight affects fertility.

Leptin is a peptide hormone secreted by adipocytes.

Deficiency of leptin results in delayed puberty and

hypogonadtrophic hypogonadism in humans .

Leptin administration reverses the infertility

associated with leptin deficiency.

Clarke H et al., 2015

 Kisspeptin is implicated as an intermediary between
leptin signaling and GnRH function.

Kisspeptin neurons express the leptin receptor.

kisspeptin expression is increased following

exogenous leptin administration.

Fasting has been shown to reduce hypothalamic

kisspeptin mRNA and delay the onset of puberty.

Clarke H et al.,2015
Clarke H et al., 2015
 Due to the critical role of Kisspeptin for GnRH physiology,
two possible approaches
were considered as therapeutic targets.

The first approach is stimulation of the reproductive functions by

inducing GnRH release from the hypothalamus, which can
potentially be used to treat conditions such as hypogonadism,
infertility anovulation, hyperprolactinemia and ART.
The second approach is the suppression of the reproductive
functions, allowing treatment of hormone-dependent diseases
such as prostate cancer, benign prostate hyperplasia, breast
cancer, endometriosis , precocious puberty, leiomyoma and
contraception.
Prague JK et al., 2015
 Hypothalamic amenorrhea is a functional condition comprising
slow GnRH pulsatility associated with a preferential decline in LH
versus FSH and low ovarian follicular activity.

Recent work suggests kisspeptin could be useful in

stimulating the hypothalamic-pituitary gonadal axis in
such patients.

Subcutaneous administration of KP-54 to women with

hypothalamic amenorrhea led to a 10-fold increase in LH
and a 2.5-fold increase in FSH Secretion.

Jayasena et al .,2009
 S.C Kisspeptin twice daily for two weeks at a dose of 6.4 nmol/kg
led to desensitization in gonadotropin response, with down
regulation occurring as early as 24 hours post KP-54 injection.

On the final day of the study a GnRH bolus was given, and women
who no longer responded to KP-54 maintained responsiveness to
GnRH.

Prolonged protocol using twice weekly S.C KP-54 at a dose of 6.4

nmol/kg for eight weeks in women with hypothalamic amenorrhea
observed an initial desensitization following by a sustained partial
gonadotropin response from day 14 to the end of the study period.

Jayasena et al .,2009
 Congenital hypo gonadotrophic hypogonadism has been
found to have inactivating mutations affecting the NKB
ligand and its receptor .

In a study looking at such patients, intravenous infusion

of kisspeptin-10 resulted in an increase in LH secretion
from baseline.
kisspeptin could be useful in treating patients with
hypogonadism secondary to a number of metabolic
disorders.

Clarke H et al., 2015

 Reduced secretion of GnRH is thought to be the causative
factor for low levels of circulating gonadotropins in type 2
diabetes, obesity and the metabolic syndrome .

Using an 11 hour intravenous infusion of KP-10, they

showed an increase in LH pulsatility and secretion with
associated increase in testosterone with similar mean
LH levels post-kisspeptin when compared to age
matched healthy males.

Pinilla L et al., 2012

 Exogenous kisspeptin administration, in humans, induces
a dose-dependent release of primarily LH and to a lesser
extent (FSH) from the anterior pituitary.

In a study by Jayasena et al., 2014, 53 normal responder

patients underwent ovarian stimulation with exogenous
FSH and GnRHa co-treatment.

Final oocyte maturation was induced by a single

subcutaneous bolus of kisspeptin-54, using four different
dose regimens (1.6–12.8nmol/kg).

Thomsen and Humaidan, 2015

 The primary outcome of the study was oocyte maturation.

Overall, fertilization was achieved in 92% of the treated patients,

the biochemical pregnancy rate was 40% and

clinical pregnancy rate 23% .

Twelve healthy babies were subsequently born.

No OHSS case was reported.

Kisspeptin may have advantages over (hCG) as a more

physiological mediator of the LH surge.

This is particularly prudent in the prevention of ovarian

hyperstimulation syndrome (OHSS).

Jayasena et al., 2014

 There have been encouraging results from a
study using KP-54 in IVF undertaken in women at
high risk of OHSS (n = 60).

Outcomes were favorable for rates of

biochemical pregnancy (63%),clinical pregnancy
(53%) and live birth rates per transfer (45%) with
no incidence of moderate, severe or critical OHSS
.

Abbara et al., 2015

hCG
•used to trigger
ovulation
•side-effect: OHSS
Kisspeptin:
Hope: more physiological and
safer medication in order to
elicit the ovulation:
 experiment (Brown et al.)
„Kisspeptin-babies”: live
births after kisspeptin
treatment 
http://image.slidesharecdn.com/kisspeptin2-150516121457-
lva1-app6891/95/kisspeptin-hope-about-to-become-reality-13-
638.jpg?cb=1431781372
 PCOS is the most common endocrinopathy in women and
increased LH pulsatility secondary to increased GnRH frequency
(with relatively little change in FSH) is the main pathophysiological
process.
We know from clinical studies that exogenous kisspeptin
preferentially increases LH secretion over FSH.

Therefore we can hypothesize that suppression of GnRH pulse

frequency by antagonists or high potency agonists, has the
potential to normalize LH hyper secretion with sparing of FSH to
promote folliculogenesis, ameliorate hyperandrogenism and
potentially induce ovulation in women with PCOS.

Clarke H et al., 2015

 Kiss1-expressing neurons are important mediators of
prolactin’s effects on reproduction.

Prolactin acts directly on Kiss1-expressing neurons and

induces suppression of Kiss1 mRNA expression and kisspeptin
secretion, leading to a lower activation of GnRH and
gonadotropins secretion.

Therefore hyperprolactinemia-induced infertility can possibly be

treated with kisspeptin replacement.

Donato J et al., 2015

 Decreased levels of kisspeptin receptor on placental
immunohistochemistry has been found in such cases

Bleeding in early Recurrent spontaneous abortion

pregnancy
Hypertension during pregnancy
Diabetes mellitus
Intra-uterine growth restriction
Pre-eclampsia

Jamil Z et al., 2015

 Kisspeptin in combination with other components
of the KNDy neurons, have a potential therapeutic
role for manipulating the KNDy system in the
treatment of menopausal hot flushes.

Celik F et al., 2016

Kisspeptins play essential roles in
reproduction.

They are involved in in utero sexual development and

determine the onset of puberty.

After sexual maturation, kisspeptins regulate HPG axis

function by modulating gonadotrophin release.
•Delayed or precocious puberty
•Subfertility
•Contraception
•Treatment of metastatic cancers
•Down regulation of sex steroids in the
treatment of sex steroid-dependent tumors,
leiomyoma and endometrios
 IVF
T
- Hypogonado
h
tropic
hypogonadi e
sm r
- Precocious a - Ovarian
puberty p cycle
- PCOS
y - Puberty
- Contraceptio
n
- Menopause
• Kasum M, Franulic D, Cehic E, Oreskovic S, Lila A, Ejubovic E. Kisspeptin as a promising oocyte maturation trigger
for in vitro fertilisation in humans. Gynecol Endocrinol 2017;33: 583-587.
• Clarke H, Dhillo WS, Jayasena CN. Comprehensive Review on Kisspeptin and Its Role in Reproductive Disorders.
Endocrinology and metabolism (Seoul, Korea) 2015;30: 124-141.
• Jamil Z, Fatima SS, Arif S, Alam F, Rehman R. Kisspeptin and embryo implantation after ICSI. Reprod Biomed
Online 2017;34: 147-153.
• Donato J, Jr., Frazao R. Interactions between prolactin and kisspeptin to control reproduction. Archives of
endocrinology and metabolism 2016;60: 587-595.
• Tng EL. Kisspeptin signalling and its roles in humans. Singapore medical journal 2015;56: 649-656.
• Donato J, Jr., Frazao R. Interactions between prolactin and kisspeptin to control reproduction. Archives of
endocrinology and metabolism 2016;60: 587-595.
• Thomsen L, Humaidan P. Ovarian hyperstimulation syndrome in the 21st century: the role of gonadotropin-
releasing hormone agonist trigger and kisspeptin. Current opinion in obstetrics & gynecology 2015;27: 210-214.
• Prague JK, Dhillo WS. Potential Clinical Use of Kisspeptin. Neuroendocrinology 2015;102: 238-245.
• Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M. Kisspeptins and reproduction: physiological roles and
regulatory mechanisms. Physiological reviews 2012;92: 1235-1316.
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Thank you for your
attention !