Therapeutic role of Kisspeptin in reproduction

2. 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

3. 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

4. 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

5. 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

7. 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).
ClarkeHetal.,2015

8. 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

9. 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

11. 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

12. 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

13. 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)

15. 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

16. 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

19. 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

20. •Bone age +
Critical fat mass
•Leptin receptors
Kisspeptin
• More and more
sensitive
GnRH • ↑ LH & FSH
• ↑ Sex-steroids
Puberty
Kisspeptin,
Puberty
Puberty
?
Tng EL et al., 2015

21. Precocious Puberty
Development of
secondary sexual
characters, before
the age of 7 for girls
and 9 for boys.
•Immature bone age
•Immature critical fat
mass
•BUT activating
mutation
Kisspeptin
•GnRH pulses
GnRH •↑ LH & FSH
•↑ Sex-steroids
• No menarches
Puberty
Tng EL et al., 2015

22. Hypogonadotropic
Hypogonadism.
Ø Kisspeptin
• KISS1R 
decrease of
signalling
pathway
Ø GnRH
• ↓ LH & FSH
• ↓ Sex-
steroids
Sexual
maturation
- Absence of
spontaneous
sexual maturation
- Low blood levels of
steroids
• Prevalence :
1/100000
Congenital
• 1/3 idiopathic
• 2003 
mutation
discovered
De Roux et al ., 2003

23. 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

24. 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

26. 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

28. 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

29. 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

30. 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

31. 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

32. kisspeptin expression is increased following
exogenous leptin administration.
Kisspeptin is implicated as an intermediary between
leptin signaling and GnRH function.
Fasting has been shown to reduce hypothalamic
kisspeptin mRNA and delay the onset of puberty.
Kisspeptin neurons express the leptin receptor.
Clarke H et al.,2015

34. Clarke H et al., 2015

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

43. 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

44. http://image.slidesharecdn.com/kisspeptin2-150516121457-
lva1-app6891/95/kisspeptin-hope-about-to-become-reality-13-
638.jpg?cb=1431781372
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 

45. 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.
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.
We know from clinical studies that exogenous kisspeptin
preferentially increases LH secretion over FSH.
Clarke H et al., 2015

46. 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

47. Decreased levels of kisspeptin receptor on placental
immunohistochemistry has been found in such cases
Bleeding in early
pregnancy
Recurrent spontaneous abortion
Diabetes mellitus
Hypertension during pregnancy
Pre-eclampsia
Intra-uterine growth restriction
Jamil Z et al., 2015

48. 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

49. 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.

50. •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

51. - Ovarian
cycle
- Puberty
- Hypogonado
tropic
hypogonadi
sm
- Precocious
puberty
- PCOS
- Contraceptio
n
- Menopause
T
h
e
r
a
p
y
IVF

52. • 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.
• Tng EL. Kisspeptin signalling and its roles in humans. Singapore medical journal 2015;56: 649-656.

53. Thank you for your
attention !