1. The role of kisspeptin in neuroendocrine disorders
Maria Földi & Esther Hazane Leroyer
JPEMS 2015, Szeged
Under the supervision of Dr. Krisztina Csabafi, M.D, PhD, Department of Pathophysiology

2. Introduction Kiss1 receptor Kisspeptin (protein)
Kiss1 receptor
Kisspeptin gene and its protein products : kisspeptin-54, kisspeptin-14, kisspeptin-13, kisspeptin-10. (
Kisspeptin (protein)
All share the same C-ter + N-ter. RF-amide  involved in nociceptive transduction, feeding behaviour, regulation of pituitary hormones secretion…

3. Localization GPR54 mRNA : Kiss1 mRNA :
M. Tena-Sempere, Handbook of biologically active peptides (2013)
Kiss1 mRNA :
Hypothalamus :
Arcuate nucleus
Anteroperiventricular nucleus
Limbic system : Amygdala
GPR54 mRNA :
Hypothalamus : Arcuate nucleus (GnRH neurons)
Limbic system :
Amygdala
Hippocampus
In the periphery, KISS1 mRNA is located at high levels in the placenta, but in the CNS  it can be mostly found in the hypothalamus, and in the limbic system  the amygdla

4. Physiology: ovarian cycle

5. Physiology: sexual dimorphism of the brain
Male
Less kisspeptin neurons in AVPV
NOT able to develop the LH surge
T, E2 : high level in the perinatal period
Female
More kisspeptin neurons in AVPV
ABLE to develop the LH surge
T, E2 : low level in the perinatal period
Clarkson et al., 2014

6. Pathology: PolyCystic Ovary Syndrome (PCOS)
Kiss1 mRNA expression
Brown et al., 2012
Pathology: PolyCystic Ovary Syndrome (PCOS)
Symtomps:
Anovulation
enlarged polycistic ovaries
irregular cycle
insulin resistance
One of the proposed causes: hyperandrogenism prepubertal or fetal (DHT)
Kisspeptin’s role

7. Kisspeptin, Puberty & Metabolism Kisspeptin GnRH Puberty
Bone age + Critical fat mass
Leptin receptors
Kisspeptin
More and more sensitive
GnRH
↑ LH & FSH
↑ Sex-steroids
Puberty
Puberty ?
Puberty : activation of the previously dormant neuroendocrine reproductive axis (apparition of GnRH pulses) + reaching bone age + critical fat mass.

8. Pathology: 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

9. Pathology : Hypogonadotropic Hypogonadism.
INACTIVATING MUTATION
Ø Kisspeptin
KISS1R  decrease of signalling pathway
Ø GnRH
↓ LH & FSH
↓ Sex-steroids
Sexual maturation
Prevalence : 1/100000
Congenital: 1/3 idiopathic
2003  mutation discovered
1/ : congenital or acquired  Idiopathic HH (1/3)
Absence of spontaneous sexual maturation + low blood levels of steroids (absent of LH pulse)
Inactivating mutations in KISS1R gene (2003)  decreased level of IP3.
In obesity and diabetes  cases of HH.
Tolson et al : increased BW + glucose-intolerance + increased leptin levels in KO KISS1R female mice
 role of KP system in HH + metabolic diseases.
Absence of spontaneous sexual maturation
Low blood levels of steroids

10. Pathology: Obesity & Diabetes.
Kiss1r KO female MICE
Ø Kisspeptin system
Glucose-resistance
↑ Body weight
↑ Leptin levels
No GnRH
↓ LH & FSH
↓ Sex-steroids
Sexual dysfunctions
Role of kisspeptin
Sexual dimorphism
Adapted from Talson et al, 2014

11. Potential therapeutic role: IVF
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 

12. Conclusion : Kisspeptin’s role in neuroendocrine disorders.
Therapy
In Vitro Fertilization
Ovarian cycle
Puberty
Physiology
Pathophysiology
Hypogonadotropic hypogonadism
Diabetes and Obesity
Precocious puberty
PCOS
Kisspeptin system

13. Thank you for your attention !