The role of kisspeptin in neuroendocrine disorders
Maria Fldi & Esther Hazane Leroyer JPEMS 2015, Szeged Under the supervision of Dr. Krisztina Csabafi, M.D, PhD, Department of Pathophysiology Introduction Kiss1 receptor Kisspeptin (protein)
Kiss1 receptor Kisspeptin gene and its protein products : kisspeptin-54, kisspeptin-14, kisspeptin-13, kisspeptin-10.(http://d6igaq6njxgjh.cloudfront.net/content/physrev/92/3/1235/F2.large.jpg) Kisspeptin (protein) All share the same C-ter + N-ter. RF-amide involved in nociceptive transduction, feeding behaviour, regulation of pituitary hormones secretion 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 Physiology: ovarian cycle
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 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) Kisspeptins role 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. Pathology: Precocious Puberty
Development of secondarysexual characters, before theage of 7 for girls and 9 forboys. Immature bone age Immature critical fat mass BUT activating mutation Kisspeptin GnRH pulses GnRH LH & FSH Sex-steroids No menarches Puberty Pathology : Hypogonadotropic Hypogonadism.
INACTIVATING MUTATION Kisspeptin KISS1R decrease of signalling pathway 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 Pathology: Obesity & Diabetes.
Kiss1r KO female MICE 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 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 Conclusion : Kisspeptins role in neuroendocrine disorders.
Therapy In Vitro Fertilization Ovarian cycle Puberty Physiology Pathophysiology Hypogonadotropic hypogonadism Diabetes and Obesity Precocious puberty PCOS Kisspeptin system Thank you for your attention !