PMID- 24615662
OWN - NLM
STAT- MEDLINE
DCOM- 20140918
LR  - 20220311
IS  - 1460-2369 (Electronic)
IS  - 1355-4786 (Print)
IS  - 1355-4786 (Linking)
VI  - 20
IP  - 4
DP  - 2014 Jul-Aug
TI  - The kisspeptin-GnRH pathway in human reproductive health and disease.
PG  - 485-500
LID - 10.1093/humupd/dmu009 [doi]
AB  - BACKGROUND: The discovery of kisspeptin as key central regulator of GnRH 
      secretion has led to a new level of understanding of the neuroendocrine 
      regulation of human reproduction. The related discovery of the 
      kisspeptin-neurokinin B-dynorphin (KNDy) pathway in the last decade has further 
      strengthened our understanding of the modulation of GnRH secretion by endocrine, 
      metabolic and environmental inputs. In this review, we summarize current 
      understanding of the physiological roles of these novel neuropeptides, and 
      discuss the clinical relevance of these discoveries and their potential 
      translational applications. METHODS: A systematic literature search was performed 
      using PUBMED for all English language articles up to January 2014. In addition, 
      the reference lists of all relevant original research articles and reviews were 
      examined. This review focuses mainly on published human studies but also draws on 
      relevant animal data. RESULTS: Kisspeptin is a principal regulator of the 
      secretion of gonadotrophins, and through this key role it is critical for the 
      onset of puberty, the regulation of sex steroid-mediated feedback and the control 
      of adult fertility. Although there is some sexual dimorphism, both 
      neuroanatomically and functionally, these functions are apparent in both men and 
      women. Kisspeptin acts upstream of GnRH and, following paracrine stimulatory and 
      inhibitory inputs from neurokinin B and dynorphin (KNDy neuropeptides), signals 
      directly to GnRH neurones to control pulsatile GnRH release. When administered to 
      humans in different isoforms, routes and doses, kisspeptin robustly stimulates LH 
      secretion and LH pulse frequency. Manipulation of the KNDy system is currently 
      the focus of translational research with the possibility of future clinical 
      application to regulate LH pulsatility, increasing gonadal sex steroid secretion 
      in reproductive disorders characterized by decreased LH pulsatility, including 
      hypothalamic amenorrhoea and hypogonadotropic hypogonadism. Conversely there may 
      be scope to reduce the activity of the KNDy system to reduce LH secretion where 
      hypersecretion of LH adds to the phenotype, such as in polycystic ovary syndrome. 
      CONCLUSIONS: Kisspeptin is a recently discovered neuromodulator that controls 
      GnRH secretion mediating endocrine and metabolic inputs to the regulation of 
      human reproduction. Manipulation of kisspeptin signalling has the potential for 
      novel therapies in patients with pathologically low or high LH pulsatility.
CI  - (c) The Author 2014. Published by Oxford University Press on behalf of the European 
      Society of Human Reproduction and Embryology.
FAU - Skorupskaite, Karolina
AU  - Skorupskaite K
AD  - MRC Centre for Reproductive Health, The Queen's Medical Research Institute, 
      University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
FAU - George, Jyothis T
AU  - George JT
AD  - Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, 
      University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, UK.
FAU - Anderson, Richard A
AU  - Anderson RA
AD  - MRC Centre for Reproductive Health, The Queen's Medical Research Institute, 
      University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK 
      richard.anderson@ed.ac.uk.
LA  - eng
GR  - G1002033/MRC_/Medical Research Council/United Kingdom
GR  - G1002118/MRC_/Medical Research Council/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
GR  - G0701682/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20140309
PL  - England
TA  - Hum Reprod Update
JT  - Human reproduction update
JID - 9507614
RN  - 0 (Gonadal Steroid Hormones)
RN  - 0 (Kisspeptins)
RN  - 33515-09-2 (Gonadotropin-Releasing Hormone)
RN  - 74913-18-1 (Dynorphins)
RN  - 86933-75-7 (Neurokinin B)
RN  - 9002-67-9 (Luteinizing Hormone)
SB  - IM
MH  - Amenorrhea/etiology/physiopathology
MH  - Animals
MH  - Dynorphins/physiology
MH  - Feedback, Physiological/physiology
MH  - Female
MH  - Gonadal Steroid Hormones/physiology
MH  - Gonadotropin-Releasing Hormone/analogs & derivatives/*metabolism
MH  - Humans
MH  - Hypogonadism/etiology/physiopathology
MH  - Infertility/*etiology/physiopathology
MH  - Kisspeptins/*physiology
MH  - Luteinizing Hormone/metabolism
MH  - Male
MH  - Neurokinin B/physiology
MH  - Neurons/physiology
MH  - Reproduction/*physiology
MH  - Sex Characteristics
MH  - Sex Factors
MH  - Sexual Development/physiology
MH  - Signal Transduction/physiology
PMC - PMC4063702
OTO - NOTNLM
OT  - GnRH
OT  - LH pulsatility
OT  - kisspeptin
OT  - kisspeptin-neurokinin B-dynorphin
EDAT- 2014/03/13 06:00
MHDA- 2014/09/19 06:00
PMCR- 2014/03/09
CRDT- 2014/03/12 06:00
PHST- 2014/03/12 06:00 [entrez]
PHST- 2014/03/13 06:00 [pubmed]
PHST- 2014/09/19 06:00 [medline]
PHST- 2014/03/09 00:00 [pmc-release]
AID - dmu009 [pii]
AID - 10.1093/humupd/dmu009 [doi]
PST - ppublish
SO  - Hum Reprod Update. 2014 Jul-Aug;20(4):485-500. doi: 10.1093/humupd/dmu009. Epub 
      2014 Mar 9.