Abstract
Background/Aims: Kisspeptin (KP) is a key player in the regulation of the release of gonadotropin-releasing hormone (GnRH), which increases the secretion of gonadotropin during puberty to establish reproductive function and regulate the hypothalamic-pituitary-gonadal axis. Premature activation of GnRH secretion leads to idiopathic/central gonadotropin-dependent precocious puberty (CPP). We aimed to compare the blood KP concentrations in girls with CPP and healthy controls. Methods: A systematic review and meta-analysis was performed. We searched MEDLINE, EMBASE, The Cochrane Library, and SciELO. Random-effects model and standardized mean difference (SMD) were used. Heterogeneity was assessed through I2. Meta-regression considered patient age, KP fraction, and analytical method for KP measurement. Results: The 11 studies included comprised 316 CPP patients and 251 controls. Higher KP levels in the CPP group were found (SMD 1.53; CI 95% = 0.56–2.51). Subgroup analysis revealed association with patient age (p = 0.048), indicating a positive correlation between elevation in KP concentration and age in CPP group. A group of patients with precocious thelarche (PT) from 5 of the included studies comprising 121 patients showed higher levels of KP (1.10; −0.25–2.45: CI 95%) and high heterogeneity (I2 = 91%). The CPP/PT ratio for KP level indicates KP 36% higher on CPP than PT patients. Conclusions: A consistent difference in KP levels between girls with CPP and controls was identified. While there are important limitations in KP assays which argue against its use as a diagnostic tool, the KP levels in CPP versus control and PT children are consistent with the predicted mechanisms and pathophysiology of CPP.
References
1.
Latronico
AC
, Brito
VN
, Carel
JC
. Causes, diagnosis, and treatment of central precocious puberty
. Lancet Diabetes Endocrinol
. 2016
;4
(3
):265
–74
. .2.
Macedo
DB
, Silveira
LF
, Bessa
DS
, Brito
VN
, Latronico
AC
. Sexual precocity–genetic bases of central precocious puberty and autonomous gonadal activation
. Endocr Dev
. 2016
;29
:50
–71
. .3.
Roelants
M
, Hauspie
R
, Hoppenbrouwers
K
. References for growth and pubertal development from birth to 21 years in Flanders, Belgium
. Ann Hum Biol
. 2009
;36
(6
):680
–94
. .4.
Fuqua
JS
. Treatment and outcomes of precocious puberty: an update
. J Clin Endocrinol Metab
. 2013
;98
(6
):2198
. .5.
Aguirre
RS
, Eugster
EA
. Central precocious puberty: from genetics to treatment
. Best Pract Res Clin Endocrinol Metab
. 2018
;32
(4
):343
–54
. .6.
Bianco
SD
. A potential mechanism for the sexual dimorphism in the onset of puberty and incidence of idiopathic central precocious puberty in children: sex-specific kisspeptin as an integrator of puberty signals
. Front Endocrinol
. 2012
;3
:149
. .7.
Kotani
M
, Detheux
M
, Vandenbogaerde
A
, Communi
D
, Vanderwinden
JM
, Le Poul
E
, et al. The metastasis suppressor gene KISS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54
. J Biol Chem
. 2001
;276
(37
):34631
–6
. .8.
Ohtaki
T
, Shintani
Y
, Honda
S
, Matsumoto
H
, Hori
A
, Kanehashi
K
, et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor
. Nature
. 2001
;411
(6837
):613
–7
. .9.
Trevisan
CM
, Montagna
E
, de Oliveira
R
, Christofolini
DM
, Barbosa
CP
, Crandall
KA
, et al. Kisspeptin/GPR54 system: what do we know about its role in human reproduction?
Cell Physiol Biochem
. 2018
;49
(4
):1259
–76
. .10.
de Roux
N
, Genin
E
, Carel
JC
, Matsuda
F
, Chaussain
JL
, Milgrom
E
. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54
. Proc Natl Acad Sci USA
. 2003
;100
(19
):10972
–6
. .11.
Seminara
SB
, Messager
S
, Chatzidaki
EE
, Thresher
RR
, Acierno
JS
Jr, Shagoury
JK
, et al. The GPR54 gene as a regulator of puberty
. N Engl J Med
. 2003
;349
(17
):1614
–27
. .12.
Harms
JF
, Welch
DR
, Miele
ME
. KISS1 metastasis suppression and emergent pathways
. Clin Exp Metastasis
. 2003
;20
(1
):11
–8
. .13.
Simoni
M
, Nieschlag
E
. FSH in therapy: physiological basis, new preparations and clinical use
. Reprod Med Rev
. 1995
;4
(3
):163
–77
. .14.
Roa
J
, Navarro
VM
, Tena-Sempere
M
. Kisspeptins in reproductive biology: consensus knowledge and recent developments
. Biol Reprod
. 2011
;85
(4
):650
–60
. .15.
Seminara
SB
. Metastin and its G protein-coupled receptor, GPR54: critical pathway modulating GnRH secretion
. Front Neuroendocrinol
. 2005
;26
(3–4
):131
–8
. .16.
Bianco
SD
, Vandepas
L
, Correa-Medina
M
, Gereben
B
, Mukherjee
A
, Kuohung
W
, et al. KISS1R intracellular trafficking and degradation: effect of the Arg386Pro disease-associated mutation
. Endocrinology
. 2011
;152
(4
):1616
–26
. .17.
Jayasena
CN
, Nijher
GM
, Narayanaswamy
S
, De Silva
A
, Abbara
A
, Ghatei
MA
, et al. Age-dependent elevations in plasma kisspeptin are observed in boys and girls when compared with adults
. Ann Clin Biochem
. 2014
;51
(Pt 1
):89
–96
. .18.
Rehman
R
, Fatima
SS
, Alam
F
, Ashraf
M
, Zafar
S
. Kisspeptin and attributes of infertile males and females: a cross-sectional study in a subset of Pakistani population
. Andrologia
. 2019
;51
(9
):e13370
. .19.
Kaya
A
, Orbak
Z
, Polat
H
, Çayır
A
, Erdil
A
, Döneray
H
. Plasma kisspeptin levels in newborn infants with breast enlargement
. J Clin Res Pediatr Endocrinol
. 2015
;7
(3
):192
–6
. .20.
Pita
J
, Barrios
V
, Gavela-Pérez
T
, Martos-Moreno
GÁ
, Muñoz-Calvo
MT
, Pozo
J
, et al. Circulating kisspeptin levels exhibit sexual dimorphism in adults, are increased in obese prepubertal girls and do not suffer modifications in girls with idiopathic central precocious puberty
. Peptides
. 2011
;32
(9
):1781
–6
. .21.
Jayasena
CN
, Abbara
A
, Veldhuis
JD
, Comninos
AN
, Ratnasabapathy
R
, De Silva
A
, et al. Increasing LH pulsatility in women with hypothalamic amenorrhoea using intravenous infusion of kisspeptin-54
. J Clin Endocrinol Metab
. 2014
;99
(6
):E953
–61
. .22.
Teilmann
G
, Pedersen
CB
, Jensen
TK
, Skakkebaek
NE
, Juul
A
. Prevalence and incidence of precocious pubertal development in Denmark: an epidemiologic study based on national registries
. Pediatrics
. 2005
;116
(6
):1323
–8
. .23.
de Vries
L
, Guz-Mark
A
, Lazar
L
, Reches
A
, Phillip
M
. Premature thelarche: age at presentation aff ects clinical course but not clinical characteristics or risk to progress to precocious puberty
. J. Pediatr.
2010
;156
:466
–71
.24.
Moher
D
, Shamseer
L
, Clarke
M
, Ghersi
D
, Liberati
A
, Petticrew
M
, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement
. Syst Rev
. 2015
;4
(1
):1
. .25.
Hozo
SP
, Djulbegovic
B
, Hozo
I
. Estimating the mean and variance from the median, range, and the size of a sample
. BMC Med Res Methodol
. 2005
;5
:13
. .26.
Modesti
PA
, Reboldi
G
, Cappuccio
FP
, Agyemang
C
, Remuzzi
G
, Rapi
S
, et al. ESH working group on CV risk in low resource settings. Panethnic differences in blood pressure in Europe: a systematic review and meta-analysis
. PLoS One
. 2016
;11
:e0147601
.27.
Borenstein
M
. Introduction to meta-analysis
. Chichester, UK
: John Wiley & Sons
; 2009
.28.
Higgins
JP
, Thompson
SG
, Deeks
JJ
, Altman
DG
. Measuring inconsistency in meta-analyses
. BMJ
. 2003
;327
(7414
):557
–60
. .29.
de Assis Rodrigues
NP
, Laganà
AS
, Zaia
V
, Vitagliano
A
, Barbosa
CP
, de Oliveira
O
, et al. The role of Kisspeptin levels in polycystic ovary syndrome: a systematic review and meta-analysis
. Arch Gynecol Obstet
. 2019
;300
:423
–34
.30.
Sterne
JA
, Egger
M
. Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis
. J Clin Epidemiol
. 2001
;54
(10
):1046
–55
. .31.
Baujat
B
, Mahé
C
, Pignon
J-P
, Hill
C
. A graphical method for exploring heterogeneity in meta-analyses: application to a meta-analysis of 65 trials: graphical method for exploring heterogeneity in meta-analyses
. Stat. Med.
2002
;21
(18
):2641
–52
.32.
Schwarzer
G
, Carpenter
JR
, Rücker
G
. Meta-analysis with R
. Cham Heidelberg New York Dordrecht London
: Springer
; 2015
.33.
Viechtbauer
W
. Conducting meta-analyses in R with the meta for package
. J Stat Soft
. 2010
;36
(3
):1
–48
. .34.
de Vries
L
, Shtaif
B
, Phillip
M
, Gat-Yablonski
G
. Kisspeptin serum levels in girls with central precocious puberty
. Clin Endocrinol
. 2009
;71
(4
):524
–8
. .35.
Rhie
YJ
, Lee
KH
, Eun
SH
, Choi
BM
, Chae
HW
, Kwon
AR
, et al. Serum kisspeptin levels in Korean girls with central precocious puberty
. J Korean Med Sci
. 2011
;26
(7
):927
–31
. .36.
Demirbilek
H
, Gonc
EN
, Ozon
A
, Alikasifoglu
A
, Kandemir
N
. Evaluation of serum kisspeptin levels in girls in the diagnosis of central precocious puberty and in the assessment of pubertal suppression
. J Pediatr Endocrinol Metab
. 2012
;25
(3–4
):313
–6
. .37.
Chen
CY
, Chou
YY
, Wu
YM
, Lin
CC
, Lin
SJ
, Lee
CC
. Phthalates may promote female puberty by increasing kisspeptin activity
. Hum Reprod
. 2013
;28
(10
):2765
–73
. .38.
Abaci
A
, Çatlı
G
, Anık
A
, Küme
T
, Çalan
OG
, Dündar
BN
, et al. Significance of serum neurokinin B and kisspeptin levels in the differential diagnosis of premature the larche and idiopathic central precocious puberty
. Peptides
. 2015
;64
:29
–33
.39.
Yang
YU
, Xiong
XY
, Yang
LI
, Xie
L
, Huang
H
. Testing of kisspeptin levels in girls with idiopathic central precocious puberty and its significance
. Exp Ther Med
. 2015
;9
(6
):2369
–73
. .40.
Özgen
İT
, Torun
E
, Bayraktar-Tanyeri
B
, Durmaz
E
, Kılıç
E
, Cesur
Y
. The relation of urinary bisphenol A with kisspeptin in girls diagnosed with central precocious puberty and premature the larche
. J Pediatr Endocrinol Metab
. 2016
;29
(3
):337
–41
. .41.
Parlak
M
, Türkkahraman
D
, Ellidağ
HY
, Çelmeli
G
, Parlak
AE
, Yılmaz
N
. Basal serum neurokinin B levels in differentiating idiopathic central precocious puberty from premature the larche
. J Clin Res Pediatr Endocrinol
. 2017
;9
(2
):101
–5
. .42.
Kang
MJ
, Oh
YJ
, Shim
YS
, Baek
JW
, Yang
S
, Hwang
IT
. The usefulness of circulating levels of leptin, kisspeptin, and neurokinin B in obese girls with precocious puberty
. Gynecol Endocrinol
. 2018
;34
(7
):627
–30
. .43.
Ge
W
, Wang
HL
, Shao
HJ
, Liu
HW
, Xu
RY
. Evaluation of serum makorin ring finger protein 3 (MKRN3) levels in girls with idiopathic central precocious puberty and premature the larche
. Physiol Res
. 2020
;69
(1
):127
–33
. .44.
Carel
JC
, Léger
J
. Clinical practice. Precocious puberty
. N Engl J Med
. 2008
;358
(22
):2366
–77
. .45.
Brito
VN
, Latronico
AC
, Arnhold
IJ
, Mendonça
BB
. Update on the etiology, diagnosis and therapeutic management of sexual precocity
. Arq Bras Endocrinol Metabol
. 2008
;52
(1
):18
–31
. .46.
Wolfe
A
, Hussain
MA
. The emerging role(s) for kisspeptin in metabolism in mammals
. Front Endocrinol
. 2018
;9
:184
. .47.
Hussain
MA
, Song
WJ
, Wolfe
A
. There is kisspeptin – and then there is kisspeptin
. Trends Endocrinol Metab
. 2015
;26
(10
):564
–72
. .48.
Shahab
M
, Mastronardi
C
, Seminara
SB
, Crowley
WF
, Ojeda
SR
, Plant
TM
. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates
. Proc Natl Acad Sci USA
. 2005
;102
(6
):2129
–34
. .49.
Navarro
VM
, Fernández-Fernández
R
, Castellano
JM
, Roa
J
, Mayen
A
, Barreiro
ML
, et al. Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54
. J Physiol
. 2004
;561
(Pt 2
):379
–86
. .50.
Ramachandran
R
, Patterson
M
, Murphy
KG
, Dhillo
WS
, Patel
S
, Kazarian
A
, et al. Preanalytical factors affecting RIA measurement of plasma kisspeptin
. Clin Chem
. 2008
;54
(3
):615
–7
. .51.
Owens
LA
, Abbara
A
, Lerner
A
, O'floinn
S
, Christopoulos
G
, Khanjani
S
, et al. The direct and indirect effects of kisspeptin-54 on granulosa lutein cell function
. Hum Reprod
. 2018
;33
(2
):292
–302
. .52.
Abbara
A
, Jayasena
CN
, Christopoulos
G
, Narayanaswamy
S
, Izzi-Engbeaya
C
, Nijher
GM
, et al. Efficacy of kisspeptin-54 to trigger oocyte maturation in women at high risk of ovarian hyperstimulation syndrome (OHSS) during in vitro fertilization (IVF) therapy
. J Clin Endocrinol Metab
. 2015
;100
(9
):3322
–31
. .53.
Albers-Wolthers
CH
, de Gier
J
, Rutten
VP
, van Kooten
PJ
, Leegwater
PA
, Schaefers-Okkens
AC
, et al. The effects of kisspeptin agonist canine KP-10 and kisspeptin antagonist p271 on plasma LH concentrations during different stages of the estrous cycle and anestrus in the bitch
. Theriogenology
. 2016
;86
(2
):589
–95
. .54.
Caraty
A
, Decourt
C
, Briant
C
, Beltramo
M
. Kisspeptins and the reproductive axis: potential applications to manage reproduction in farm animals
. Domest Anim Endocrinol
. 2012
;43
(2
):95
–102
. .55.
Whitlock
BK
, Daniel
JA
, Amelse
LL
, Tanco
VM
, Chameroy
KA
, Schrick
FN
. Kisspeptin receptor agonist (FTM080) increased plasma concentrations of luteinizing hormone in anestrous ewes
. Peer J
. 2015
;3
:e1382
. .56.
Delemarre-van de Waal
HA
. Regulation of puberty
. Best Pract Res Clin Endocrinol Metab
. 2002
;16
(1
):1
–12
. .57.
Rosenfield
RL
. Normal and almost normal precocious variations in pubertal development. Premature pubarche and premature thelarche revisited
. Hormone Res
. 1994
;41
:7
–13
.58.
Farello
G
, Altieri
C
, Cutini
M
, Pozzobon
G
, Verrotti
A
. Review of the literature on current changes in the timing of pubertal development and the incomplete forms of early puberty
. Front Pediatr
. 2019
;7
:147
. .59.
Sanchez-Garrido
MA
, Tena-Sempere
M
. Metabolic control of puberty: roles of leptin and kisspeptins
. Horm Behav
. 2013
;64
(2
):187
–94
. .60.
Castellano
JM
, Navarro
VM
, Fernández-Fernández
R
, Nogueiras
R
, Tovar
S
, Roa
J
, et al. Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition
. Endocrinology
. 2005
;146
(9
):3917
–25
. .61.
Smith
JT
, Acohido
BV
, Clifton
DK
, Steiner
RA
. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse
. J Neuroendocrinol
. 2006
;18
(4
):298
–303
. .© 2021 S. Karger AG, Basel
2021
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
