Background/Aims: Studies are lacking regarding the timing of peak growth hormone (PGH) response. We aim to elucidate the timing of PGH response to arginine and levodopa (A-LD) and evaluate the influence of body mass index (BMI) and other metabolic parameters on PGH. Methods: During growth hormone (GH) stimulation testing (ST) with A-LD, serum GH was measured at baseline and every 30 min up to 180 min. The PGH cut-off was defined as <10 ng/mL. IGF-1, IGF BP3, BMI, and metabolic parameters were obtained in a fasting state at baseline. Results: In the 315 tested children, stimulated PGH levels occurred at or before 120 min in 97.8% and at 180 min in 2.2%. GH area under the curve (AUC) positively correlated with PGH in all patients and with IGF-1 in pubertal males and females. BMI negatively correlated with PGH in all subjects. GH AUC negatively correlated with HOMA-IR and total cholesterol. Conclusion: We propose termination of the GH ST with A-LD at 120 min since omission of GH measurement at 180 min did not alter the diagnosis of GH deficiency based on a cut-off of < 10 ng/mL. BMI should be considered in the interpretation of GH ST with A-LD. The relationships between GH AUC and metabolic parameters need further study.

1.
Chesover
AD
,
Dattani
MT
.
Evaluation of growth hormone stimulation testing in children
.
Clin Endocrinol (Oxf)
.
2016
May
;
84
(
5
):
708
14
.
[PubMed]
0300-0664
2.
Grimberg
A
,
DiVall
SA
,
Polychronakos
C
,
Allen
DB
,
Cohen
LE
,
Quintos
JB
, et al.;
Drug and Therapeutics Committee and Ethics Committee of the Pediatric Endocrine Society
.
Guidelines for Growth Hormone and Insulin-Like Growth Factor-I Treatment in Children and Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and Primary Insulin-Like Growth Factor-I Deficiency
.
Horm Res Paediatr
.
2016
;
86
(
6
):
361
97
.
[PubMed]
1663-2818
3.
Cohen
P
,
Rogol
AD
,
Deal
CL
,
Saenger
P
,
Reiter
EO
,
Ross
JL
, et al.;
2007 ISS Consensus Workshop participants
.
participants ISSCW: Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop
.
J Clin Endocrinol Metab
.
2008
Nov
;
93
(
11
):
4210
7
.
[PubMed]
0021-972X
4.
Cohen
P
,
Germak
J
,
Rogol
AD
,
Weng
W
,
Kappelgaard
AM
,
Rosenfeld
RG
;
American Norditropin Study Group
.
Variable degree of growth hormone (GH) and insulin-like growth factor (IGF) sensitivity in children with idiopathic short stature compared with GH-deficient patients: evidence from an IGF-based dosing study of short children
.
J Clin Endocrinol Metab
.
2010
May
;
95
(
5
):
2089
98
.
[PubMed]
0021-972X
5.
Graber
E
,
Rapaport
R
.
Growth and growth disorders in children and adolescents
.
Pediatr Ann
.
2012
Apr
;
41
(
4
):
e1
9
.
[PubMed]
0090-4481
6.
van Vught
AJ
,
Nieuwenhuizen
AG
,
Gerver
WJ
,
Veldhorst
MA
,
Brummer
RJ
,
Westerterp-Plantenga
MS
.
Pharmacological and physiological growth hormone stimulation tests to predict successful GH therapy in children
.
J Pediatr Endocrinol Metab
.
2009
Aug
;
22
(
8
):
679
94
.
[PubMed]
0334-018X
7.
Gandrud
LM
,
Wilson
DM
.
Is growth hormone stimulation testing in children still appropriate?
Growth Horm IGF Res
.
2004
Jun
;
14
(
3
):
185
94
.
[PubMed]
1096-6374
8.
Cohen
P
.
Statement 1: a serum insulin-like growth factor I (IGF-I) level should be part of the evaluation of children with short stature
.
Pediatr Endocrinol Rev
.
2008
Apr
;
5
Suppl 3
:
834
6
.
[PubMed]
1565-4753
9.
Muster
L
,
Zangen
DH
,
Nesher
R
,
Hirsch
HJ
,
Muster
Z
,
Gillis
D
.
Arginine and clonidine stimulation tests for growth hormone deficiency revisited—do we really need so many samples?
J Pediatr Endocrinol Metab
.
2009
Mar
;
22
(
3
):
215
23
.
[PubMed]
0334-018X
10.
Jaruratanasirikul
S
,
Leethanaporn
K
,
Sriplung
H
.
Should the duration of the insulin tolerance test be shortened to 90 minutes?
J Pediatr Endocrinol Metab
.
2004
Aug
;
17
(
8
):
1105
9
.
[PubMed]
0334-018X
11.
Galluzzi
F
,
Stagi
S
,
Parpagnoli
M
,
Losi
S
,
Pagnini
I
,
Favelli
F
, et al.
Oral clonidine provocative test in the diagnosis of growth hormone deficiency in childhood: should we make the timing uniform?
Horm Res
.
2006
;
66
(
6
):
285
8
.
[PubMed]
0301-0163
12.
Strich
D
,
Terespolsky
N
,
Gillis
D
.
Glucagon stimulation test for childhood growth hormone deficiency: timing of the peak is important
.
J Pediatr
.
2009
Mar
;
154
(
3
):
415
9
.
[PubMed]
0022-3476
13.
Lee
HS
,
Hwang
JS
.
Influence of body mass index on growth hormone responses to classic provocative tests in children with short stature
.
Neuroendocrinology
.
2011
;
93
(
4
):
259
64
.
[PubMed]
0028-3835
14.
Ho
KY
,
Evans
WS
,
Blizzard
RM
,
Veldhuis
JD
,
Merriam
GR
,
Samojlik
E
, et al.
Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations
.
J Clin Endocrinol Metab
.
1987
Jan
;
64
(
1
):
51
8
.
[PubMed]
0021-972X
15.
Iranmanesh
A
,
Lizarralde
G
,
Veldhuis
JD
.
Age and relative adiposity are specific negative determinants of the frequency and amplitude of growth hormone (GH) secretory bursts and the half-life of endogenous GH in healthy men
.
J Clin Endocrinol Metab
.
1991
Nov
;
73
(
5
):
1081
8
.
[PubMed]
0021-972X
16.
Makimura
H
,
Feldpausch
MN
,
Rope
AM
,
Hemphill
LC
,
Torriani
M
,
Lee
H
, et al.
Metabolic effects of a growth hormone-releasing factor in obese subjects with reduced growth hormone secretion: a randomized controlled trial
.
J Clin Endocrinol Metab
.
2012
Dec
;
97
(
12
):
4769
79
.
[PubMed]
0021-972X
17.
Radack
JA
,
White
PC
,
Adams-Huet
B
,
Oden
JD
.
Stimulated growth hormone concentrations in obese pediatric patients with mild and severe insulin resistance: a pilot study
.
J Pediatr Endocrinol Metab
.
2010
Apr
;
23
(
4
):
355
61
.
[PubMed]
0334-018X
18.
Qu
XD
,
Gaw Gonzalo
IT
,
Al Sayed
MY
,
Cohan
P
,
Christenson
PD
,
Swerdloff
RS
, et al.
Influence of body mass index and gender on growth hormone (GH) responses to GH-releasing hormone plus arginine and insulin tolerance tests
.
J Clin Endocrinol Metab
.
2005
Mar
;
90
(
3
):
1563
9
.
[PubMed]
0021-972X
19.
Stanley
TL
,
Feldpausch
MN
,
Murphy
CA
,
Grinspoon
SK
,
Makimura
H
.
Discordance of IGF-1 and GH stimulation testing for altered GH secretion in obesity
.
Growth Horm IGF Res
.
2014
Feb
;
24
(
1
):
10
5
.
[PubMed]
1096-6374
20.
Loche
S
,
Guzzetti
C
,
Pilia
S
,
Ibba
A
,
Civolani
P
,
Porcu
M
, et al.
Effect of body mass index on the growth hormone response to clonidine stimulation testing in children with short stature
.
Clin Endocrinol (Oxf)
.
2011
Jun
;
74
(
6
):
726
31
.
[PubMed]
0300-0664
21.
Rasmussen
MH
,
Hvidberg
A
,
Juul
A
,
Main
KM
,
Gotfredsen
A
,
Skakkebaek
NE
, et al.
Massive weight loss restores 24-hour growth hormone release profiles and serum insulin-like growth factor-I levels in obese subjects
.
J Clin Endocrinol Metab
.
1995
Apr
;
80
(
4
):
1407
15
.
[PubMed]
0021-972X
22.
Argente
J
,
Caballo
N
,
Barrios
V
,
Muñoz
MT
,
Pozo
J
,
Chowen
JA
, et al.
Multiple endocrine abnormalities of the growth hormone and insulin-like growth factor axis in patients with anorexia nervosa: effect of short- and long-term weight recuperation
.
J Clin Endocrinol Metab
.
1997
Jul
;
82
(
7
):
2084
92
.
[PubMed]
0021-972X
23.
Williams
T
,
Berelowitz
M
,
Joffe
SN
,
Thorner
MO
,
Rivier
J
,
Vale
W
, et al.
Impaired growth hormone responses to growth hormone-releasing factor in obesity. A pituitary defect reversed with weight reduction
.
N Engl J Med
.
1984
Nov
;
311
(
22
):
1403
7
.
[PubMed]
0028-4793
24.
Tanaka
K
,
Inoue
S
,
Numata
K
,
Okazaki
H
,
Nakamura
S
,
Takamura
Y
.
Very-low-calorie diet-induced weight reduction reverses impaired growth hormone secretion response to growth hormone-releasing hormone, arginine, and L-dopa in obesity
.
Metabolism
.
1990
Sep
;
39
(
9
):
892
6
.
[PubMed]
0026-0495
25.
Luque
RM
,
Kineman
RD
.
Impact of obesity on the growth hormone axis: evidence for a direct inhibitory effect of hyperinsulinemia on pituitary function
.
Endocrinology
.
2006
Jun
;
147
(
6
):
2754
63
.
[PubMed]
0013-7227
26.
Lee
EJ
,
Kim
KR
,
Lee
HC
,
Cho
JH
,
Nam
MS
,
Nam
SY
, et al.
Acipimox potentiates growth hormone response to growth hormone-releasing hormone by decreasing serum free fatty acid levels in hyperthyroidism
.
Metabolism
.
1995
Nov
;
44
(
11
):
1509
12
.
[PubMed]
0026-0495
27.
Kok
P
,
Buijs
MM
,
Kok
SW
,
Van Ierssel
IH
,
Frölich
M
,
Roelfsema
F
, et al.
Acipimox enhances spontaneous growth hormone secretion in obese women
.
Am J Physiol Regul Integr Comp Physiol
.
2004
Apr
;
286
(
4
):
R693
8
.
[PubMed]
0363-6119
28.
Coutant
R
,
Lahlou
N
,
Bouvattier
C
,
Bougnères
P
.
Circulating leptin level and growth hormone response to stimulation tests in obese and normal children
.
Eur J Endocrinol
.
1998
Dec
;
139
(
6
):
591
7
.
[PubMed]
0804-4643
29.
Popovic
V
.
Approach to testing growth hormone (GH) secretion in obese subjects
.
J Clin Endocrinol Metab
.
2013
May
;
98
(
5
):
1789
96
.
[PubMed]
0021-972X
30.
Murray
RD
,
Wieringa
GE
,
Lissett
CA
,
Darzy
KH
,
Smethurst
LE
,
Shalet
SM
.
Low-dose GH replacement improves the adverse lipid profile associated with the adult GH deficiency syndrome
.
Clin Endocrinol (Oxf)
.
2002
Apr
;
56
(
4
):
525
32
.
[PubMed]
0300-0664
31.
Hoffman
AR
,
Kuntze
JE
,
Baptista
J
,
Baum
HB
,
Baumann
GP
,
Biller
BM
, et al.
Growth hormone (GH) replacement therapy in adult-onset gh deficiency: effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial
.
J Clin Endocrinol Metab
.
2004
May
;
89
(
5
):
2048
56
.
[PubMed]
0021-972X
32.
Baronio
F
,
Mazzanti
L
,
Girtler
Y
,
Tamburrino
F
,
Fazzi
A
,
Lupi
F
, et al.
The Influence of Growth Hormone Treatment on Glucose Homeostasis in GrowthHormone-Deficient Children: A Six-Year Follow-Up Study
.
Horm Res Paediatr
.
2016
;
86
(
3
):
196
200
.
[PubMed]
1663-2818
33.
Kuromaru
R
,
Kohno
H
,
Ueyama
N
,
Hassan
HM
,
Honda
S
,
Hara
T
.
Long-term prospective study of body composition and lipid profiles during and after growth hormone (GH) treatment in children with GH deficiency: gender-specific metabolic effects
.
J Clin Endocrinol Metab
.
1998
Nov
;
83
(
11
):
3890
6
.
[PubMed]
0021-972X
34.
Capalbo
D
,
Mattace Raso
G
,
Esposito
A
,
Di Mase
R
,
Barbieri
F
,
Meli
R
, et al.
Cluster of cardiometabolic risk factors in children with GH deficiency: a prospective, case-control study
.
Clin Endocrinol (Oxf)
.
2014
Jun
;
80
(
6
):
856
62
.
[PubMed]
0300-0664
35.
Husbands
S
,
Ong
KK
,
Gilbert
J
,
Wass
JA
,
Dunger
DB
.
Increased insulin sensitivity in young, growth hormone deficient children
.
Clin Endocrinol (Oxf)
.
2001
Jul
;
55
(
1
):
87
92
.
[PubMed]
0300-0664
36.
Salomon
F
,
Cuneo
R
,
Sönksen
PH
.
Insulin sensitivity and insulin resistance in growth-hormone-deficient adults
.
Horm Res
.
1993
;
40
(
1-3
):
34
6
.
[PubMed]
0301-0163
37.
Johansson
JO
,
Fowelin
J
,
Landin
K
,
Lager
I
,
Bengtsson
BA
.
Growth hormone-deficient adults are insulin-resistant
.
Metabolism
.
1995
Sep
;
44
(
9
):
1126
9
.
[PubMed]
0026-0495
38.
Stanley
T
.
Diagnosis of growth hormone deficiency in childhood
.
Curr Opin Endocrinol Diabetes Obes
.
2012
Feb
;
19
(
1
):
47
52
.
[PubMed]
1752-296X
39.
Koppeschaar
HP
,
Popovic
V
,
Leal
A
,
Otero
XL
,
Torres
E
,
Paramo
C
, et al.
Growth hormone (GH) peaks versus areas under the curve in the diagnosis of adult GH deficiency: analysis of the variables provided by the GHRH + GHRP-6 test
.
Pituitary
.
2004
;
7
(
1
):
15
20
.
[PubMed]
1386-341X
40.
Matthews
DR
,
Hosker
JP
,
Rudenski
AS
,
Naylor
BA
,
Treacher
DF
,
Turner
RC
.
Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man
.
Diabetologia
.
1985
Jul
;
28
(
7
):
412
9
.
[PubMed]
0012-186X
41.
Loenneke
JP
,
Barnes
JT
,
Wilson
JM
,
Lowery
RP
,
Isaacs
MN
,
Pujol
TJ
.
Reliability of field methods for estimating body fat
.
Clin Physiol Funct Imaging
.
2013
Sep
;
33
(
5
):
405
8
.
[PubMed]
1475-0961
42.
Al Khalifah
R
,
Moisan
L
,
Bui
H
.
The shortened combined clonidine and arginine test for growth hormone deficiency is practical and specific: a diagnostic accuracy study
.
J Pediatr Endocrinol Metab
.
2016
Mar
;
29
(
3
):
305
10
.
[PubMed]
0334-018X
43.
Grimberg
A
,
Kutikov
JK
,
Cucchiara
AJ
.
Sex differences in patients referred for evaluation of poor growth
.
J Pediatr
.
2005
Feb
;
146
(
2
):
212
6
.
[PubMed]
0022-3476
44.
Rhee
N
,
Oh
KY
,
Yang
EM
,
Kim
CJ
.
Growth hormone responses to provocative tests in children with short stature
.
Chonnam Med J
.
2015
Apr
;
51
(
1
):
33
8
.
[PubMed]
2233-7385
45.
Gonçalves
JP
,
Correia
F
,
Cardoso
H
,
Borges
T
,
Oliveira
MJ
.
[Provocative tests in the diagnosis of childhood onset growth hormone insufficiency]
.
Acta Med Port
.
2014
Sep-Oct
;
27
(
5
):
587
92
.
[PubMed]
1646-0758
46.
Growth Hormone Research Society
;
GH Research Society
.
Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society
.
J Clin Endocrinol Metab
.
2000
Nov
;
85
(
11
):
3990
3
.
[PubMed]
0021-972X
47.
Murray
PG
,
Dattani
MT
,
Clayton
PE
.
Controversies in the diagnosis and management of growth hormone deficiency in childhood and adolescence
.
Arch Dis Child
.
2016
Jan
;
101
(
1
):
96
100
.
[PubMed]
0003-9888
48.
Stanley
TL
,
Levitsky
LL
,
Grinspoon
SK
,
Misra
M
.
Effect of body mass index on peak growth hormone response to provocative testing in children with short stature
.
J Clin Endocrinol Metab
.
2009
Dec
;
94
(
12
):
4875
81
.
[PubMed]
0021-972X
49.
Gleeson
HK
,
Souza
AH
,
Gill
MS
,
Wieringa
GE
,
Barretto
ES
,
Barretto-Filho
JA
, et al.
Lipid profiles in untreated severe congenital isolated growth hormone deficiency through the lifespan
.
Clin Endocrinol (Oxf)
.
2002
Jul
;
57
(
1
):
89
95
.
[PubMed]
0300-0664
50.
Cordido
F
,
Garcia-Buela
J
,
Sangiao-Alvarellos
S
,
Martinez
T
,
Vidal
O
.
The decreased growth hormone response to growth hormone releasing hormone in obesity is associated to cardiometabolic risk factors
.
Mediators Inflamm
.
2010
;
2010
:
434562
.
[PubMed]
0962-9351
51.
Russell
M
,
Bredella
M
,
Tsai
P
,
Mendes
N
,
Miller
KK
,
Klibanski
A
, et al.
Relative growth hormone deficiency and cortisol excess are associated with increased cardiovascular risk markers in obese adolescent girls
.
J Clin Endocrinol Metab
.
2009
Aug
;
94
(
8
):
2864
71
.
[PubMed]
0021-972X
52.
Utz
AL
,
Yamamoto
A
,
Hemphill
L
,
Miller
KK
.
Growth hormone deficiency by growth hormone releasing hormone-arginine testing criteria predicts increased cardiovascular risk markers in normal young overweight and obese women
.
J Clin Endocrinol Metab
.
2008
Jul
;
93
(
7
):
2507
14
.
[PubMed]
0021-972X
53.
Ho
KK
,
Participants
GH
;
2007 GH Deficiency Consensus Workshop Participants
.
Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia
.
Eur J Endocrinol
.
2007
Dec
;
157
(
6
):
695
700
.
[PubMed]
0804-4643
54.
Corneli
G
,
Di Somma
C
,
Baldelli
R
,
Rovere
S
,
Gasco
V
,
Croce
CG
, et al.
The cut-off limits of the GH response to GH-releasing hormone-arginine test related to body mass index
.
Eur J Endocrinol
.
2005
Aug
;
153
(
2
):
257
64
.
[PubMed]
0804-4643
55.
Gómez
JM
,
Espadero
RM
,
Escobar-Jiménez
F
,
Hawkins
F
,
Picó
A
,
Herrera-Pombo
JL
, et al.
Growth hormone release after glucagon as a reliable test of growth hormone assessment in adults
.
Clin Endocrinol (Oxf)
.
2002
Mar
;
56
(
3
):
329
34
.
[PubMed]
0300-0664
56.
Popovic
V
,
Leal
A
,
Micic
D
,
Koppeschaar
HP
,
Torres
E
,
Paramo
C
, et al.
GH-releasing hormone and GH-releasing peptide-6 for diagnostic testing in GH-deficient adults
.
Lancet
.
2000
Sep
;
356
(
9236
):
1137
42
.
[PubMed]
0140-6736
57.
Kelestimur
F
,
Popovic
V
,
Leal
A
,
Van Dam
PS
,
Torres
E
,
Perez Mendez
LF
, et al.
Effect of obesity and morbid obesity on the growth hormone (GH) secretion elicited by the combined GHRH + GHRP-6 test
.
Clin Endocrinol (Oxf)
.
2006
Jun
;
64
(
6
):
667
71
.
[PubMed]
0300-0664
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.