Impact of body mass index on growth hormone stimulation tests in children and adolescents: a systematic review and meta-analysis

Figures & data

Figure 1. Schematic representation of the hypothalamic-pituitary-somatotropic axis and the effect of several GH secretagogues used in GH stimulation tests. GH secretagogues can be administered orally (indicated by the tablet icon), intramuscularly, or intravenously (indicated by the syringe icon). Clonidine and hypoglycemia, either introduced by insulin in the ITT or by glucagon administration, directly stimulate pituitary secretion of GH. Beta-adrenergic receptor agonists such as arginine and L-dopa exert their GH stimulating effect by lowering the chronic inhibitory somatostatinergic tone. At the hypothalamic level, the neuropeptide galanin stimulates the release of GHRH. The synthetic growth hormone-releasing peptide hexarelin is a ligand for the growth hormone secretagogue receptor that stimulates the production of GHRH and inhibits the release of somatostatin [5]. GHRH: growth hormone-releasing hormone; GH: growth hormone; IGF-1: insulin-like growth factor-1; ITT: insulin tolerance test.

Figure 2. The PRISMA flow diagram for the systematic review. GH: growth hormone; IGF-1: insulin-like growth factor-1.

Table 1. Overview of baseline characteristics of included studies. In total, 58 studies were included describing n = 5135 children.

Study	n patients	Individual participant data available	Stature	Sex	Pubertal status	Age in years M ± SD or range (min–max)			Weight status M ± SD or range (min-max)
			Short or normal	% Male	% Pre-pubertal	GHD+	No GHD, OB+	No GHD, OB-	Type of weight measure*	GHD+	No GHD, OB+	No GHD, OB−
Referred for short stature
Patel et al. [57]	176	Yes	Short	61%	66%	–	NM	NM	BMI%	–	143.4 ± 16.0	93.6 ± 10.6
Stanley et al. [67]	116	Yes	Short	68%	72%	–	NM	NM	BMI SDS	–	1.9 ± 0.4	−0.1 ± 0.9
Lee et al. [42]	187	No	Short	66%	93%	8.3 ± 2.9	–	8.6 ± 2.9	BMI SDS	−0.5 ± 1.1	–	−0.9 ± 1.0
Loche et al. [49]	199	No GHD, OB + only	Short	67%	73%	10.1 ± 3.1	11.0 ± 4.6	10.7 ± 3.3	BMI SDS	−0.1 ± 1.5	2.3 ± 0.3	−0.6 ± 1.1
Lee et al. [43]	88	Yes	Short	58%	83%	–	NM	NM	BMI SDS	–	1.7 ± 0.2	−0.9 ± 0.9
Barrett et al. [24]	67	No	Short	67%	100%	11.8 ± 2.6	NM	NM	BMI SDS	0.2 ± 1.0	NM	NM
Yang et al. [78]	460	Yes	Short	39%	100%	7.4 ± 3.1	–	–	BMI SDS	0.3 ± 1.1	–	–
Yau et al. [79]	315	Yes	Short	70%	54%	11.5 ± 2.2	NM	NM	BMI SDS	0.0 ± 1.1	2.0	−0.5 ± 0.9
Case-control design
Wegienka et al. [77]	2	No	NM	0%	–	–	14.0 ± 0.0	–	–	–	NM	–
Croughs et al. [34]	27	No	Normal and short	52%	–	9.9 ± 3.1	9.5 ± 2.7	6.3 ± 3.4	–	NM	NM	NM
Kaplan et al. [40]	49	No	Normal and short	61%	100%	10.1 ± 3.7	4.0	7.5 ± 3.0	–	NM	NM	NM
Carnelutti et al. [28]	27	Yes	Normal	48%	–	–	7.6 ± 2.7	7.6 ± 1.4	IBW%	–	153.4 ± 11.4	NM
Weber et al. [76]	35	Yes	Normal and short	46%	–	–	13.0 ± 2.7	10.6 ± 2.8	BMI SDS	–	2.7 ± 0.4	−0.4 ± 2.1
Parra et al. [55]	25	No	Normal	44%	–	–	12.4 ± 3.0	14.1 ± 3.2	BMI SDS	–	3.3 ± 0.6	0.2 ± 0.7
Girard et al. [38]	80	Yes	Normal and short	–	–	–	10.5 ± 2.9	10.5 ± 1.3	BMI SDS	–	2.7 ± 0.6	1.5 ± 0.4
Komatsu et al. [41]	9	No	NM	78%	–	16.0	8.1 ± 3.3	–	–	NM	NM	–
Vanderschueren et al. [74]	43	No	Normal	–	100%	NM	NM	NM	–	NM	NM	NM
Josefsberg et al. [39]	717	No	Normal and short	72%	–	–	13.4 ± 3.2	12.1 ± 3.9	Weight SDS	–	1.3 ± 1.5	−2.0
Topper et al. [71]	19	Yes	Short	53%	47%	–	10.0 ± 3.7	11.8 ± 2.4	Skinfold mm	–	29.4 ± 6.6	6.2 ± 1.2
Pertzelan et al. [59]	9	Yes	NM	58%	22%	–	11.5 ± 3.3	–	Weight SDS – height SDS	–	4.0 ± 1.7	–
Pintor et al. [60]	37	No GHD, OB + only	Normal and short	79%	64%	10.3 ± 2.5	8.7 ± 1.5	10.7 ± 3.9	BMI SDS	NM	2.7 ± 0.4	NM
Ranke et al. [62]	68	No	Normal and short	–	62%	12.2 ± 4.4	NM	10.7	–	NM	NM	NM
Van Vliet et al. [73]	34	Yes	Short	62%	88%	11.3 ± 5.3	10.9 ± 4.0	10.6 ± 2.5	BMI SDS	0.7 ± 1.1	2.6 ± 0.4	0.1 ± 1.0
Loche et al. [47]	30	No GHD, OB + only	Normal	57%	100%	NM	9.3 ± 2.2	NM	BMI SDS	NM	3.1 ± 0.8	NM
Rosskamp et al. [64]	40	No	Normal	50%	58%	–	10.6 ± 3.3	11.1 ± 3.4	–	–	NM	NM
Cordido et al. [30]	2	Yes	Normal	50%	–	–	14.0 ± 2.8	–	BMI SDS	–	2.5 ± 0.5	–
Ghigo et al. [37]	17	No	Normal	71%	100%	–	8.7 ± 0.9	9–14	BMI	–	26.7 ± 1.5	NM
Loche et al. [50]	19	No	Short	68%	100%	–	5.2–13.0	6.8–11.3	IBW%	–	145.8–198.2	NM
Cordido et al. [31]	4	Yes	Normal	0%	–	–	13.0 ± 0.8	–	BMI SDS	–	2.7 ± 0.4	–
Loche et al. [52]	12	No	Short	75%	100%	–	8.8–10.0	7.7–12.8	–	–	NM	NM
Reiter et al. [63]	12	No	Short	0%	100%	–	–	10.6 ± 2.8	IBW%	–	–	93 ± 3.5
Singh et al. [65]	40	No	Normal	60%	–	–	9.0–14.0	9.0–16.0	–	–	NM	NM
Tanaka et al. [68]	6	No	NM	33%	0%	–	17.2 ± 2.4	–	BMI	–	34.7 ± 4.7	–
Tanaka et al. [69]	942	No	NM	65%	84%	9.8 ± 3.5	–	–	–	NM	–	–
Loche et al. [51]	17	No	Short	59%	–	–	5.3–10.7	6.8–11.3	IBW%	–	148–200	90–110
Loche et al. [45]	13	No	Short	69%	100%	–	6.4–10.6	6.8–11.0	IBW%	–	141–186	90–110
Cappa et al. [27]	17	No GHD, OB + only	Normal and short	65%	100%	–	9.4 ± 2.4	10.4 ± 1.6	IBW%	–	NM	90–110
Loche et al. [48]	14	No	Short	64%	–	–	5.3–12.8	6.8–11.3	IBW%	–	142–225	90–110
Martul et al. [53]	106	No	Normal	–	100%	NM	NM	NM	–	NM	NM	NM
Loche et al. [46]	60	No	Short	58%	–	8.4–21	7.5–12.0	5.9–14	BMI	NM	23.0–30.5	NM
Vaccaro et al. [72]	24	No	Normal and short	67%	100%	–	9.6 ± 1.3	10.7 ± 2.5	IBW%	–	131.5 ± 15.8	98.5 ± 9.2
Volta et al. [75]	53	No	Normal and short	58%	55%	–	10.9 ± 2.5	10.2 ± 3.1	BMI	–	28.4 ± 3.6	NM
Bideci et al. [26]	82	No	Normal	51%	49%	–	10.5 ± 3.0	10.3 ± 2.9	BMI	–	27.6 ± 4.1	18.8 ± 2.0
Coutant et al. [33]	42	No	NM	60%	100%	–	9.6 ± 1.9	–	BMI	–	25.6 ± 2.6	–
Pirazzoli et al. [61]	56	No	Short	0%	100%	NM	NM	NM	–	NM	NM	NM
Misra et al. [54]	30	No	Normal	0%	0%	–	13.7 ± 1.7	16.1 ± 1.6	BMI SDS	–	3.7 ± 1.5	0.0 ± 0.5
Perotti et al. [58]	30	No	Normal	47%	0%	–	–	15.9 ± 1.4	BMI	–	–	21.4 ± 2.9
Liang et al. [44]	108	No	Normal	84%	68%	–	12.2 ± 1.4	11.7 ± 2.0	BMI SDS	–	2.5 ± 0.9	−0.1 ± 0.9
Syndromic obesity – PWS
Pertzelan et al. [59]	3	Yes	NM	58%	100%	10.9 ± 1.8	–	–	Weight SDS – height SDS	5.9 ± 2.7	–	–
Costeff et al. [32]	6	Yes	Normal and short	17%	83%	8.8 ± 0.6	–	10.4 ± 1.4	BMI SDS	1.5 ± 1.4	–	0.4 ± 0.7
Cappa et al. [27]	9	Yes	Normal and short	56%	–	12.8	10.5 ± 3.1	–	BMI SDS	4.3	4.3 ± 1.0	–
Beccaria et al. [25]	11	Yes	Normal and short	55%	18%	12.7 ± 1.2	11.8 ± 3.1	13.6 ± 1.9	BMI SDS	2.2 ± 0.9	2.1 ± 0.0	1.2 ± 0.8
Thacker et al. [70]	18	Yes	Normal and short	63%	–	8.1 ± 4.4	6.5 ± 0.5	11.6	BMI SDS	2.6 ± 1.3	3.9 ± 1.1	1.3
Casamitjana et al [80]	4	Yes	Normal	25%	0%	–	17.0	16.0 ± 1.0	BMI SDS	–	2.3	0.9 ± 0.1
Syndromic obesity – Turner syndrome
Reiter et al. [63]	17	Yes	Short	0%	100%	–	12.2 ± 2.3	10.6 ± 3.1	BMI SDS	–	2.5 ± 0.3	0.7 ± 0.8
Pasquino et al. [56]	15	Yes	Short	0%	100%	13.5 ± 1.9	10.9	12.2 ± 3.0	BMI SDS	0.8 ± 1.1	2.4	0.2 ± 1.4
Patel et al. [57]	48	No	Short	0%	87.5%	–	NM	NM		–	NM	NM
Vaccaro et al. [72]	15	No	Normal and short	0%	100%	–	NM	NM	–	–	NM	NM
Cavallo et al. [29]	300	No	NM	0%	0%	10.2 ± 3.0	NM	NM	BMI SDS	1.5 ± 1.5	NM	NM
Pirazzoli et al. [61]	75	No	Short	0%	100%	NM	NM	NM	–	NM	NM	NM
Syndromic obesity – BBS
Soliman et al. [66]	5	Yes	Normal and short	100%	100%	7.0	9.8 ± 3.5	–	BMI SDS	4.3	3.7 ± 0.3	–
Syndromic obesity – PHP1a
Germain-Lee et al. [36]	8	Yes	Normal and short	38%	63%	8.9 ± 2.3	–	6.8 ± 4.8	BMI	24.4 ± 2.5	–	15.6 ± 0.2
de Sanctis et al. [35]	10	Yes	Normal and short	20%	–	12.6 ± 0.8	4.9 ± 1.6	11.7 ± 3.2	BMI SDS	2.1 ± 0.1	3.5 ± 0.9	1.2 ± 1.2
Syndromic obesity – Kabuki syndrome
Schott et al. [81]	26	Yes	Normal and short	44%	100%	5.9 ± 2.2	6.8 ± 2.2	7.0 ± 2.0	BMI SDS	1.1 ± 1.6	3.1 ± 1.0	−0.2 ± 1.2

M: mean; SD(S): standard deviation (score); GHD+: patients with growth hormone deficiency; No GHD, OB+: patients without growth hormone deficiency with obesity; No GHD, OB−: patients without growth hormone deficiency without obesity; IBW%: ideal body weight %; NM: not mentioned; PWS: Prader-Willi syndrome; BBS: Bardet-Biedl syndrome; PHP1a: pseudohypoparathyroidism type 1a.

*In case several weight measures were reported, BMI SDS was the preferred outcome that we report, followed by BMI and IBW%.

Figure 3. Weighted mean peak GH values in the studies of children with non-syndromic obesity, stratified on GHD status and weight status. Data was available for n = 2518 children from k = 51 subcohorts. The dots represent the mean of individual subcohorts and the barplot represents the weighted mean peak GH ± SEM. In the case of the DOPA, GHRH, and GHRH + ARG tests, no studies with results on children with GHD were identified. GHD+: children with growth hormone deficiency; No GHD, OB+: children without GDH with obesity; No GHD, OB−: children without GDH without obesity; ARG: arginine test; CLON: clonidine test; DOPA: dopamine test; GHRH: growth hormone-releasing hormone test; GHRH + ARG: combined growth hormone-releasing hormone + arginine test; ITT: insulin tolerance test; GH: growth hormone; GHD: growth hormone deficiency; SEM: standard error of the mean.

Figure 4. Forest plot showing the meta-analysis of correlation coefficients between peak GH and BMI SDS in children without GHD. Data was available for n = 2434 patients from k = 29 subcohorts. CLON: clonidine; GHRH: growth hormone-releasing hormone; PD: pyridostigmine; ITT: insulin tolerance test; ARG: arginine; DOPA: dopamine; GAL: galanine; HEX: hexareline; GHRP-6: growth hormone-releasing peptide-6; Corr: correlations; CI: confidence interval; RE: random effects; df: degrees of freedom.

Table 2. Results of meta-regressions and subgroup analyses for the meta-analysis of correlation coefficients between peak GH and BMI SDS.

Continuous moderators (meta-regression)	k Cohorts	% Between-study heterogeneity explained	Effect size (slope)	95% CI	Qm	p-Value
Years since publication	29	0.6	−0.001	−0.007; 0.006	0.04	0.85
% Males	25	17.4	0.591	0.028; 1.154	4.24	0.04
% Prepubertal	19	3.4	−0.108	−0.255; 0.471	0.34	0.56
Mean age	21	0.8	−0.030	−0.105; 0.045	0.62	0.43
Mean BMI SDS	13	4.0	−0.067	−0.200; 0.065	0.99	0.32
Categorical moderators (subgroup analysis)	k Cohorts	Between-study heterogeneity (I^2)	Effect size (pooled r)	95% CI	Qm	p-Value
Type of (non-syndromic) study					7.37	0.007
Cohort referred for short stature	6	25.7	−0.18	−0.26; −0.10
Case-control	23	75.1	−0.38	−0.48; −0.26
Stimulation agent used					4.79	0.31
Arginine and/or dopamine	7	85.4	−0.27	−0.44; −0.09
Clonidine	3	53.0	−0.34	−0.49; −0.17
GHRH	6	34.4	−0.44	−0.56; −0.29
GHRH + second agent	4	32.7	−0.43	−0.57; −0.26
Hexarelin	1	–	−0.20	–
Insulin and/or glucagon	7	74.0	−0.23	−0.41; −0.04
Risk of bias					0.62	0.73
Low	3	82.6	−0.25	−0.49; 0.02
Moderate	7	73.7	−0.37	−0.54; −0.18
High	19	76.2	−0.32	−0.43; −0.19
Correlation origin					0.04	0.84
Originally provided by authors	7	57.4	−0.31	−0.42; −0.18
Calculated for this meta-analysis	22	79.8	−0.32	−0.44; −0.19
Correlation calculation method					0.22	0.64
Standardized mean difference	18	53.3	−0.35	−0.44; −0.25
Pearson/Spearman	4	92.8	−0.24	−0.62; 0.23

CI: confidence interval; SDS: standard deviation score; k: number of cohorts; r: correlation coefficient; Q_m: Cochrane’s Q for the moderator variable.

Data was available for k = 29 subcohorts.

Table 3. Overview of non-syndromic patients without GHD with obesity and without obesity who showed an inadequate response in the GH stimulation test based on a pre-specified peak GH cutoff values.

	k Cohorts	n No GHD, OB + below cutoff/total (%)	n No GHD, OB − below cutoff/total (%)	p-Value	RR^a (95% CI)
All tests	30	213/391 (55)	260/1643 (16)	<0.0001	3.44 (2.98–3.97)
Stimulation agent
ARG	4	20/65 (31)	84/543 (16)	0.003	1.98 (1.31–3.01)
CLON	6	32/51 (63)	52/318 (16)	<0.0001	3.84 (2.77–5.32)
DOPA	2	4/9 (44)	25/85 (29)	0.45	1.51 (0.68–3.37)
GHRH	6	26/59 (44)	0/95	<0.0001	NA
GHRH + ARG	2	3/15 (20)	3/45 (7)	0.32	3.00 (0.68–13.31)
GHRH + PD	1	3/8 (38)	0/9	0.08	NA
ITT	7	53/104 (51)	64/404 (16)	<0.0001	3.22 (2.40–4.31)
Various stimulation agents
ARG/DOPA	1	70/78 (90)	0/30	<0.001	NA
ARG + CLON/DOPA + PROP/CLON +  DOPA + PROP/ARG + DOPA	1	2/2 (100)	32/114 (28)	0.15	3.56 (2.66–4.78)

k: number of cohorts; n: number of patients; No GHD, OB+: patients without GHD with obesity; No GHD, OB−: patients without GHD without obesity; ARG: arginine; CLON: clonidine; GHRH: growth hormone-releasing hormone; PD: pyridostigmine; ITT: insulin tolerance test; PROP: propranolol; NA: not applicable.

Data was available from n = 2034 children from k = 30 subcohorts.

^aRelative risk for showing an inadequate response in the GH stimulation test based on a pre-specified peak GH cutoff value for patients without GHD with obesity compared to patients without GHD without obesity.

Figure 5. Weight status-adjusted cutoffs for children with overweight and obesity based on our meta-analysis results. Adjusted cutoffs based on BMI SDS (BMI z-score adjusted for age and sex) are provided for stimulation tests with cutoffs for children with normal weights of 5, 7, 10, or 20 µg/L.

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Data availability statement

All data supporting the analyses in this paper are provided in the manuscript, Supplementary Material 1, and Supplementary Material 2, Individual Participant Dataset.