Growth hormone treatment response: associated factors and stimulated growth hormone secretion indices in prepubertal children with idiopathic GH deficiency

doi:10.21203/rs.3.rs-4265731/v1

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Growth hormone treatment response: associated factors and stimulated growth hormone secretion indices in prepubertal children with idiopathic GH deficiency

https://doi.org/10.21203/rs.3.rs-4265731/v1

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Purpose

The aim of this study is to correlate the growth response in prepubertal children with idiopathic growth hormone (GH) deficiency after one year of treatment with growth hormone to the initial clinical and biochemical parameters. It also aims to study the secretory dynamics of GH by analyzing the profiles of GH stimulation tests in relation to the recombinant GH (rhGH) treatment response.

Methods

This a retrospective study which included 84 prepubertal children (47 males and 37 females) with a definitive diagnosis of GH deficiency. The GH secretory indexes GHmax, GH secretion rate (GHSR) and GH secretion volume (GHSV) were analyzed in relation to the response to rhGH treatment as defined by the index of responsiveness (IoR). Correlation and regression models were used to identify the best clinical and biochemical predictors to rhGH treatment.

Results

IoR was correlated negatively with the age (r=-0.607, p < 0.01) and positively with the distance of child’s height from its MPH r = 0.466 (p < 0.01) and pretreatment growth velocity (r = 0.247, p < 0.05). GH secretory indexes correlated together, with the highest association being observed between GHmax and GHSV (r = 0.883, p < 0.01). Regarding the GH secretory indexes, GHmax was the best predictor of IoR (β coef. = -0.514, p < 0.001) followed by the GHSV (β coef. = -0.47, p < 0.001) and GHSR (β coef. = -0.367 p < 0.001).

Conclusions

The age and the distance of child’s height from its MPH are major predictors of rhGH treatment response in children with idiopathic GH deficiency. The calculation of the other GH secretory indexes GHSR and GHSV are not better predictors of response to rhGH than GHmax. The combination of clinical and biochemical indexes may improve the pretreatment assessment of response to rhGH treatment.

Growth hormone deficiency

Index of Responsiveness

GH stimulation test

GH secretory indexes

Idiopathic GH deficiency is not an easy diagnosis to establish because no single test has increased specificity and sensitivity for GH deficiency.
Prediction to treatment response with recombinant GH (rhGH) depends on multiple factors as well as the validity of the initial diagnosis.
The age and the distance of child’s height from its mid-parental height are major predictors of rhGH treatment response in children with idiopathic GH deficiency.

What is new

The calculation of the GH secretory indexes, GH secretion rate and GH secretion volume are not better predictors of response to rhGH than GHmax currently used in pediatric practice.
The combination of clinical and biochemical indexes (GHmax * Height dist. SDS) improve the pre-treatment estimation of response to rhGH treatment.

In current clinical practice, the diagnosis of growth hormone (GH) deficiency in short stature is based on an integrated approach that assesses family history, auxological parameters of growth, baseline biochemical indices like IGF-I and the secretion of GH with dynamic tests [1]. Although the above diagnostic process has been standardized over the years with the help of consensus statements, diagnostic pitfalls are possible due to conditions such as constitutional delay of growth and puberty that phenotypically and biochemically overlaps with GH deficiency [2].

Many pediatric endocrinology centers use the GH stimulation tests as a key step in the diagnostic procedure of short stature. GH peaks after stimulation with a pharmacological agent that does not surpass a certain cut-off value, are considered indicative of a GH deficient state. However, several issues complicate the interpretation of GH test results. First, different stimulation agents generate different GH responses that poorly correlate with each other [3, 4]. Second, the GH peak is changing with advancing age [5] and is different between the prepubertal and pubertal children because of the effect that steroids have on GH secretion [6]. Third, obesity negatively effects GH secretion and is a confounding factor in the interpretation of GH stimulatory tests [7, 8].

After initiation of GH therapy, there is a high individual variability in height gain, suggesting variable responsiveness to rhGH treatment. While most subjects display an expected growth trajectory, some of them respond less well while others respond better than expected [9, 10]. Furthermore, a proportion of patients do not even reach an adult height within their MPH range after many years of GH treatment, questioning the diagnosis. Apart from its main target to improve the final height, treatment with rhGH should also be safe and cost-effective [11].

In monitoring the rhGH treatment effect, the deviation of the actual versus the expected course of height has been adequately described by growth prediction models (GPMs). GPMs, based on the auxological features and rhGH treatment doses, can predict the growth response of an individual. Over the last 3 decades, many GPMs for children with short stature, treated with rhGH have been developed [12, 13]. One of latest published, is the individualized growth response optimization (iGRO) model, which was based on the pharmaco-epidemiological survey KIGS (Pfizer® International Growth Database) that had 83,803 children/277,264 patient years who received rhGH therapy (mainly Genotropin™) [14]. This cloud-based model was developed to help physicians access the response to GH treatment and therefore to optimally manage their patients. It calculates an individual child’s level of responsiveness to rhGH treatment, termed the Index of Responsiveness (IoR). The IoR is the difference between observed (obs) and predicted (preTd) height velocity (HV) divided by the SD of the predicted HV during the first treatment year ([obsHV − predHV]/SD predHV). When using the SDS values of IoR, a positive value of the IoR SDS indicates a better growth response and a negative value indicates a reduced growth response in comparison to the reference cohort’s growth response contained in the database [15].

The aim of this study is to correlate the index of responsiveness (IoR) after one year of treatment in prepubertal children with GH deficiency to the basal anthropometric and laboratory values before and after treatment. It also aims to study the secretion dynamics of GH by analyzing the profiles of GH stimulation tests with clonidine in relation to the rhGH treatment response.

This is a retrospective cross-sectional and longitudinal study. The participants were 84 prepubertal children with short stature that after evaluation based on the current guidelines[1] were diagnosed with idiopathic GH deficiency. They received treatment with rhGH with a dose of 0.22 mg/week, as allowed by the Greek National Committee. Subjects with organic GH deficiency, combined pituitary deficiency, chronic disease or with a syndrome were excluded from the study. In addition, children who required priming with sex steroids before the clonidine test according to guidelines, or those who presented their GHmax value at t=0 since it was considered that the pharmaceutical agent acted on or shortly after the endogenous GH pulse, were also excluded from the study. Body height and weight were measured using standard anthropometric techniques. Height as the average of two measurements with a calibrated Harpenden stadiometer, was recorded to the nearest millimeter. Weight was measured on a calibrated scale (Seca, model 760) and recorded to the nearest 100 gr. MPH was calculated as (mothers’ height + fathers’ height ± 13 cm) ÷ 2. BMI was calculated using the formula weight/height ^ 2 (kg/m²). BMI standard deviation score (SDS) was computed for each subject using the formula: BMI-SDS = (actual BMI-mean BMI for age, race and gender)/BMI SD for age and gender. SDS values for the heights, and BMI were calculated using the LMS data Centers for Disease Control and Prevention 2000 growth charts [16]. The study was approved by the local Ethics Committee of the University Hospital of Patras. Written informed consent from participants and their parents was obtained. All participants’ data were uploaded to the web-based platform of iGRO, and the output from the growth prediction model was the Index of Responsiveness (IoR) and IoR SDS at the end of 1 year after initiation of rhGH treatment [15]. The dynamics of stimulated GH secretion were characterized by the three following indices:

The maximum value of GH (GHmax) of blood samples at 30’, 60’, 90’or 120’, obtained during the clonidine test.
The GH secretion rate (GHSR) = \(\frac{{\text{G}\text{H}}_{\text{m}\text{a}\text{x} }-{ \text{G}\text{H}}_{(\text{t}=0)}}{{\text{T}\text{i}\text{m}\text{e}}_{\left(\text{G}\text{H}\text{m}\text{a}\text{x}\right)}}\) which is the variable derived by dividing the GH maximum value with the time class value. The latter was divided in the following 4 classes (1st class: GH peak at 30’, 2nd class: GH peak at 60’, 3rd class: GH peak at 90’, 4th class: GH peak at 120’).
The GH secretion volume (GHSV) = Area under the Curve [GH=f(t_0-120)] where AOC is calculated by the sum of all trapezoids formed by the function of GH values in the time points 30’,60’,90’or 120’ of the clonidine test.

The above calculations were performed only on the GH stimulation profiles after the administration of clonidine as GH secretagogue. The cutoff for a “normal” GH peak was considered the 10 μg/L. All children with a subnormal GHmax value at two subsequent GH stimulation tests (clonidine 150 μg/m² and L-Dopa 10mg/kg) were subjected to magnetic resonance imaging of the hypothalamic/pituitary region. The diagnosis of idiopathic GH deficiency was proven only after the whole evaluation with a normal MRI scan was concluded.

The IGF-I assay was performed with the IDS-Isys system (Immunodiagnostic Systems), in an automated procedure based on ELISA with detection by chemiluminescence. Serum IGF-I concentrations were interpreted by comparison with the reference intervals set up specifically for this iSYS device [17]. The intra-assay coefficient of variation for IGF-I was 3.1%. IGF-I levels are shown as standard deviation scores (SDS) due to their variability according to sex and age. The SDS conversion was performed using previously published LMS charts [17, 18]. Fasting blood samples were collected and after centrifugation, all samples were kept frozen at -7 C^o until assayed.

Statistical analysis

Data were expressed as mean ± SD. Correlations between datasets were performed using the Pearson correlation coefficient. Classical tests of significance among the groups were done using ANOVA. Regression was performed using robust standard errors (to control for heteroskedasticity) and standardized beta coefficients after excluding in the same model independent variables with multicollinearity. A p value of < 0.05 was considered significant. Statistical analysis was performed by using Stata ver. 16.

The anthropometric clinical parameters and IGF-I SDS levels of the eighty-four children (47 males and 37 females) with a mean age of 6.6 years are presented in Table 1. The correlations among the IoR and the other clinical and biochemical variables are shown in Table 2. IoR correlated significantly with age with a negative coefficient (r=-0.607, p<0.01). It was also significantly correlated to the height distance of the child from its mid-parental height (Height dist. SDS) with r=0.466 (p<0.01). In addition, pretreatment growth velocity (r=0.247, p<0.05) as well as posttreatment growth velocity (r=0.410, p<0.01) were significantly correlated to IoR. On the contrary, IoR was not correlated either to pre rhGH treatment IGF-I levels, nor to post treatment IGF-I SDS (Table 2).

GH secretory indexes tightly correlated together, with the highest association being observed between GH_maxand GHSV (r=0.883, p<0.01), and followed by GH_maxand GHSR (r=0.558, p<0.01). GHSV was also significantly linked to GHSR, although with a lower strength, (r=0.403, p<0.001). GH_max,GHSR and GHSV showed no significant association with pre or post rhGH treatment IGF-I SDS values (Table 3). To estimate the value of each GH secretory index in the prediction of IoR, we run three separate regression models (IoR model A, B and C) each for one for GH_max,GHSR and GHSV including in each model all other common clinical and biochemical factors (Table 4). This was preformed to avoid the co-analysis of GHmax, GHSR and GHSV as variables with inherent collinearity in the same regression model. In all three models, the age, and the height distance from the mid-parental height (Height dist. SDS) were the best predictors of IoR one year after initiation of treatment with rhGH (Table 4). They were followed by the pre-treatment height SDS and BMI SDS. Pre-treatment growth velocity and IGF-I SDS levels did not have any statistical significance in predicting the IoR. Regarding the GH secretory indexes, it was observed that GH_max was the best predictor of IoR (β coef. = -0.514, p<0.001) followed by the GHSV (β coef. = -0.47, p<0.001) and GHSR (β coef. = -0.367 p<0.001).

Based on the observations that the best IoR predictors were the height dist. SDS and GH_maxafter stimulation, we arbitrarily combined them by generating a new index calculated as follows: GHmax * Height dist. SDS. After using the new index into the same regression model, we found that GHmax * Height dist. SDS increased the predictability of GHmax considerably (β coef. =-0.68 p<0.001), meaning that this combined clinic-biochemical index may account for 68% of the variability of IoR (Table 5).

In this study, we aimed to investigate the clinical and biochemical predictors of response to rhGH treatment in a very well characterized cohort of children with the diagnosis of short stature due to idiopathic GH deficiency. Treatment response was generated by the validated growth model prediction tool (iGRO). Our analysis showed a signiﬁcant negative association between IoR and age at diagnosis, and a positive relation with the distance between the height of the child and its mid-parental height. As it is also expected, pre- and post-treatment growth velocity correlate very well with IoR. Age has been previously reported to be a basic predictor of rhGH treatment response [19]. The significant correlation of IoR to the distance in SD between the height of the child and its mid-parental height is observed in all regression models in our study and has been confirmed to be a principal predictor of growth response in other studies [14, 15]. Pretreatment height SDS is also associated well to the IoR. Interestingly, we found that, although IGF-I serum levels have a basic role in the diagnostic algorithm of short stature [1, 20], pretreatment as well as posttreatment IGF-I SDS did not show any statistical correlation to the IoR.

Next, we investigated the potential of increasing the GH treatment response predictability of GH stimulation tests that we usually perform in current practice. It is known that the reproducibility of a GH stimulation test is low due to the temporal random action of the pharmacologic agent in relation to the spontaneous GH pulse that can be followed by a state of refractoriness [21]. Moreover, different pharmacological agents generate different mean GH peaks, with clonidine generating a higher GH response than arginine, insulin, or glucagon tests [22, 23], while puberty and obesity have their own effect on the pituitary GH secretion [6, 24]. We chose to include only prepubertal children to avoid the strong effect of sex steroids on GH levels after stimulation [24]. The calculated GHSR parameter aimed to incorporate into our evaluation the speed of pituitary gland response, which is how quickly can increase the GH levels after pharmacologic stimulation. GHSV index provides an indication of the somatotroph pituitary capacity. Above GH secretion values cannot be estimated by the GH_maxvalue of the stimulation test. For the reasons described above, we chose to calculate GHSR and GHSV only from the GH profiles generated by stimulation of clonidine. The potent stimulation of clonidine could accentuate any existing differences in GHSR and GHSV indices. Both GHSR and GHSV showed a good correlation to IoR. Although an earlier study had shown that GH peak at 45 min was associated with a better response to treatment [25], our results did not support that GHSR contributed additively to the diagnostic ability of the single GHmax value. We reached the same conclusion for the GHSV index, showing that the total GH secreted does not contribute to increased predictability of growth response to rhGH treatment. In addition, both GHSR and GHSV did not significantly correlate to pretreatment IGF-I SDS.

Based on our results we combined the best predictor capabilities from clinics and laboratory by creating the variable of GHmax * Height dist. SDS derived from the arbitrary multiplication of GHmax and Height dist. SDS. In the application of the same regression model, the potential for prediction to rhGH response increased to 68.2 % of IoR variability compared to 51.2% of GHmax.

In conclusion, we found that age and the distance of child’s height from its MPH are major predictors of rhGH treatment response in children with idiopathic GH deficiency. The calculation of the other GH secretory indexes GHSR and GHSV are not better predictors of response to rhGH than GHmax. The combination of clinical and biochemical indexes may improve the pretreatment assessment of response to rhGH treatment.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Aristeidis Giannakopoulos, Eleni Kallimani, Alexandra Efthymiadou and Dionisios Chrysis. . The first draft of the manuscript was written by Aristeidis Giannakopoulos and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University Hospital of Patras (Date 16/2/2022 /No 262).

Consent to participate

Informed consent was obtained from the parents of all individual participants included in the study.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Table 1

Clinical and biochemical indexes of GHD children pre- and 1-year post GH treatment (preT: pre-treatment, postT: post-treatment, BMI: body mass index, MPH: mid-parental height)
	N	Mean	Std. Dev.	Min	Max
Age (years)	84	6.607	2.443	1.75	11.9
PreT Height (cm)	84	106.753	13.206	77	132.3
PreT Height SDS	84	-2.303	0.442	-3.51	-1.53
PostT Height (cm)	84	113.767	17.005	82.2	141.5
PostT Height SDS	84	− .855	1.895	-1.38	1.1
PreT Growth vel. (cm/y)	84	4.49	1.102	2.2	9.9
PostT Growth vel. (cm/y)	84	8.137	1.420	5.6	12.5
Height dist. SD	84	1.703	0.842	.21	4.05
PreT BMI (kg/m²)	84	16.277	1.843	13.4	21
PreT BMI SDS	84	.128	0.993	-1.93	2.58
MPH (cm)	84	166.94	8.233	150.5	185.5
MPH SDS	84	− .6	0.838	-2.48	2.2
PreT IGF-I (µg/L)	84	66.145	47.793	5	284
PreT IGF-I SDS	84	-1.862	1.085	-4.21	1.72
PostT IGF-I (µg/L)	84	191.264	98.782	57	675
PostT IGF-I SDS	84	.321	1.944	-2.02	3.87

Table 2

Correlations among IoR and other clinico-biochemical pre and post rhGH treatment indices in children with idiopathic GH deficiency.
Variables	(1)	(2)	(3)	(4)	(5)	(6)	(7)	(8)	(9)	(10)
(1) IoR	1.000
(2) Age (years)	-0.607***	1.000
(3) PreT Height SDS	0.069	0.169	1.000
(4) PostT Height SDS	0.151	-0.073	0.159	1.000
(5) BMI SDS	0.202	-0.065	0.024	0.082	1.000
(6) PreT IGF-I SDS	-0.074	0.008	-0.174	0.102	-0.091	1.000
(7) PostT IGF-I SDS	0.205	-0.183	-0.126	0.029	0.165	0.224**	1.000
(8) PreT Growth vel. (cm/y)	0.247**	-0.433***	0.111	0.112	0.086	0.071	0.142	1.000
(9) PostT Growth vel. (cm/y)	0.410***	-0.320***	-0.002	0.182	0.186	-0.156	0.131	0.096	1.000
(10) Height dist. SDS	0.466***	-0.317***	-0.273**	-0.056	-0.191	0.049	0.177	0.016	0.165	1.000
* p < 0.01, p < 0.05 referred to r coefficients

Table 3

Correlation among the Growth Hormone Stimulation Dynamic Indices GH_max, GHSR and GHSV and pre post rhGH treatment IGF-I SDS.
Variables	(1)	(2)	(3)	(4)	(5)
(1) GH_max	1.000
(2) GHSR	0.558***	1.000
(3) GHSV	0.883***	0.403***	1.000
(4) PreT IGF-I SDS	0.065	-0.124	0.061	1.000
(5) PostT IGF-I SDS	0.048	-0.128	0.087	0.224**	1.000
* p < 0.01, p < 0.05

Table 4

Regression models A, B and C of IoR for the Growth Hormone Stimulation Dynamic Indexes GH_max, GHSR and GHSV, respectively.
	IoR model A	CI (95%)	IoR model B	CI (95%)	IoR model C	CI (95%)
	(GH_max)		(GHSR)		(GHSV)
Age	-0.615^***	[-0.412, -0.246]	-0.576^***	[-0.406, -0.225]	-0.634^***	[-0.436, -0.243]
Sex (male)	0.080	[-0.159, 0.571]	0.158	[-0.0737, 0.887]	0.067	[-0.239, 0.582]
Height SDS	0.261^***	[0.444, 1.066]	0.331^***	[0.591, 1.293]	0.275^***	[0.425, 1.162]
BMI SDS	0.175^***	[0.0954, 0.352]	0.145^*	[0.0231, 0.341]	0.168^**	[0.0715, 0.356]
IGF-I SDS	0.057	[-0.0381, 0.173]	0.044	[-0.118, 0.217]	0.039	[-0.0906, 0.183]
PreT Growth vel. (cm/y)	-0.020	[-0.161, 0.115]	-0.053	[-0.209, 0.0855]	0.001	[-0.154, 0.156]
Height dist. SD	0.354^***	[0.318, 0.774]	0.416^***	[0.390, 0.870]	0.426^***	[0.401, 0.915]
GH_max	-0.514^***	[-0.348, -0.215]
GHSR			-0.367^***	[-0.538, -0.227]
GHSV					-0.470^***	[-0.126, -0.0628]
N	84		84		84
Standardized beta coefficients; 95% confidence intervals in brackets
^* p < 0.05, ^ p < 0.01, ^* p < 0.001

Table 5

Regression model for the IoR incorporating the combined clinico-biochemical index [GHmax * Height Dist. SDS].
	IoR model D	CI (95%)
	( GH_max * Height Dist. SDS )
Age	-0.581^***	[-0.407, -0.215]
Sex (male)	0.116	[-0.123, 0.723]
Height SDS	0.320^***	[0.552, 1.294]
BMI SDS	0.194^***	[0.113, 0.381]
PreT IGF-I SDS	0.084	[-0.0376, 0.234]
PreT Growth vel. (cm/y)	-0.013	[-0.174, 0.143]
Height dist. SDS	0.916^***	[1.008, 1.818]
GH_max * Height Dist. SDS	-0.682^***	[-0.183 -0.09]
N	84

No competing interests reported.

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Growth hormone treatment response: associated factors and stimulated growth hormone secretion indices in prepubertal children with idiopathic GH deficiency

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Declarations

References

Tables

Additional Declarations

Status:

Version 1