Rev Esp Endocrinol Pediatr

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Rev Esp Endocrinol Pediatr 2015;6(2):39-50 | Doi. 10.3266/RevEspEndocrinolPediatr.pre2015.Sep.315
Results after the first year of treatment with recombinant human growth hormone therapy in a group of Spanish children with short stature
Resultados tras el primer año de tratamiento con hormona de crecimiento humana recombinante en un grupo de niños españoles con talla baja

Sent for review: 4 Aug. 2015 | Accepted: 22 Sep. 2015  | Published: 30 Nov. 2015
Amparo Rodríguez1, María D. Rodríguez Arnao 1, José I. Labarta2, María J. Martínez-Aedo3, María Alija4, Ignacio Díez López5, Ramón Cañete6, Julia Otero Villar7, Datac study investigators*
1Endocrinología pediátrica. Hospital General Universitario Gregorio Marañón. Madrid (Spain)
2Hospital Universitario Miguel Servet. Zaragoza (Spain)
3Hospital materno-Infantil de Málaga. Málaga (Spain)
4Endocrinologia Pediátrica. Hospital Universitario de Guadalajara. Guadalajara (Spain)
5Hospital Universitario de Álava. Vitoria-Gasteiz, Álava (Spain)
6Endocrinologia Pediátrica. Hospital Universitario Reina Sofía. Córdoba (Spain)
7Medical department. Merck, Spain. Madrid (Spain)
Correspondence:María D. Rodríguez Arnao , Endocrinologia Pediátrica, Hospital General Universitario Gregorio Marañón, C/ Doctor Esquerdo, 46., 28007, Madrid, Spain
E-mail: mrarnao@salud.madrid.org
*Group members:

Alija Merillas M (H.G.U. de Guadalajara, Guadalajara); Aragonés Gallego A (H. Virgen de la Salud, Toledo); Argente Oliver J (H.I.U. Niño Jesús, Madrid); Arroyo Díez FJ (H. San Pedro de Alcántara, Cáceres); Bermúdez de la Vega JA (H.U. Virgen de la Macarena, Sevilla); Bernal Cerrato S (H.U. Virgen de la Macarena, Sevilla); Bezanilla López C (Fundación H. de Alcorcón, Madrid); Bonet Alcaina M (H. del Mar, Barcelona); Borrás Pérez MV (H. G. de Granollers, Barcelona); Bosch Muñoz J (H. Arnau de Vilanova, Lérida); Cabrinety Pérez N (H. Sagrado Corazón, Barcelona); Cañete Estrada R (H.U. Reina Sofía. Córdoba); Caro Cruz E13 (H.G.E. Ciudad de Jaén, Jaén); Carranza Ferrer M (H. Nostra Senyora de Meritxell, Andorra); Casas Rivero J (H. Ruber Internacional, Madrid); Corripio Collado R, Nosás Cuervo R16 (H. Parc Taulí Sabadell, Barcelona); Domínguez García A (H. Materno Infantil, Las Palmas); Feliu Rovira A (H.I. San Joan de Deu, Barcelona); Fernández García JM (H. Clínico San Cecilio, Granada); Fernández López JI (H. Nuestra Señora de Valme, Sevilla); Fernández Tena I (Clínica Clideba, Badajoz); Ferrer Lozano M (H.G. San Jorge. Zaragoza); Fuentes Castelló MA (H.G.U. de Elche, Alicante); Garagorri Otero JM (H.C.U. Lozano Blesa, Zaragoza); García Cuartero B (H.U. Severo Ochoa, Madrid); García-Rey C (Medical Department, Merck SL, Madrid); Gavilán Villarejo I (H. U. Puerta del Mar, Cádiz); Gentil González FJ(H.U. Virgen de la Macarena, Sevilla); González Vergaz A (H.U. Severo Ochoa, Madrid); Gutiérrez Díez MP (H.U. de Getafe, Madrid); Hernando Mayor JC (H. del Río Ortega, Valladolid); Jiménez Fernández ER (H. Infanta Elena, Huelva); Jurado Muñoz MC (Clínica Esperanza de Triana, Sevilla); Lalaguna Mallada P (H. de Barbastro, Huesca); Lechuga Campoy JL(H. U. Puerta del Mar, Cádiz); López Capapé M (H. La Moraleja, Madrid); López Siguero JP (H. U. Materno Infantil Carlos Haya, Málaga); Martín Hernández T (H.U. Virgen de la Macarena, Sevilla); Martínez Aedo MJ (H. U. Materno Infantil Carlos Haya, Málaga); Macías López FJ (H. de Jerez, Cádiz); Moreno Macián F (H.U. La Fe, Valencia); Núñez Estévez M (H. Materno Infantil Infanta Cristina, Badajoz); Oliver Iguácel A (H.U. La Paz, Madrid); Ortega Gamboa D(Medical Department, Merck SL, Madrid); Quinteiro González S (H. Materno Infantil, Las Palmas); Ramírez Fernández J (H.U. Príncipe de Asturias, Alcalá de Henares); Rial Rodríguez JM (C. H. Nuestra Señora de la Candelaria, Tenerife); Rodríguez Arnao MD (H.G.U. Gregorio Marañón, Madrid. Study Coordinator); Rodríguez Rodríguez I (C. H. Nuestra Señora de la Candelaria, Tenerife); Rodríguez Sánchez A (H.G.U. Gregorio Marañón, Madrid. Study Coordinator); Ruíz Cano R (C.H.U. de Albacete, Albacete); Sala Sánchez G (H. Virgen de los Lirios, Alicante); Sánchez Huelva H(H. Infanta Elena, Huelva); Sendón Pérez A (H.U. Virgen de la Macarena, Sevilla); Yturriaga Matarranz R (H.U. Ramón y Cajal, Madrid); Zapico Álvarez-Cascos M (H.G.U. de Alicante, Alicante)

Table 1 - Gender (female %) and age (years), birth weight and height (SDS), and target height (SDS) for every condition
Table 2 - Weight (SDS) and Height (SDS) for every condition at start (SoT) and end of 1-year Treatment (EoT) with rhGH
Table 3 - Growth velocity (SDS) in the previous year for every condition before and after 1-year treatment with rhGH
Table 4 - Bone age delay (bone age minus chronological age) (years) in males and females and height for bone age (SDS) for every condition before and after 1-year treatment with rhGH
Table 5 - Final height prognosis (SDS) in children with bone age >6 years for every condition before and after 1-year treatment with rh-GH
Table 6 - Mean IGF-1 (ng/mL) and IGFBP-3 (ng/mL) of Tanner stage I children with every condition before and after 1-year treatment with rhGH compared to Tanner stage I adjusted reference value (192 ng/mL for IGF-1 and 3.8 ng/mL for IGFBP-3; Immulite 2000)
Figure 1 - Mean Height-to-mean weight (SDS Height/SDS Weight) ratio at start (SoT) and end of treatment (EoT)
Figure 2 - Height velocity (SDS) at start (SoT) and end of treatment (EoT)(p<0.01 for the change in every condition
Abstract

Background. Height velocity (HV) during the first year of treatment with recombinant human Growth Hormone (rhGH) is a common predictive factor for adequate treatment response in GH deficiency (GHD), Turner Syndrome (TS) and Small for Gestational Age (SGA). It was of interest to identify variables associated with HV in the first year of rhGH treatment. Methods. Retrospective multicenter study in 504 rhGH-naïve children with TS 29, SGA 152 or GHD 323 [partial pGHD 123, complete GHD with pathological MRI (cGHD pMRI) 37 and with normal MRI (cGHD nMRI) 163], treated for one year with rhGH to assess potential factors related to HV. Demographical, auxological and biochemical variables were recorded. A multiple linear regression analysis was performed. Results. After the 1-yr of rhGH treatment, mean height and height velocity had increased significantly (p<0.01) in every group. The variables independently associated with height velocity (R2 =0.511) were target height in SDS (B coefficient: 0.405; p=0.02), bone age delay in years (B: 0.253; p=0.002), baseline height velocity in SDS (B: 0.164; p=0.002) and height prognosis in cm (B: 0.018; p<0.001). Doses ranged from the lower end to slightly above recommended dosages. One local adverse event was reported (0.2%). Conclusion. 1-yr of rhGH treatment is effective in children with TS, SGA and GHD. Half the height velocity increase is explained by target height, bone age delay, baseline height velocity and height prognosis.

Resumen

Antecedentes. La velocidad de crecimiento (VC) durante el primer año de tratamiento con hormona del crecimiento recombinante humana (GHrh) es un factor predictivo de la adecuada respuesta al tratamiento en la deficiencia de hormona de crecimiento (DGH), Síndrome de Turner (ST) y pequeño para edad gestacional (PEG). Intentamos identificar las variables asociadas con VC durante el primer año de tratamiento con GHrh. Métodos. Estudio retrospectivo multicéntrico en 504 niños con ST 29, PEG 152 o DGH 323 [parcial DGHp 123, completa con RM patológica (DGHc-RMp) 37 y con RM normal (GHDc-RMn) 163], tratados por primera vez y durante un año con GHrh para evaluar los posibles factores relacionados con VC. Se recogieron variables demográficas, auxológicas y bioquímicas y se realizó un análisis de regresión lineal múltiple. Resultados. Después de un año con GHrh, la altura y la VC medias habían aumentado significativamente (p<0,01) en todos los grupos. Las variables asociadas independientemente con la VC (R2=0,511) fueron la talla diana (coeficiente B: 0,405; p=0,02), retraso en la edad ósea (B: 0,253; p=0,002), VC al inicio (B: 0,164; p=0,002) y pronóstico de altura (B: 0,018; p<0,001). Las dosis oscilaron entre el límite más bajo y ligeramente por encima de las recomendadas. Se objetivó un único acontecimiento adverso local (0,2%). Conclusión. El tratamiento con GHrh durante un año es efectivo en niños con TS, PEG y DGH. La mitad del incremento en VC se explica por la talla diana, retraso en edad ósea, VC de inicio y pronóstico de altura.

Key Words: growth hormone, growth disorders, growth hormone deficiency, Turner syndrome, small for gestational age, rhGH Palabras clave: Hormona de crecimiento, Alteraciones del crecimiento, deficiencia de hormona del crecimiento, síndrome de Turner, pequeño para la edad gestacional, GHrh

INTRODUCTION

Recombinant human growth hormone (rhGH) is used as a replacement therapy for total or partial GH deficiency (GHD). It has additional indications for conditions such as children born small for their gestational age (SGA), chronic renal failure, Turner syndrome (TS), Prader-Willi syndrome and short stature homeobox-containing gene (SHOX) deficiency (1). In the U.S.A., rhGH is also indicated in idiopathic short stature and Noonan´s syndrome (2).

The electronic auto-injector device EasypodTM, used to administer rhGH (Saizen®), not only provides an accurate monitoring of rhGH dosage but also confirms the adherence to this therapy (3-5).

In states of GH deficiency, the height velocity (HV) is the most important parameter to be assessed (6, 7). The best predictive factors for the right therapeutic response are birth weight, bone age delay and chronological age at start of therapy, the height velocity after the first year of treatment and the existence of hypothalamic-pituitary abnormalities revealed by magnetic resonance imaging (MRI) (8-12). Predictive factors for greater final height in girls with TS are duration of treatment, velocity of growth in the first year of treatment, bone age delay and target height (13-15). In SGA children treated with rhGH, the velocity of growth is a key parameter to be considered, mostly during the first year (16, 17).

Hence, height velocity during the first year of treatment with rhGH seems to be a common feature in the three aforementioned conditions in order to predict an adequate response to GH therapy. The current study was conducted to identify and quantify the possible variables associated with the magnitude of growth after the first year of treatment with rhGH in previously GH-naïve children with short stature, with a special attention to the identification of potential factors associated with the velocity of growth.

 

PATIENTS AND METHODS

This study was a retrospective multicenter survey including data from GH-naïve children with short stature, treated for one year with rhGH (Saizen®) in order to assess potential factors related to the magnitude of growth at the end of the observational period. Inclusion criteria consisted of children older than 6 months, diagnosed with TS, SGA or GHD, who started rhGH treatment between 2007 and 2009. Exclusion criteria excluded children who started treatment with rhGH in that period of time, but for other indications, such as SHOX gene disorders, Prader-Willi syndrome, or kidney failure. 

Baseline and post-treatment information were retrieved from the children’s medical charts. At the time of inclusion, the following information was recorded: demographic data, auxological data, physical exploration, laboratory data, pubertal stage (Tanner), additional laboratory data [Insulin-like Growth Factor-1 (IGF-1), Insulin-like Growth Factor Binding Protein 3 (IGFBP-3), GH after pharmacological stimuli, Free Thyroxine (FT4), Thyroid-stimulating hormone (TSH), celiac disease markers], karyotype, bone age (BA), MRI, diagnosis and treatment. Regarding treatment administration, lost injections were counted according to the EasypodTM information or to what parents reported when the patient did not use EasypodTM.

TS had been confirmed by karyotype in peripheral blood. SGA was defined as newborns with height and/or weight two standard deviations (2SD) below the mean for their gestational age, gender and population. GHD was defined as a GH response <10 ng/ml after two pharmacological stimuli. A diagnosis of partial GHD was given to children with auxological criteria of GHD and Adult Height Prediction (AHP) lower than -2SD of the target height, together with a GH response <10 ng/ml after only one pharmacological test and/or low IGF-1 for the matched gender, age and pubertal stage (18).

Outcome transformations followed the national standards valid at that moment(19). The standard deviation (SD) score (SDS) was calculated as follows: patient's measured value (Vobserved) minus mean value for age and sex-matched normal subjects (meanreference) divided by the SD of the value for age- and sex-matched normal subjects (SDreference). Formula: SDS =(Vobserved-meanreference)/SDreference

Biochemical data were assessed according to the reference standards of each hospital indicating normal, low or high range of the values. Bone age was assessed following the Greulich-Pyle’s method(20), whereas AHP was calculated following the Bayley-Pinneau’s method (21). Target height was calculated using the following formula: Mean of parental height (cm) + 6.5 in males or – 6.5 in females. Bone age advancement (BAA) was defined as bone age minus chronological age (22). Tanner stage I adjusted Reference Values (RVs) for IGF-1 and IGFBP-3 were those defined by the Immulite 2000 manufacturer (23).

Statistical analyses

Descriptive analyses of the collected data, both quantitative (mean, standard deviation (SD), median, minimum, maximum, 25 percentile and 75 percentile) and qualitative (absolute frequencies and percentages) were carried out.

In order to make between-groups comparisons for continuous variables, the ANOVA or the Student t-tests were used (or their non parametric Kruskal-Wallis and Mann-Whitney equivalents, if normality and homoscedasticity were not met). Regarding discrete variables, comparisons were tested using the Chi-square test.

Statistical significance level was set at 5%. All the analyses were made with the SPSS statistical software.

The study protocol was approved by the Clinical Research Ethics Committee of Clínica Tecknon, Barcelona. All ethical standards for protecting human subjects have been followed in accordance with the World Medical Association Declaration of Helsinki.

 

RESULTS

Naïve GH patients with growth disorders who had followed one-year treatment with rhGH (Saizen®), were retrospectively studied in order to assess potential factors related to the magnitude of growth at the end of the observation period.

The total sample was made up of 504 children, of whom 29 (5.8%) had TS, 152 (30.2%) were children born SGA, and 323 (64.1%) had GHD. Those later ones, in turn, were subdivided into 123 children (24.4%) with partial (pGHD) and 200 children (39.7%) with complete GHD (cGHD), which were further subdivided into 37 (7.3%) with pathological MRI (cGHD pMRI) and 163 (32.3%) with normal MRI (cGHD nMRI). Every child stayed within Tanner stage I during the first year of rhGH therapy.

Demographics, birth weight and length, and target height data

Age and proportion of females for every condition is shown in Table 1. Mean age was considerably lower in children with TS and those born SGA than in children with GHD, who were mainly in their preadolescence. Females were underrepresented in the groups with GHD. Birth weight and length were especially below standard values in children born SGA (Table 1). Children with GHD had birth weight and length closer to standard values than had children with the other two conditions.

Auxological data pre- and post-treatment with rhGH

A significant (p<0.05) improvement of the mean weight and height after only one year of treatment with rhGH was observed in all the groups (Table 2). The mean weight improvement was 0.35 SDS for children born SGA, 0.27 for cGHD pMRI, 0.23 for TS, 0.20 for cGHD nMRI and 0.17 for pGHD. The mean height improvement was 0.70SDS for children born SGA, 0.64 for cGHD nMRI, 0.57 for cGHD pMRI, 0.50 for TS and 0.48 for pGHD.

The height-to-weight (SDS Height/SDS Weight) ratio (values over 1 mean overweight regarding normal group and gender matched population) changed favorably in all the conditions after one year of treatment, except for TS (Figure 1).

The expected catch-up growth after the first year on treatment is shown in Figure 2 as change in height velocity (SDS), being positive, more than +1 SDS, in every patient. Patients cGHD pMRI presented the largest response to rhGH therapy.

Mean growth velocities (SDS) at End of Treatment (EoT) tended to be higher in children with GH deficiency as compared with the other two disorders, which had very similar values (2.33 and 2.34 for TS and SGA, respectively) (Table 3). Increase in mean height velocity (SDS) was 4.08, 3.77, 6.03, 4.92 and 4.39 SDS for TS, SGA, cGHD pMRIm, cGHD nMRI and pGHD, respectively.

Skeletal maturation and predicted height

Considerable bone age delay persisted after one year of treatment with rhGH (Table 4). The group of boys with complete GH deficiency and normal MRI had a significant (p<0.01) improvement of mean bone age but it still remained low as compared to matched normal population. In the group of girls born SGA, mean bone age seems to be further delayed (p<0.01) after one year of rhGH.

Only in the group of children with an abnormal MRI and complete GH deficiency did the height for bone age show a significant improvement (p=0.05) (Table 4). No significant change was observed for any of the other conditions.

Final height prognosis showed a significant improvement after one year of treatment with rhGH only in children with GH deficiency (Table 5). This predicted adult final height for the three GHD groups still ranged between -0.76 and -0.99 SDS after one year on rhGH.

Biomarkers response

IGF-1 and IGFBP-3 biomarkers overall increased significantly in all groups from values below reference before treatment to values within or even above the normal range for Tanner I stage after treatment with rhGH (Table 6).

Treatment administration and safety

Mean dosages of rhGH were at the lower end (or even slightly below) for TS girls (0.042-0.046), at the higher end for children with a partial or complete GH deficiency (0.032-0.035), and slightly above for children born SGA (0.038-0.039) of the recommended rhGH dosages for each condition (0.045-0.05, 0.025-0.035 and 0.035, respectively).

Not every child used the EasypodTMdevice and rhGH was not administered with 100% adherence in some cases. Irregular therapy administration was observed in 2 (7.4%) patients with TS, 5 (3.3%) with SGA, 9 (5.6%) with cGHD nMRI, 3 (8.1%) with cGHD pMRI and 15 (12.3%) with pGHD.

Only one child out of 152 (0.66%) belonging to the SGA group reported local slight pain at the injection site as adverse event (AE). No other AEs were reported in any of the other groups. Therefore, the overall reported prevalence of AEs was 1 out of 504 (0.2%).

The administration of rhGH for Turner syndrome was 7 days a week in every patient. EasypodTM was the device used in 81.5% of cases. Self-administration was recorded in 48.1% of patients. Two patients (7.4%) did not have complete adherence, one of them only occasionally and the other with a frequency higher than once per month. No problems with the administration technique were recorded.

In 139 (91.4%) of SGA patients, the administration of rhGH was 7 days a week. EasypodTM was the device used in 129 (84.8%) of cases for GH delivery. Self-administration was observed in 77 (51.0%) of patients. Five patients (3.3%) failed to follow the correct timely administration pattern; four of them occasionally and for the other one there was no concrete information. One patient had problems learning how to manage the EasypodTM device; the device had to be replaced on three occasions, and the patient was able to make it work properly thereafter.

In GHD, the administration of rhGH was 7 days a week in 306 (94.7%) of the patients. EasypodTM was the device used in 290 (89.7%) of cases for rhGH delivery. Self-administration was observed in 246 (76.3%) of patients. Twenty-seven patients (8.4%) did not have 100% adherence: 20 of them did not receive rhGH only occasionally, 3 of them with a frequency higher than 1 time per week, 2 of them higher than 1 time per month, and no specific data were available for another 2 children (not on EasypodTM). There were 6 patients reporting small difficulties that were easily solved at the beginning of learning the administration technique.

Factors influencing the height velocity

In order to determine the parameters that could influence the height velocity in the first year of treatment, we first assessed its correlation with any of the variables at baseline. Only variables with a p-value <0.1 in the correlation with the dependent variable height velocity at EoT were chosen for the regression analyses: weight (kg), age (yr.), bone age delay (yr.), height prognosis (SDS), height prognosis (cm), height (cm), height minus target height (cm), target height (SDS), baseline height velocity (SDS), birth length (SDS), bone age (yr.), birth length (cm), birth weight (gr), weight (SDS), birth weight (SDS) and IGFBP-3 (ng/ml).

Variables that showed independent association with height velocity at EoT in the regression analysis (R2 =0.511) were target height in SDS (B coefficient: 0.405; p=0.02), bone age delay in years (B: 0.253; p=0.002), baseline height velocity in SDS (B: 0.164; p=0.002) and height prognosis in cm (B: 0.018; p<0.001).

 

DISCUSSION

In GH deficiency, TS and SGA, the height velocity in the first year of rhGH treatment is a common factor for treatment response prediction. Hence, it was important to identify the possible variables associated with the velocity of growth during the first year of treatment with rhGH in previously GH-naïve children with short stature. The current study identified target height, delay in bone age and previous HV, as variables influencing on the HV value.

Mean chronological age was higher in the different GHD groups (11.5 yrs. in cGHD pMRI, 12 yrs. in cGHD nMRI and 12.4 yrs. in pGHD) than in the TS (8.3 yrs.) and the SGA (8.6 yrs.) groups, and this was also observed in a previous study conducted in Spanish children prior to rhGH treatment (24). In fact, the mean chronological ages observed after one year of treatment agree with those observed at diagnosis in the mentioned study, in a naïve population at start of treatment, which were 9.9, 10.5 and 10.7 years in the cGHD pMRI, cGHD nMRI and pGHD groups, respectively, 7.0 in the TS group and 7.1 in the SGA group.

As expected, birth weight and length were especially under standard values in children born SGA, since SGA is defined as birth weight and/or length at least 2 standard deviations below the mean for gestational age (≤-2 SD) (25). In SGA children, who had a mean age of 8.6 years, height velocity (SDS) increased significantly (p<0.01) from baseline (-1.43) to 1 yr. of rhGH treatment (2.34), in agreement with data from a previous study in Spanish SGA children (26). In the mentioned study, mean height velocity increased from slightly above 5 cm/yr. to almost 8 cm/yr. after 1-yr. of GH treatment, with about 90% of patients showing height velocity above the 50th percentile. Height velocity 50th percentile is 5.5 cm/yr. in boys and slightly below in girls in the 8 year-old children population (19). The efficacy of GH treatment in increasing height velocity has also been observed in children population of other countries. In the study by Tanaka et al. conducted in Japanese SGA children in Tanner stage I (27), HV increased remarkably one year after starting rhGH treatment in both dose treatment groups (0.033 and 0.067 mg/Kg/day). Mean height (SDS) of SGA children also increased significantly (p<0.01) from -3.14 to -2.44 after one year of rhGH treatment, in agreement with data from the study by Tanaka et al., in which, mean height (SDS) improved from –3.5 to –3.0 in the 0.033mg/Kg/day dose group, and from –3.4 to –2.5 in the 0.067 mg/Kg/day group, after one year of rhGH treatment. Although there has been some concern that GH treatment might accelerate the onset of puberty, Tanaka et al. did not observe a correlation between GH treatment and onset of puberty for children with SGA short stature (27). This finding would agree with our study data showing overall no change in bone age. The study by Kim et al. (28) also showed that rhGH treatment had no effect on BA advancement, suggesting that rhGH treatment might lead to improved final height without inducing advanced bone maturation. In our study, bone age delay was less intense in females than in males.

Regarding height for bone age, only the group of children with the most severe GH deficiency (complete GH deficiency and abnormal MRI) showed a significant improvement (p=0.05), since these children have very delayed initial bone age. 

Girls with TS also showed a significant (p<0.01) increase in HV at one year of rhGH treatment since baseline, as shown in previous studies (29-31). In the study by Clayton et al. (31), TS girls from 14 different countries had a median basal height velocity of 4 cm/year, which increased to 7.2 cm/yr. over the first year of GH treatment.

The increase in height velocity was significant (p<0.01) after 1-yr. treatment in all three modalities of GHD. Data from a previous Spanish study (26) showed an increase in mean height velocity in GHD children from slightly above 4 cm/yr. to almost 9 cm/yr. after one year, which was significant in 92.6% of GHD children. Similarly, in the aforementioned international study (31), the height velocity in GHD children increased from a median baseline of 4 cm/year to 8.5 cm over the first year of GH treatment. In our study, although at baseline children with cGHD and pathological MRI were shorter than those with normal MRI, they showed better catch up growth with an increase in height velocity (SDS) of 6.03, as compared to 4.92 in those with normal MRI.

Since target height is predicted based on the parents’ height (32), it is interesting to note that the mean target height SDS was below 0 in all the groups, which implies short stature of the parents, and thus, it might suggest a strong genetic background affecting the stature in the children of our study. However, in case of short parents, malnutrition or other nonhereditary events occurring in early childhood may account for their shortness but will not impair the genetic potential for their offspring, and thus, the Tanner formula for predicting target height might not be the most adequate, since it may underestimate target height by an error of 6 cm (33).

Individual responses to GH treatment could be variable (34), and patients may be divided into high, average and low responders, with recommendations suggesting to stop treatment after one year in these latter ones (35). Bakker et al. constructed curves of response to rhGH during the first year of treatment plotting HV as a factor of age at baseline and proposed that HV below the mean -1SD on these plots be considered a poor response (36).

IGF-I and IGFBP3 may be used as markers of sensitivity to GH treatment (31, 34). In previous studies, the median serum IGF-I, as well as IGFBP3, increased significantly (p<0.001) already at 1 month of rhGH treatment and remained elevated during rhGH therapy (37, 38),and the percent increase in the IGF-I level after 1 month of GH treatment, as well as after one year of treatment, showed a significant positive correlation with that of the GH-induced improvement in the percent increase in height velocity during one year of GH therapy (27, 38). Furthermore, polymorphisms in IGFBP3 gene have been shown to be associated with first-year growth response to GH treatment in GHD and TS children (31).

In the current study, after one year of rhGH treatment, IGF-I and IGFBP3 values had increased from significantly below RVs to RV levels or from close to RV levels to significantly above them in every condition, except in cGHD nMRI females, in which levels were similar to RVs at baseline and stayed the same after 1-yr. of GH treatment. Children with cGHD nMRI showed a significant (p<0.01) increase in HV and in height at 1-yr. treatment (i.e. a significant response).

Target height (SD), bone age delay (yrs.), baseline height velocity (SDS) and height prognosis (cm) were independently associated to height velocity at the end of 1-yr. rhGH treatment. However, the determination coefficient was only 0.511, which means that the best model we were able to build could only explain half of the ultimate variability of height velocity at EoT after one year of rhGH treatment, which is consistent with a similar model developed by Ranke et al. (39). Regarding the remaining variability, on one hand, groups were heterogeneous and, on the other, we still do not completely understand the mechanisms of responsiveness.

rhGH treatment at recommended doses is fairly safe. It was discontinued in a very low percentage of patients and only one child (0.2%) referred an AE associated to treatment, which was just slight local pain related to the injection. In previous studies, other AEs have been shown due to high-dose rhGH (27).

Although the study has the limitations of every retrospective study, including incomplete or missing documentation and/or absent information, it assesses the outcomes of a large number of children (504) on first-year rhGH treatment, providing valuable and extensive information on such treatment. This group of patients might be useful to compare groups from future studies where treatment adherence may be objectively measured with an appropriate rhGH administration device.

In conclusion, treatment with rhGH of TS, SGA and GHD patients was highly efficient in the first year, as shown by the different growth-related outcomes. In addition, treatment response had a direct translation into biomarkers values. Results are quite impressive regarding the efficacy of treatment on the height gain attained in the first year, and offer hope in terms of the ultimate height in adulthood. Only one single local AE was reported during the first year of treatment with rhGH.

 

Conflicts of interest

Mª Dolores Rodríguez Arnao received grants from Merck and NovoNordisk, speaker honoraria from Sandoz, and traveling funds from Merck, NovoNordisk, Pfizer and Sandoz. Ignacio Díez received grants from SEEP, is member of Consejo Asesor Cribado Neonatal, and received traveling funds from Merck. Amparo Rodríguez received advisory honoraria from Merck. Julia Otero is from Merck Medical Department. The remainding authors declare no potential conflicts of interest related to this article.

 

Acknowledgements

We want to show our gratitude to Patricia Santagueda for her help with the statistical analyses and Almudena Pardo Mateos for writing assistance. The DATAC study has been sponsored by Merck Serono.

References

1. Somatropin SPC. US Food and Drug Administration (FDA); [updated 08/04/2011; cited 2013 October 1st]; Available from: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm237839.htm.

2. Franklin SL, Geffner ME. Growth hormone: the expansion of available products and indications. Pediatr Clin North Am. 2011;58:1141-65.[Pubmed]

3. Dahlgren J. Easypod: a new electronic injection device for growth hormone. Expert Rev Med Devices. 2008;5:297-304.[Pubmed]

4. Bozzola M, Colle M, Halldin-Stenlid M, Larroque S, Zignani M, easypod survey study g. Treatment adherence with the easypod growth hormone electronic auto-injector and patient acceptance: survey results from 824 children and their parents. BMC Endocr Disord. 2011;11:4.[Pubmed]

5. Hartmann K, Ittner J, Muller-Rossberg E, Schonau E, Stephan R, Ullrich KP, et al. Growth hormone treatment adherence in prepubertal and pubertal children with different growth disorders. Horm Res Paediatr. 2013;80:1-5.[Pubmed]

6. Allen DB. Clinical review: Lessons learned from the hGH era. J Clin Endocrinol Metab. 2011;96:3042-7.[Pubmed]

7. Collett-Solberg PF. Update in growth hormone therapy of children. J Clin Endocrinol Metab. 2011;96:573-9.[Pubmed]

8. Bernasconi S, Arrigo T, Wasniewsk M, Ghizzoni L, Ruggeri C, Di Pasquale G, et al. Long-term results with growth hormone therapy in idiopathic hypopituitarism. Horm Res. 2000;53 Suppl 1:55-9.[Pubmed]

9. Ranke MB. New paradigms for growth hormone treatment in the 21st century: prediction models. J Pediatr Endocrinol Metab. 2000;13 Suppl 6:1365-9.[Pubmed]

10. Saenger P. A lifetime of growth hormone deficiency: a US pediatric perspective. J Pediatr Endocrinol Metab. 2000;13 Suppl 6:1337-42.[Pubmed]

11. Wetterau L, Cohen P. New paradigms for growth hormone therapy in children. Horm Res. 2000;53 Suppl 3:31-6.[Pubmed]

12. Coutant R, Rouleau S, Despert F, Magontier N, Loisel D, Limal JM. Growth and adult height in GH-treated children with nonacquired GH deficiency and idiopathic short stature: the influence of pituitary magnetic resonance imaging findings. J Clin Endocrinol Metab. 2001;86:4649-54.[Pubmed]

13. Soriano-Guillen L, Coste J, Ecosse E, Leger J, Tauber M, Cabrol S, et al. Adult height and pubertal growth in Turner syndrome after treatment with recombinant growth hormone. J Clin Endocrinol Metab. 2005;90:5197-204.[Pubmed]

14. van Pareren YK, de Muinck Keizer-Schrama SM, Stijnen T, Sas TC, Jansen M, Otten BJ, et al. Final height in girls with turner syndrome after long-term growth hormone treatment in three dosages and low dose estrogens. J Clin Endocrinol Metab. 2003;88:1119-25.[Pubmed]

15. Krysiak R, Gdula-Dymek A, Bednarska-Czerwinska A, Okopien B. Growth hormone therapy in children and adults. Pharmacol Rep. 2007;59:500-16.[Pubmed]

16. Poduval A, Saenger P. Safety and efficacy of growth hormone treatment in small for gestational age children. Curr Opin Endocrinol Diabetes Obes. 2008;15:376-82.[Pubmed]

17. Simon D, Leger J, Carel JC. Optimal use of growth hormone therapy for maximizing adult height in children born small for gestational age. Best Pract Res Clin Endocrinol Metab. 2008;22:525-37.[Pubmed]

18. Carrascosa A, Audi L, Fernandez-Cancio M, Yeste D, Gussinye M, Albisu MA, et al. Growth hormone secretory status evaluated by growth hormone peak after two pharmacological growth hormone release stimuli did not significantly influence the two-year catch-up growth induced by growth hormone therapy in 318 prepubertal short children with idiopathic growth retardation. Horm Res Paediatr. 2011;75:106-14.[Pubmed]

19. Sobradillo B, Aguirre A, Aresti. U, Bilbao A, Fernández-Ramos C, Lizárraga A, et al. Curvas y tablas de crecimiento. Estudios longitudinal y transversal. Bilbao: Fundación Faustino Orbegozo. 2002:1-31.[Pubmed]

20. Greulich WW, Pyle SI. Radiographic Atlas of Skeletal Development of the Hand and Wrist. 2nd ed. Standford: Standford University Press; 1959.

21. Bayley N, Pinneau SR. Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standards. J Pediatr. 1952;40:423-41.[Pubmed]

22. Flor-Cisneros A, Roemmich JN, Rogol AD, Baron J. Bone age and onset of puberty in normal boys. Mol Cell Endocrinol. 2006;254-255:202-6.[Pubmed]

23. Argente J, Barrios V, Pozo J, Munoz MT, Hervas F, Stene M, et al. Normative data for insulin-like growth factors (IGFs), IGF-binding proteins, and growth hormone-binding protein in a healthy Spanish pediatric population: age- and sex-related changes. J Clin Endocrinol Metab. 1993;77:1522-8.[Pubmed]

24. Rodriguez Arnao MD, Sanchez AR, Garcia-Rey C, Arroyo Diez FJ, Estrada RC, Cuartero BG, et al. The DATAC study: a new growth database. Description of the epidemiology, diagnosis and therapeutic attitude in a group of Spanish children with short stature. J Pediatr Endocrinol Metab. 2014;27:1201-8.[Pubmed]

25. Lee PA, Chernausek SD, Hokken-Koelega AC, Czernichow P. International Small for Gestational Age Advisory Board consensus development conference statement: management of short children born small for gestational age, April 24-October 1, 2001. Pediatrics. 2003;111:1253-61.[Pubmed]

26. Lavaredas A, de la Puerta R, Alvarez Del Vayo C. Programme review of somatropin deficit in pediatrics at the Hospital Universitario Virgen del Rocio. Farm Hosp. 2013;37:161-5.[Pubmed]

27. Tanaka T, Yokoya S, Fujieda K, Seino Y, Tada H, Mishina J, et al. Efficacy and Safety of Up to 8 Years of Long-term Growth Hormone Treatment in Short Children Born Small for Gestational Age in Japan: Analysis of the Subpopulation According to the Japanese Guideline. Clin Pediatr Endocrinol. 2012;21:57-68.[Pubmed]

28. Kim HS, Yang SW, Yoo HW, Suh BK, Ko CW, Chung WY, et al. Efficacy of short-term growth hormone treatment in prepubertal children with idiopathic short stature. Yonsei Med J. 2014;55:53-60.[Pubmed]

29. Wasniewska M, De Luca F, Bergamaschi R, Guarneri MP, Mazzanti L, Matarazzo P, et al. Early treatment with GH alone in Turner syndrome: prepubertal catch-up growth and waning effect. Eur J Endocrinol. 2004;151:567-72.[Pubmed]

30. Khadilkar VV, Khadilkar AV, Nandy M, Maskati GB. Growth hormone in turner syndrome. Indian Pediatr. 2006;43:236-40.[Pubmed]

31. Clayton P, Chatelain P, Tato L, Yoo HW, Ambler GR, Belgorosky A, et al. A pharmacogenomic approach to the treatment of children with GH deficiency or Turner syndrome. Eur J Endocrinol. 2013;169:277-89.[Pubmed]

32. Tanner JM, Goldstein H, Whitehouse RH. Standards for children's height at ages 2-9 years allowing for heights of parents. Arch Dis Child. 1970;45:755-62.[Pubmed]

33. Luo ZC, Albertsson-Wikland K, Karlberg J. Target height as predicted by parental heights in a population-based study. Pediatr Res. 1998;44:563-71.[Pubmed]

34. Stevens A, Clayton P, Tato L, Yoo HW, Rodriguez-Arnao MD, Skorodok J, et al. Pharmacogenomics of insulin-like growth factor-I generation during GH treatment in children with GH deficiency or Turner syndrome. Pharmacogenomics J. 2014;14:54-62.[Pubmed]

35. Kaspers S, Ranke MB, Han D, Loftus J, Wollmann H, Lindberg A, et al. Implications of a data-driven approach to treatment with growth hormone in children with growth hormone deficiency and Turner syndrome. Appl Health Econ Health Policy. 2013;11:237-49.[Pubmed]

36. Bakker B, Frane J, Anhalt H, Lippe B, Rosenfeld RG. Height velocity targets from the national cooperative growth study for first-year growth hormone responses in short children. J Clin Endocrinol Metab. 2008;93:352-7.[Pubmed]

37. Lu W, Shen S, Luo X, Gong C, Gu X, Li Y, et al. Comparative evaluation of short-term biomarker response to treatment for growth hormone deficiency in Chinese children with growth hormone deficiency born small for or appropriate for gestational age: a randomized phase IV open-label study. Ther Adv Endocrinol Metab. 2013;4:41-9.[Pubmed]

38. Kawai N, Kanzaki S, Takano-Watou S, Tada C, Yamanaka Y, Miyata T, et al. Serum free insulin-like growth factor I (IGF-I), total IGF-I, and IGF-binding protein-3 concentrations in normal children and children with growth hormone deficiency. J Clin Endocrinol Metab. 1999;84:82-9.[Pubmed]

39. Ranke MB, Lindberg A. Growth hormone treatment of idiopathic short stature: analysis of the database from KIGS, the Kabi Pharmacia International Growth Study. Acta Paediatr Suppl. 1994;406:18-23.[Pubmed]



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