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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2180
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 3 764-770
Copyright © 2008 by The Endocrine Society

The Exon 3-Deleted/Full-Length Growth Hormone Receptor Polymorphism Did Not Influence Growth Response to Growth Hormone Therapy over Two Years in Prepubertal Short Children Born at Term with Adequate Weight and Length for Gestational Age

A. Carrascosa1, L. Audí1, M. Fernández-Cancio1, C. Esteban, P. Andaluz, E. Vilaró, M. Clemente, D. Yeste, M. A. Albisu and M. Gussinyé

Department of Pediatrics, Institut de Recerca, Hospital Vall d’Hebron, Centre for Biomedical Research on Rare Diseases, Autonomous University, 08035 Barcelona, Spain

Address all correspondence and requests for reprints to: Antonio Carrascosa, Servicio de Pediatría, Unidad de Endocrinología, Hospital Maternoinfantil Vall d’Hebron, Paseo Vall d’Hebron 119, 08035 Barcelona, Spain. E-mail: ancarrascosa{at}vhebron.net.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Consensus is lacking as to whether the exon 3-deleted (d3)/full-length (fl) GH receptor (GHR) polymorphism is associated with responsiveness to GH therapy.

Objective: Our objective was to evaluate, in short, prepubertal, appropriate-for-gestational age (AGA) patients, 2-yr growth response to GH therapy (31.7 ± 3.5 µg/kg·d) according to exon 3-deleted/full-length GHR genotypes.

Design: We conducted a retrospective study.

Patients: We studied 106 short AGA children, 58 boys and 48 girls, 7.8 ± 2.3 yr, (d3/d3 n = 18, d3/fl n = 42, and fl/fl n = 46). The GH response to two provocative stimuli were under 10 ng/ml in 65 and one or both over 10 ng/ml in 41 patients.

Main Outcome Measures: Patients were followed by a single clinical team and remained prepubertal during the study. The exon 3-deleted/full-length GHR genotypes were determined and analyzed in the same hospital.

Results: Growth velocity significantly (P < 0.0001) increased during the first and second years of therapy, as did height SD score (SDS). These increases were similar in each exon 3-deleted/full-length GHR genotype. Total 2-yr height gain (SDS) did not differ statistically among genotypes: 15.5 ± 2.2 cm and 1.2 ± 0.5 SDS in d3/d3, 15.9 ± 2.0 cm and 1.3 ± 0.4 SDS in d3/fl, and 15.4 ± 2.1 cm and 1.1 ± 0.3 SDS in fl/fl. No significant differences among the three genotypes were found in both sexes or in patients with different GH peak response to provocative stimuli for these parameters. An analysis of previously published studies was also performed.

Conclusions: These results confirm in AGA patients those previously found by us and others in small-for-gestational-age patients and suggest that neither sex nor GH peaks after provocative stimuli might influence significantly the responsiveness to GH therapy according to the exon 3-deleted/full-length GHR genotypes.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Consensus is lacking as to whether the exon 3-deleted (d3)/full-length (fl) GH receptor (GHR) polymorphism is associated with responsiveness to GH therapy. It has been reported that in small-for-gestational-age (SGA) patients, Turner syndrome patients, GH-deficient (GHD) patients, and idiopathic short stature (ISS) patients, those with d3/d3 or d3/fl genotypes grew more than those with the fl/fl genotype (1, 2, 3, 4). However, more recent studies have failed to confirm these results in SGA patients treated for 1 yr (2) or 2 yr (3, 5, 6) and in GHD patients treated for 1 yr (7, 8).

Here we report the growth response, for each of the three exon 3-deleted/full-length GHR polymorphism genotypes, to 2-yr GH therapy in 106 Spanish short children born at term with adequate weight and length [appropriate for gestational age (AGA)], treated with GH at a dosage of 31.7 ± 3.5 µg/kg·d and followed by the same clinical team. In addition, the results of the present and previously published studies (1, 2, 3, 4, 5, 6, 7, 8) are summarized and discussed.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

One hundred six prepubertal Spanish Caucasian short AGA patients (58 boys and 48 girls, aged 7.8 ± 2.3 yr) treated with GH (31.7 ± 3.5 µg/kg·d) were studied retrospectively to evaluate 2-yr growth response according to their exon 3-deleted/full-length GHR genotypes. Patients were followed by a single clinical team at the Pediatric Endocrine Unit of the Children’s Hospital Vall d’Hebron, Barcelona, and GH therapy was started between January 1999 and March 2005. Inclusion criteria were gestational age more than 37 wk, birth weight and/or birth length more than –2 SD of those of gestational age- and sex-matched controls (9, 10), prepubertal stage, height less than –2 SD of that of age- and sex-matched controls (11, 12, 13), never having been treated with GH or other anabolic agents, normal thyroid, kidney, gastrointestinal, lung, and liver functions, normal karyotype in girls, and height SD score (SDS) increase after the 2 yr of GH therapy of more than 0.5. Exclusion criteria were neonatal brain injury, chromosomopathies, malformation syndromes, chronic diseases, and steroid therapy. All patients remained prepubertal during the 2 yr of the study.

GH response peaks to two provocative stimuli (14) (insulin-induced hypoglycemia and exercise propranolol or L-dopa) were under 10 ng/ml in 65 patients (61.3%), one under and the other over 10 ng/ml in 27 patients (25.4%), and both over 10 ng/ml in 14 patients (13.2%). Paternal, maternal, and target heights of patients were similar and not statistically significantly different in all patients (–1.34 ± 1.56 SDS, –1.29 ± 1.08 SDS, and –1.31 ± 0.89 SDS, respectively) or among exon 3-deleted/full-length GHR genotypes (data not shown).

Height and weight were measured 12 months before start of GH therapy, at the start of GH therapy, and every 4 months thereafter. Growth velocities before inclusion (PGV) and for the two following 1-yr periods were calculated. Height and weight were transformed into SDS according to age-, sex-, and pubertal stage-matched control values recently reported in Spanish cross-sectional and longitudinal studies (11, 12, 13). Total height gain (first-year height gain + second-year height gain in SDS and in centimeters), body mass index (BMI), and BMI SDS were calculated. Serum IGF-I was measured and results expressed as SDS according to age- and sex-matched control values (15, 16).

Exon 3-deleted/full-length GHR genotyping

The exon 3-deleted/full-length GHR genotypes were evaluated according to Pantel et al. (17) with modifications as previously reported. When a homozygous d3/d3 genotype was detected (a single band corresponding to 532 bp) and/or when a band potentially corresponding to the 935-bp product was mildly amplified, a second PCR using only G1 and G3 primers was carried out, followed by electrophoresis (5, 6, 18).

Hormone measurements

Serum GH and IGF-I were measured by commercial assays (Immulite; Diagnostic Products Corp., Los Angeles, CA). Reference values for IGF-I SDS calculations were those previously reported (17).

Ethics

Because this work formed part of the usual care of these patients, the study was not submitted to the Ethics Committee of Hospital Vall d’Hebron. However, written informed consent was obtained for each subject over 12 yr of age, and informed parental consent was also obtained for all patients regardless of age. In addition, all treatments were authorized by the Committee for GH and Growth Factor Therapy of the Catalonia Health Service.

Statistical analysis

Results are expressed as percentages and mean ± SD. Differences for the variables evaluated among the exon 3-deleted/full-length GHR genotypes were calculated using ANOVA parametric tests (Bonferroni/Dunn). Differences for the exon 3-deleted/full-length GHR genotype frequencies were analyzed by the {chi}2 test. The Statview 4.5 program (Abacus Concepts, Inc., Berkeley, CA) was used.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
GH therapy response according to exon 3-deleted/full-length GHR genotypes

Clinical and anthropometric parameters for the 106 patients are shown in Table 1Go. Birth length and birth weight (data not shown), chronological age, height SDS and PGV (centimeters per year, SDS) at the start of GH therapy did not differ statistically among the three different exon 3-deleted/full-length GHR genotypes. GH therapy dosages were similar among exon 3-deleted/full-length GHR genotypes. In each exon 3-deleted/full-length GHR genotype, GH therapy significantly (P < 0.0001) increased PGV (centimeters per year, SDS) and height SDS during the first and second years. These increases and, consequently, the total 2-yr height gain (SDS and centimeters) were similar and did not differ statistically among the three exon 3-deleted/full-length GHR genotypes.


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  		TABLE 1. Clinical and anthropometric parameters in prepubertal short AGA children treated with GH (32.1 ± 3.8 µg/kg·d) during the 2-yr follow-up according to exon 3-deleted/full-length GHR genotypes (mean ± SD)

 
A significant increase (P < 0.01) in IGF-I SDS basal values was observed during the first and second years of GH therapy (–0.76 ± 0.54, +0.40 ± 0.81, and +0.58 ± 1.09, respectively). IGF-I SDS values did not differ statistically among exon 3-deleted/full-length GHR genotypes at the start of GH therapy and at the end of the first and second years of GH therapy (data not shown). BMI SDS values at inclusion and during the 2 yr of follow-up were similar and not statistically different among exon 3-deleted/full-length GHR genotypes (data not shown).

GH therapy response according to sex and exon 3-deleted/full-length GHR genotypes

Fifty-eight patients were boys, and 48 were girls. Exon 3-deleted/full-length GHR genotype frequencies were similar in both boys and girls (d3/d3 n = 10 and n = 8; d3/fl n = 23 and n = 19; fl/fl n = 25 and n = 21, respectively). At the start of GH therapy, although chronological ages (8.6 ± 1.9 and 6.8 ± 2.4 yr, respectively) and height SDS (–3.19 ± 0.61 and –3.69 ± 0.93, respectively) differed statistically (P < 0.001) between sexes, PGV (4.18 ± 0.92 and 4.69 ± 0.94 cm/yr; –2.45 ± 0.63 and –2.77 ± 0.92 SDS) did not (Fig. 1Go). At the end of the second year of GH therapy, height SDS (–2.06 ± 0.54 and –2.30 ± 0.91, respectively) and total height gain (first-year height gain + second-year height gain in centimeters and SDS) were statistically significantly different (P = 0.01) between sexes despite a similar dispersion of the values (14.97 ± 1.91 and 16.04 ± 2.34 cm; 1.13 ± 0.40 and 1.39 ± 061 SDS, respectively) (Fig. 1Go). Girls gained 1.04 cm and 0.26 SDS more than boys. However, no statistically significant differences were observed for any of the anthropometric parameters evaluated at the start, during, and at the end of the 2 yr of GH therapy among the three exon 3-deleted/full-length GHR genotypes in boys or in girls or when each genotype was compared between sexes. Figure 1Go, A1 and A2, shows PVG (centimeters per year) and total height gain (centimeters) during the 2 yr of GH therapy for boys and girls (A1) and for each exon 3-deleted/full-length GHR genotype in boys and in girls (A2). Figure 1Go, B1 and B2, shows the same data expressed as SDS (B1 for boys and girls, and B2 for each exon 3-deleted/full-length GHR genotype in boys and in girls).


Figure 1
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  		FIG. 1. Box plot of PVG (centimeters per year) and total height gain (centimeters) during the 2 yr of GH therapy for boys and girls (A1) and for each exon 3-deleted/full-length GHR genotype in boys and in girls (A2). The same data expressed as SDS are shown in B1 and B2. *, P = 0.01 (boys vs. girls).

 
GH therapy response according to GH peak response to two acute provocative stimuli and exon 3-deleted/full-length GHR genotypes

GH response peaks to two provocative stimuli were under 10 ng/ml in 65 patients (isolated GHD) and one or both over 10 ng/ml in 41 (non-GH-deficient ISS patients). Exon 3-deleted/full-length GHR genotype frequencies were as follows: d3/d3 n = 8 and n = 10; d3/fl n = 26 and n = 16; fl/fl n = 31 and n = 15, respectively. At the start of GH therapy, chronological age, bone age, IGF-I SDS, height SDS, and PGV (centimeters and SDS) were similar in both groups, as also occurred for growth velocity (SDS and centimeters), total height gain (first-year height gain + second-year height gain in SDS and in centimeters) and IGF-I SDS values during the 2 yr of GH therapy (Fig. 2Go, and data not shown). No statistically significant differences were observed for these anthropometric parameters among the three exon 3-deleted/full-length GHR genotypes in GHD or in ISS patients or when each genotype was compared between GHD and ISS patients. Figure 2Go, A1 and A2, shows PVG (centimeters per year) and total height gain (centimeters) during the 2 yr of GH therapy for GHD and ISS patients (A1) and for exon 3-deleted/full-length GHR genotypes in GHD and in ISS patients (A2). Figure 2Go, B1 and B2, shows the same data expressed as SDS (B1 for GHD and ISS patients, and B2 for each exon 3-deleted/full-length GHR genotype in GHD and ISS patients).


Figure 2
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  		FIG. 2. Box plot of PVG (centimeters per year) and total height gain (centimeters) during the 2 yr of GH therapy for GHD and ISS patients (A1) and for each exon 3-deleted/full-length GHR genotype in GHD and ISS patients (A2). The same data expressed as SDS are shown in B1 and B2.

 
GH therapy response according to exon 3-deleted/full-length GHR genotypes: summary of results of the present and previously published studies (1, 2, 3, 4, 5, 6, 7, 8)

Growth response to GH therapy in the present and previous studies according to exon 3-deleted/full-length GHR genotypes is summarized in Table 2Go. The clinical diagnosis, study protocol, GH dosage, number of patients, years on GH therapy, and growth response reported in each study are also shown. To date, exon 3-deleted/full-length GHR genotypes have been determined in 942 short children with different clinical conditions treated with varying GH dosages for 1 or 2 yr (1, 2, 3, 4, 5, 6, 8). In addition to these studies, another study failed to find any significant difference in growth response in 54 GH-deficient children treated with 28 µg/kg·d for 1 yr, although in that study, the exon 3-deleted/full-length GHR genotypes were not described in detail and have therefore not been included (7).


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  		TABLE 2. Growth response to GH therapy according to exon 3-deleted/full-length-GHR genotypes: summary of reported and present studies

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In previous studies, we analyzed the growth response to GH therapy according to exon 3-deleted/full-length GHR genotypes in SGA patients and found similar spontaneous growth and similar GH therapy response for each genotype whether the patients were treated with 32.1 ± 3.8 µg/kg·d (6) or with 66 µg/kg·d (5). Here, using a similar methodology, we report our results in short prepubertal children born AGA followed by our clinical team.

One hundred six prepubertal children were studied, and gastrointestinal, renal, and known causes of short stature were ruled out. Anthropometric data were compared with those of age-, sex-, and pubertal stage-matched Spanish controls obtained in recent cross-sectional and longitudinal studies (10, 11, 12, 13). As in our previous studies (5, 6), patients with poor growth response (total 2-yr GH therapy height SDS gain < 0.5) were excluded, which suggests that main genotype anomalies of the GHR-IGF-I axis could be ruled out (19, 20, 21, 22). According to this criterion, in the present study, 16 patients were excluded from the initial sample of 122 patients. Of these 16, one carried the d3/d3 GHR genotype, eight the d3/fl GHR genotype, and seven the fl/fl GHR genotype; these data show that poor GH responders were distributed in all exon 3-deleted/full-length GHR genotypes, as occurred in the SGA patients (6); the inclusion of these 16 patients in the sample did not change the results obtained for the analyzed sample of 106 patients (data not shown).

Fifty-eight patients were boys, and 48 were girls. Girls were significantly younger and shorter than boys at the start of GH therapy, and this could explain why they gained a mean of 1.04 cm (0.26 SDS) more than boys during the 2 yr of GH therapy, although the value dispersion was similar (Fig. 1Go). Exon 3-deleted/full-length GHR genotype distribution was similar in both sexes with 10 boys and eight girls included in the d3/d3 genotype. Despite the differences in height gain during GH therapy between boys and girls, height gain was similar in each sex and not statistically different among the three exon 3-deleted/full-length GHR genotypes. The same occurred when each genotype was compared between sexes. This allowed us to analyze both sexes as a single group with a considerable number of patients for each exon 3-deleted/full-length GHR genotype: 18 for d3/d3, 42 for d3/fl, and 46 for fl/fl.

GH secretion peaks were in the range of GHD patients in 65 and above this range in 51 (14). According to this, patients were considered as isolated GHD secretors and as normal GH secretors with ISS. Because chronological age and clinical and anthropometric evaluations before GH therapy and during the 2 yr of GH therapy were similar in both groups and in each exon 3-deleted/full-length GHR genotype, patients were evaluated as a single group. As discussed above for sex, this allowed us to analyze a considerable number of patients for each exon 3-deleted/full-length GHR genotype: 18 for d3/d3, 42 for d3/fl, and 46 for fl/fl.

Spontaneous growth in our patients did not differ among exon 3-deleted/full-length GHR genotypes, and this concurs with data published by us and others in previous studies in short SGA, GHD, ISS, and Turner syndrome patients (2, 3, 4, 5, 6, 8); this suggests that under these clinical conditions, exon 3-deleted/full-length GHR genotypes do not play an important role in regulating skeletal growth.

The results of the present study comparing growth response to GH therapy among the three exon 3-deleted/full-length GHR genotypes in AGA patients confirm those previously reported by us using similar methods in SGA patients, with a considerable number of patients and genotypes evaluated in our studies [n = 252, 146 SGA and 106 AGA (65 GHD and 41 ISS); 34 d3/d3, 103 d3/fl and 115 fl/fl)] (5, 6) (present study). They also concur with those reported for 1 yr (2) or 2 yr (3) of GH therapy in 60 and 240 SGA patients, respectively, and disagree with those reported by others in two cohorts including 60 SGA and 112 ISS treated for 2 yr (1) and in 53 Turner syndrome patients treated for 1 yr (2).

To date, exon 3-deleted/full-length GHR genotypes have been determined in 942 short children with different clinical conditions treated with varying GH dosages for 1 or 2 yr (1, 2, 3, 4, 5, 6, 8). In 777 patients, data were analyzed by comparing growth response to GH therapy among the three genotypes: d3/d3, d3/fl, and fl/fl (1, 2, 3, 5, 6). Despite differences in clinical conditions (SGA, ISS, GHD, and Turner syndrome patients), GH dosage (30–66 µg/kg·d) and duration of GH therapy (1 or 2 yr), the interesting and clinically significant findings of Dos Santos et al. (1) were unfortunately observed in only 29% of the 777 patients evaluated (n = 225: 35 d3/d3, 77 d3/fl, and 113 fl/fl) (1, 2), whereas no significant differences were found in the remaining 71% (n = 552: 73 d3/d3, 191 d3/fl, and 288 fl/fl) (2, 3, 5, 6) (present study). Whether differences in the methods used for patient recruitment, study protocol, GH dosage, GH therapy duration, and exon 3-deleted/full-length GHR genotyping could help to explain these discordant results is something to be considered.

In 458 patients, [293 included in the above-mentioned 777 patients (2, 3) and 165 new patients (4, 8)], growth response to GH therapy was analyzed by comparing combined data from the d3/d3 plus d3/fl genotypes with those of the fl/fl genotype. Following this criterion, significant differences of 1.7 cm were found in 58 multiple and isolated GHD patients treated for 1 yr (4) and of 0.4 cm in 240 SGA patients treated for 2 yr (3). However, no significant differences were found in 107 isolated GHD patients treated for 1 yr (8). In addition, when we analyzed in this way the results of our 252 patients (5, 6) (present study), we found no statistically significant differences for SGA or AGA patients or for either of the GH dosages used (66 or 32.1 ± 3.8 µg/kg·d) (data not shown). Although this type of analysis may reveal a tendency, comparison among the three different genotypes (d3/d, d3/fl, and fl/fl) better represents what occurs in human biology.

As discussed above, in our studies (5, 6) (present study), we excluded patients with poor growth response (total 2 yr of GH therapy with height SDS gain of <0.5) to rule out the main genotype anomalies of the GHR-IGF-I axis (19, 20, 21, 22) not evaluated in the present and previous studies (1, 2, 3, 4, 5, 6, 7, 8), which could give rise to heterogeneous results, although poor clinical compliance may not have been completely ruled out. This information was not reported in the Dos Santos et al. (1) and Binder et al. (2) studies; thus, it remains unknown whether this could help to explain the different results obtained. In addition, according to this criterion, 23 patients were excluded from our initial sample of 275 patients (153 SGA and 122 AGA) (5, 6) (present study). Of these 23 patients, three carried the d3/d3 GHR genotype, 10 the d3/fl GHR genotype, and 10 the fl/fl GHR genotype. These data show that poor GH responders were found in all exon 3-deleted/full-length GHR genotypes.

In our studies, because we (5, 6, 18) and others (23) found a certain percentage of inaccuracy in amplifying the fl GHR allele and, consequently, in genotype assignment with the multiplex competitive PCR technique described by Pantel et al. (17), when a homozygous d3/d3 GHR was detected, we performed a second PCR using only G1 and G3 primers; this led to a genotype reassignment to d3/fl GHR in approximately 20% of previously d3/d3 GHR results. Because this method was not applied in the other published studies (1, 2, 3, 4, 7, 8), the fact that the different technique used in genotype assignment might contribute to the different results obtained cannot be ruled out.

Prospective studies for each clinical condition (SGA, ISS, isolated GHD, multiple GHD, and Turner syndrome), including a similar and statistically significant number of patients for each of the three exon 3-deleted/full-length GHR genotypes evaluated with the same method, with similar inclusion and exclusion criteria and treated with similar GH dosage (30 and 60 µg/kg·d) and followed from infancy to adulthood, are required to ascertain whether exon 3-deleted/full-length GHR genotypes could contribute to significant differences in growth response to GH therapy during prepubertal and pubertal growth and consequently in adult height.

In summary, in the present study, we found no differences in spontaneous growth or in 2-yr growth response to GH therapy among the three exon 3-deleted/full-length GHR genotypes in AGA patients, and these results concur with those previously published by us in SGA patients. In addition, we also found that despite differences in the degree of growth response to GH therapy between boys and girls, this response was similar and did not differ among the three exon 3-deleted/full-length GHR genotypes in boys and in girls or when each genotype was compared between sexes. Finally, we also found that growth response to 2-yr GH therapy was not related to previous GH peak response to two acute stimuli in AGA patients and that this response was similar among the three exon 3-deleted/full-length GHR genotypes.

Because consensus is lacking as to whether the exon 3-deleted/full-length GHR polymorphism is associated with responsiveness to GH therapy and the interesting and clinically significant results of the earlier reports (1, 2, 4) have not been confirmed (3, 5, 6, 7, 8) (present study), prospective controlled clinical studies including a similar number of patients for each genotype are required to ascertain whether or not exon 3-deleted/full-length GHR genotypes would influence the response to GH therapy in short children with different clinical conditions.


   Acknowledgments
 
Christine O’Hara is acknowledged for useful help with the English version of the manuscript.


   Footnotes
 
This work was supported by grants from Institute of Health Carlos III, RCMN (C03/08) and FIS PI-020803 from Ministerio de Sanidad y Consumo, Madrid, Spain, and from Pfizer Spain.

Disclosure Summary: A.C., L.A., M.F.-C., C.E., P.A., E.V., M.C., D.Y., M.A.A., and M.G. have nothing to declare.

First Published Online December 26, 2007

1 A.C., L.A., and M.F.-C. have contributed equally to this work. Back

Abbreviations: AGA, Appropriate for gestational age; BMI, body mass index; GHD, GH-deficient; GHR, GH receptor; ISS, idiopathic short stature; PGV, growth velocities before inclusion; SDS, SD score; SGA, small for gestational age.

Received September 28, 2007.

Accepted December 18, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Dos Santos C, Essioux L, Teinturier C, Tauber M, Goffin V, Bougneres P 2004 A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat Genet 36:720–724[CrossRef][Medline]
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