help button home button Endocrine Society JCEM JCEM Call for Nominations for EIC
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2007-0176
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
92/7/2758    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jensen, R. B.
Right arrow Articles by Juul, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jensen, R. B.
Right arrow Articles by Juul, A.
Related Collections
Right arrow Metabolism
Right arrow Neuroendocrinology and Pituitary
Right arrow Pediatric Endocrinology
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 7 2758-2763
Copyright © 2007 by The Endocrine Society

The Presence of the d3-Growth Hormone Receptor Polymorphism Is Negatively Associated with Fetal Growth but Positively Associated with Postnatal Growth in Healthy Subjects

Rikke Beck Jensen, Signe Vielwerth, Torben Larsen, Gorm Greisen, Henrik Leffers and Anders Juul

University Departments of Growth and Reproduction (R.B.J., H.L., A.J.), and Neonatology (S.V., G.G.), Rigshospitalet, DK-2100 Copenhagen, Denmark; and Department of Gynaecology and Obstetrics (T.L.), Holbaek Sygehus, Sygehus Vestsjaelland DK-4300, Denmark

Address all correspondence and requests for reprints to: Rikke Beck Jensen, M.D., University Department of Growth and Reproduction, Rigshospitalet, Section 5064, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. E-mail: rikke.beck{at}rh.hosp.dk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: A common polymorphism in the GH receptor (GHR) gene has been linked to increased growth response in GH-treated patients. No former study has focused on the association to prenatal growth.

Objective: The aim of the study was to evaluate the association between the d3-GHR isoforms and spontaneous pre- and postnatal growth.

Design: A prospective study was conducted on third-trimester fetal growth velocity (FGV), birth weight, birth length, and postnatal growth.

Setting: The study was conducted at Copenhagen University Hospital.

Participants: A total of 115 healthy adolescents were divided into those born small for gestational age (SGA) and appropriate for gestational age with or without intrauterine growth restriction.

Main Outcome Measures: FGV was measured by serial ultrasonography, birth weight, birth length, and adolescent height. Isoforms of the d3-GHR gene (fl/fl, d3/fl, and d3/d3) were determined.

Results: The prevalence of the d3-GHR isoforms was 50% but differed among the groups (P = 0.006), with a high prevalence (88%) in the group born SGA with verified intrauterine growth restriction. The d3-GRH allele were associated with decreased third-trimester FGV (P = 0.05) in SGA subjects. In the entire cohort, carriers of the d3-GHR allele had a significantly increased height (–0.10 vs. 0.34 SD score; P = 0.017) and change in height from birth to adolescence compared with carriers of the full-length GHR allele (0.57 vs. –0.02 SD score; P = 0.005).

Conclusions: This study showed an increased spontaneous postnatal growth velocity in the carriers of the d3-GHR allele. Interestingly, we found the opposite effect on prenatal growth in the SGA group, with a decreased FGV in carriers of the d3-GHR allele.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ADEQUATE TRANSPLACENTAL substrate transport to the fetus is a prerequisite for normal growth, and a suboptimal environment in utero like third-trimester placental dysfunction often results in intrauterine growth restriction (IUGR). However, a limited period of IUGR may not necessarily result in smallness at birth [small for gestational age (SGA)]; despite limited substrate supply at some point during gestation, the infant may still be born appropriate for gestational age (AGA). Decreased fetal growth velocity (FGV) throughout gestation often results in smallness at birth, exemplified by small mothers giving birth to healthy but small newborns; this is thought to be genetically determined. Thus, SGA and IUGR are not necessarily synonymous entities.

The genetic and endocrine regulation of the transplacental fluxes of glucose and amino acids to the fetus is poorly understood. Associations between common genetic polymorphisms and IUGR have been proposed. The polymorphism insulin gene (INS) variable number of tandem repeats in the insulin gene seems to be related to the size at birth (1, 2), and this polymorphism is also associated with insulin resistance later in life (3), hereby linking fetal growth with adult onset of disease. Other genetic polymorphisms have been related to IUGR, such as polymorphisms in the gene encoding the CYP17 enzyme (4).

Fetal growth is generally considered independent of fetal GH levels, whereas fetal IGF-I levels are associated with fetal size (5, 6, 7, 8, 9). Genetic variations in the promotor region of the gene encoding IGF-I have been associated with low birth weight (BW) (10, 11), although controversy exists (12). Recently, genetic polymorphisms in the GH receptor (GHR) gene have been related to the postnatal growth response to exogenous GH in children born SGA (13, 14, 15), but to our knowledge, no studies have evaluated the influence of GHR genetic polymorphisms on fetal growth in humans.

The aim of this study was to investigate the association between a common genetic polymorphism in the gene encoding the GHR (fl/fl, d3/fl, and d3/d3) and spontaneous pre- and postnatal growth in a cohort of healthy young men and women.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Participants

A total of 123 healthy young Caucasian subjects (52 males) participated in a follow-up study of a larger randomized controlled trial on fetal growth (16). The original study was performed in 1985–1987 on their mothers, from whom data were collected on third-trimester FGV and BW for gestational age. In the former study, pregnant women who had one or more risks factors (reported in detail earlier) for giving birth to a small child were recruited (16, 17). Calculations of third-trimester FGV were based on serial ultrasound measurements (three to nine measurements with a mean of four) from wk 28 until birth. A linear regression analysis was performed to calculate the changes in estimated fetal weight SD score (SDS) per 28 d, with a SE of 0.22 SDS/28 d. From these calculations, it was evaluated whether the fetus was growth restricted (IUGR) during the third trimester using the 10th percentile (equivalent to –0.39 SDS/28 d) of normal third-trimester FGV as the cutoff (18). Furthermore, the cohort was divided into infants born AGA or SGA using the 10th percentile for BW (equivalent to –1.28 SDS) as the cutoff value based on the previously published reference data (18). In the follow-up study performed in 2003–2005, it was possible to trace 547 young men and women born as singletons at term and with sufficient ultrasound data to estimate FGV. A sample of 271 was invited, including all the children who were born SGA and/or IUGR, and a random selection of one third of those born AGA. A total of 123 (52 males) agreed to participate (participation rate 45%). There were no significant differences in either BW (–0.63 vs. –0.61 SDS) or FGV in third trimester (–0.17 vs. –0.19 SDS/28 d) between the participants and nonparticipants, respectively. A DNA sample was obtained from 115 participants in whom sufficient data on prenatal growth were available; 69 participants were born AGA (25 with verified IUGR), and 46 were born SGA (17 with verified IUGR).

Study design

The participants (n = 115) arrived fasting between 0800 and 0900 h, where blood samples were drawn. Height (cm) was measured to the nearest 0.1 cm using a calibrated wall-mounted stadiometer (Force Institute, Brøndby, Denmark), and weight (kg) was measured on a digital weight scale, with a precision of 0.01 kg (Lindeltronic 8000; Copenhagen, Denmark). SDSs for height and weight were calculated based on a Danish national reference material (19). Pubertal stages were determined by Tanner’s classification (20), and testicular size was estimated using Prader’s orchidometer (21). Maternal and paternal height (SDS) was calculated using the national reference material (19), and target height (SDS) was calculated: maternal height (SDS) + paternal height (SDS)/2. Sufficient data for target height calculation were available in 95 subjects.

Hormone assays

Serum IGF-I was determined by RIA, as previously described (22). Briefly, serum was extracted by acid-ethanol and cryoprecipitated to remove interfering IGF binding proteins (IGFBPs) (23). Interassay and intraassay coefficients of variation were 9% and 6%, respectively. IGFBP-3 was determined by a RIA previously described (24). Reagents for the assay were obtained from Mediagnost GmbH (Tübingen, Germany). Sensitivity was 0.29 ng/ml (3 SD above zero standard). Interassay and intraassay coefficients of variation were 10.7% and 7.6%, respectively (25).

Genotyping

Genomic DNA was extracted from blood lymphocytes. The frequency of GHR transcript variants with retention (fl-GHR) or exclusion (d3-GHR) of exon 3 was tested by the multiplex PCR assay described by Pantel et al. (26). This was performed with primers G1, G2, and G3 (GenBank accession no. AF155912) as follows: initial step of denaturation of 3 min at 95 C, followed by 25 cycles consisting of 30 sec at 95 C, 1 min at 64 C, 1 min at 72 C, followed by an extension period at 72 C for 5 min. Amplification of DNA fragments was analyzed by electrophoresis on a 1% agarose gel stained with ethidium bromide. A 935-bp band represented the full-length (fl) allele (fl-GHR), and a 532-bp fragment represented the d3 allele (d3-GHR). To avoid possible problems caused by the multiplex PCR (27, 28), all samples were also analyzed by PCR using only the G1 and G3 primers, however, giving identical results in all cases. The distribution of the GHR genotypes did not deviate significantly from Hardy-Weinberg equilibrium.

Statistical analysis

Results were expressed as mean and SD or as median and interquartile range (IQR). Differences between the three groups with different genotypes were tested by ANOVA, and the significant results were further analyzed by the Student’s t test. Most anthropometric variables were presented as SDSs to evaluate males and females together. All variables were analyzed for normal distribution, and those with a skewed distribution were log transformed, or data were presented as median and IQR, and tested using the Mann-Whitney U test.

Ethical aspects

The study was performed according to the Helsinki II declaration, and approved by the local Ethical Committee (KF 01-229/02 and KF 01-065/03) and The Danish Data Protection Agency. Written informed consent was obtained from all participants and also from the parents/guardians of the participants under 18 yr of age.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The entire cohort consisted of 115 adolescents (51 males) who were all singletons born at term (37 wk > GA < 42 wk), with a mean BW deviation corrected for gestational age of –0.68 (SD 1.17) and a mean birth length (BL) SDS of –0.22 (SD 0.95). Mean third-trimester FGV assessed by serial ultrasonography was –0.18 {Delta}SDS/28 d (SD 0.39). At the follow-up study, mean age was 17.5 yr (SD 0.7), mean height SDS was 0.10 (SD 1.0), and height SDS corrected for target height was 0.13 SDS (SD 0.9). Age at follow-up and pubertal development (pubic hair, testicular volume in boys, and breast stages in girls) did not differ between subjects with the different GHR isoforms.

Of the 115 participants, 57 (50%) were homozygous for the fl allele (fl/fl), 47 (41%) were heterozygous (d3/fl), and 10 (9%) were homozygous for the d3 allele (d3/d3), hence the prevalence of the d3/fl and d3/d3 GHR isoforms (heterozygous or homozygous) was 50% in the entire cohort. The prevalence was increased in the group defined as SGA with IUGR (88%) (Fig. 1Go), and this difference was significant in an overall comparison of the four groups ({chi}2; P = 0.006).


Figure 1
View larger version (15K):
[in this window]
[in a new window]

  		FIG. 1. Presence of GHR isoforms in 115 adolescents born SGA or AGA with or without IUGR. The bars represent the number of carriers of the different d3/fl-GHR Isoforms. The black bars represent the fl allele (fl/fl), the dark gray bars represent the heterozygous d3-deleted allele (d3/fl), and the light gray bars represent the homozygous d3-deleted allele (d3/d3). The cohort is divided into those born SGA and AGA with and without IUGR.

 
The clinical characteristics of the subjects according to their GHR isoforms are given in Table 1Go. There was a trend toward lower BL (ANOVA; P = 0.07) among carriers of the d3-GHR compared with the fl/fl group. Third-trimester FGV did not differ among the three groups in the entire cohort (ANOVA; P = 0.50). There were no differences in either paternal, maternal, or target height among the three groups, respectively. At follow-up, there was no significant difference between height (SDS), but when this was corrected for target height (HSDScorr), there was a significant difference between the GHR isoforms (ANOVA; P = 0.017); both the carriers of the d3/fl and d3/d3 GHR alleles were significantly taller than carriers of the fl/fl allele (P = 0.04 and P = 0.01, respectively) (Table 1Go). Carriers of at least one d3-allele had a lower weight SDS compared with the fl/fl group (median 0.29 vs. 0.89), but this did not reach statistical significance (P = 0.08). The change in height (SDS) from birth to adolescence corrected for target height ({Delta}HSDScorr) was significantly increased among the carriers of at least one d3 allele compared with the fl/fl group (mean 0.57, SD 1.05 vs. mean –0.02, SD 0.92; P = 0.005). There was a significant difference when comparing the three different isoforms (ANOVA; P = 0.01), with a significantly higher {Delta}HSDScorr in subjects carrying the d3/fl (P = 0.02) and d3/d3 (P = 0.02) isoforms compared with subjects carrying the fl/fl isoform (Fig. 2Go). To depict the time of catch-up growth, we looked at the change in weight and length during the first year of life, which was available in a part of the cohort (n = 69). There was a significantly higher change in weight from birth to 1 yr in the carriers of at least one d3 allele compared with the fl/fl group (mean –0.002 vs. –0.55; P = 0.035), and regarding length, the same tendency was found but did not reach statistical significance (mean –0.26 vs. –0.59; P = 0.13). In a multiple regression analysis with HSDScorr as dependent variable and the GHR isoforms, BW (SDS) and FGV as independent variables, we found a significant positive association with the GHR isoforms [B = 0.49, 95% confidence interval (CI) 0.21–0.76; P = 0.001) and BW SDS (B = 0.31, 95% CI 0.17–0.45; P < 0.0001), but no significant association to FGV (B = 0.19, 95% CI –0.18–0.30; P = 0.37).


View this table:
[in this window]
[in a new window]

  		TABLE 1. Clinical and anthropometric measurements at birth and in adolescence according to GHR genotype

 

Figure 2
View larger version (9K):
[in this window]
[in a new window]

  		FIG. 2. FGV in third trimester (expressed as {Delta}SDS/28 d) according to GHR genotypes. The black diamonds represent the fl allele (fl/fl) (n = 18), the dark gray diamonds represent the heterozygous d3-deleted allele (d3/fl) (n = 21), and the light gray diamonds represent the homozygous d3-deleted allele (d3/d3) (n = 7).

 
When analyzing the SGA group alone, there were no significant differences of BW or BL between groups with the GHR isoforms. However, we found a significant difference in FGV among the three groups (ANOVA; P = 0.05), with a lower FGV in both carriers of the d3/fl (mean –0.33, SD 0.36; P = 0.05) and the d3/d3 (mean –0.42, SD 0.30; P = 0.03) genotypes, respectively, when compared with the fl/fl group (mean –0.10, SD 0.31) (Fig. 3Go). In the SGA group, there was a trend toward a higher HSDScorr in the groups with at least one d3 allele; this did not reach significance (P = 0.08).


Figure 3
View larger version (9K):
[in this window]
[in a new window]

  		FIG. 3. Change in height SDS from birth to near-final height corrected for target height. Black diamonds represent fl/fl (n = 46), dark gray diamonds represent d3/fl (n = 44), and light gray diamonds represent d3/d3 (n = 5).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this prospective cohort study on long-term effects of fetal growth in healthy subjects, we found that carriers of the d3-GHR allele who were born SGA had significantly decreased third-trimester FGV compared with carriers of the fl-GHR allele, and that the d3-GHR allele was more prevalent in the SGA/IUGR group. In contrast, significantly increased postnatal growth as well as adolescent height was found among carriers of the d3-GHR alleles in the entire cohort. The increase in spontaneous postnatal growth among carriers of the d3 allele is in accordance with previous studies on growth response in GH-treated children. Interestingly, the presence of the d3-GHR allele had the opposite effect on prenatal growth in the SGA group, with a decreased FGV in the heterozygous and homozygous d3-GHR groups. To our knowledge, this is the first study to examine the associations between d3-GHR genotypes and prenatal growth, as well as spontaneous postnatal growth.

Prenatal growth

Hormonal regulation of normal fetal growth is not fully understood, but fetal insulin is one of the major signals of nutrient availability promoting fetal growth via anabolic effects on the metabolism and via stimulation of IGF-I secretion. Traditionally, hormone regulation has been thought to be independent of fetal GH levels, but some reports seem to challenge this. First, several reports have uniformly reported decreased BLs of newborns with GH deficiency (GHD) corresponding to –1.1 SDS (n = 44) (29), –1.3 to –1.7 SDS (n = 14) (30), –0.57 SDS (n = 11) (31), and –0.83 SDS (n = 52) (32), respectively. Second, decreased BLs corresponding to –1.0 SDS in 82 newborns with GHR dysfunction were reported (33). Moreover, GHRs (GHR mRNA expression) have been demonstrated in fetal tissues as early as the first trimester of fetal life (34), which could theoretically be activated after GH binding. Together, these findings suggest that fetal GH may play an important direct role in regulation of fetal growth (30, 32).

Furthermore, GH may play an indirect role in regulation of fetal growth. The pregnancy-specific GH variant (termed placental GH) is primarily expressed in the syncytiotrophoblasts of the placenta and is secreted into the maternal circulation. Placental GH secretion gradually replaces maternal pituitary GH during pregnancy and is positively associated with fetal growth (35). It is suggested that placental GH operates indirectly via changes in maternal IGF-I and/or maternal metabolism regulating substrate supply to the fetus. GHRs are present in abundance in placenta, and placental GHs have similar binding affinity toward these receptors compared with that of pituitary GHs (36). Placental GH may theoretically stimulate GHRs on the surface of the syncytiotrophoblast by autocrine or paracrine actions, thereby affecting placental growth, placental IGF-I production, or substrate transfer to the fetus. The different isoforms of the GHR gene are also present in placenta, and binding studies have demonstrated that placental GH and pituitary GH have similar affinities toward the heterozygous (d3/fl) and homozygous (d3/d3) d3-GHR isoforms compared with the fl-GHR isoform (fl/fl) (37). Importantly, pituitary GH binding to the d3-GH-R may result in increased intracellular signaling compared with binding to the fl-GHR at equimolar concentrations, despite similar binding characteristics (15). It remains unknown whether or not differences in the intracellular signaling events after GHR activation could result in different biological actions of placental GH, depending on the presence of specific GHR isoforms at the cell surface.

Prevalence of the d3-GHR isoform

The prevalence of the d3-GHR isoform (heterozygous or homozygous) in the present study was 50%, with a distribution of 41% (d3/fl) and 9% (d3/d3) between heterozygous and homozygous individuals, respectively. The prevalence of homozygous d3/d3 carriers is comparable to the prevalence found in other studies (11–15%) (13, 27, 38, 39). Interestingly, when our present cohort was divided into four groups according to third-trimester FGV and BW, there was a strikingly high prevalence of the d3-GHR isoforms (88%) in the group born SGA with verified IUGR. Thus, our study indicates that the polymorphism in the gene encoding the GHR is associated with fetal growth, suggesting that GH is involved in regulation of fetal growth in contrast to the general belief. One of the limitations of this study is the small sample size, which was due to the antenatal selection of the offspring of the mothers participating in a former cohort study. The relatively low participation rate (45%) of a limited cohort reduced the sample size. However, other studies investigating the relationship between the GHR genotypes and postnatal growth have similar sample sizes, thus larger epidemiological studies are needed to confirm the findings.

Postnatal growth

The majority of SGA children show catch-up growth during the first 2 yr of life. It is not entirely understood why the remaining 5–10% do not catch up and, thereby, reach a final height below the normal range (40, 41, 42). Linear growth in childhood is regulated by the GH-IGF-I axis, and alterations of this axis will influence the growth rate. Most SGA children have a moderately decreased GH secretion (43). It remains to be seen if GH binding properties or changes in the GH signaling pathways are altered in SGA children.

Recent clinical studies have demonstrated an association between the presence of a d3-GHR allele and an increased growth response to GH treatment in SGA children, as well as in other groups of GH-treated patients (GHD, Turner syndrome, and idiopathic short stature) (13, 15, 44), although controversy exists (45, 46). Recently, Dos Santos et al. (15) found that among SGA children, carriers of the d3-GHR isoforms (d3/fl and d3/d3) had an increased growth response after GH treatment, compared with carriers of the fl-GHR isoform, in accordance with the findings of Binder et al. (13). By contrast, Carrascosa et al. (14) did not find such associations. These varying results may reflect the use of different GH doses in the three studies because a high GH dose could potentially mask the difference between the d3/fl-GHR genotypes. In addition to the findings among GH-treated SGA individuals, the majority of studies found positive associations between the d3-GHR isoform and an increased growth response to GH treatment in patients with Turner syndrome (13), idiopathic short stature (15), and GHD (44), although it was not found in all studies (45, 46).

In our present study, we found that subjects carrying the d3-GHR isoforms had an increased postnatal growth as well as an increased near-final height. Importantly, the majority of the SGA subjects in our study had spontaneous catch-up growth and a near-final height within the normal limits. In line with this, Audi et al. (27) found that the fl-GHR genotype was more common in the group of short SGA children without spontaneous catch-up growth compared with healthy subjects. In contrast, population-based studies of healthy subjects found no association between the d3-GHR genotype and final adult height (27, 39) or bone mineral density (39).

Recent preliminary reports revealed contrasting results. One study suggested that d3-GHR carriers had lower IGF-I and were more insulin resistant (assessed by homeostasis model of assessment) compared with carriers of the fl-GHR allele (47). Conversely, type 2 diabetics who were homozygous for the d3-GHR allele had higher IGF-I levels (48). We found no differences in IGF-I serum levels between GHR genotypes.

In conclusion, we found that carriers of the d3-GHR allele who were born SGA had significantly decreased third-trimester FGV, and that the d3-GHR alleles were significantly more prevalent in the SGA/IUGR group compared with subjects with normal BW. In contrast, a significantly increased adolescent height and a significantly increased change in height from birth to adolescence were found among carriers of the d3-GHR alleles. Thus, variations in the gene encoding the GHR seem oppositely associated with fetal and postnatal growth, respectively.


   Footnotes
 
Disclosure Statement: R.B.J., S.V., and G.G. received financial support for the project from Novo Nordisk A/S. T.L., H.L., and A.J. have nothing to declare.

First Published Online April 10, 2007

Abbreviations: AGA, Appropriate for gestational age; BL, birth length; BW, birth weight; CI, confidence interval; FGV, fetal growth velocity; fl, full-length; GHD, GH deficiency; GHR, GH receptor; HSDScorr, height SDS corrected for target height; IGFBP, IGF binding protein; IQR, interquartile range; IUGR, intrauterine growth restriction; SDS, SD score; SGA, small for gestational age.

Received January 24, 2007.

Accepted April 2, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Dunger DB, Ong KK, Huxtable SJ, Sherriff A, Woods KA, Ahmed ML, Golding J, Pembrey ME, Ring S, Bennett ST, Todd JA 1998 Association of the INS VNTR with size at birth. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Nat Genet 19:98–100[Medline]
  2. Ibanez L, Ong K, Potau N, Marcos MV, De Zegher F, Dunger D 2001 Insulin gene variable number of tandem repeat genotype and the low birth weight, precocious pubarche, and hyperinsulinism sequence. J Clin Endocrinol Metab 86:5788–5793[Abstract/Free Full Text]
  3. Ong KK, Phillips DI, Fall C, Poulton J, Bennett ST, Golding J, Todd JA, Dunger DB 1999 The insulin gene VNTR, type 2 diabetes and birth weight. Nat Genet 21:262–263[CrossRef][Medline]
  4. Yamada H, Sata F, Kato EH, Saijo Y, Kataoka S, Morikawa M, Shimada S, Yamada T, Kishi R, Minakami H 2004 A polymorphism in the CYP17 gene and intrauterine fetal growth restriction. Mol Hum Reprod 10:49–53[Abstract/Free Full Text]
  5. Bang P, Westgren M, Schwander J, Blum WF, Rosenfeld RG, Stangenberg M 1994 Ontogeny of insulin-like growth factor-binding protein-1, -2, and -3: quantitative measurements by radioimmunoassay in human fetal serum. Pediatr Res 36:528–536[Medline]
  6. Bocconi L, Mauro F, Maddalena SE, De Iulio C, Tirelli AS, Pace E, Nicolini U 1998 Insulinlike growth factor 1 in controls and growth-retarded fetuses. Fetal Diagn Ther 13:192–196[CrossRef][Medline]
  7. Langford K, Nicolaides K, Miell JP 1998 Maternal and fetal insulin-like growth factors and their binding proteins in the second and third trimesters of human pregnancy. Hum Reprod 13:1389–1393[Abstract/Free Full Text]
  8. Leger J, Noel M, Limal JM, Czernichow P 1996 Growth factors and intrauterine growth retardation. II. Serum growth hormone, insulin-like growth factor (IGF) I, and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects: prospective study from birth to two years of age. Study Group of IUGR. Pediatr Res 40:101–107[Medline]
  9. Ostlund E, Bang P, Hagenas L, Fried G 1997 Insulin-like growth factor I in fetal serum obtained by cordocentesis is correlated with intrauterine growth retardation. Hum Reprod 12:840–844[Abstract/Free Full Text]
  10. Arends N, Johnston L, Hokken-Koelega A, van Duijn C, de Ridder M, Savage M, Clark 2002 A polymorphism in the IGF-I gene: clinical relevance for short children born small for gestational age (SGA). J Clin Endocrinol Metab 87:2720
  11. Vaessen N, Janssen JA, Heutink P, Hofman A, Lamberts SW, Oostra BA, Pols HA, van Duijn CM 2002 Association between genetic variation in the gene for insulin-like growth factor-I and low birthweight. Lancet 359:1036–1037[CrossRef][Medline]
  12. Day IN, King TH, Chen XH, Voropanov AM, Ye S, Syddall HE, Sayer AA, Cooper C, Barker DJ, Phillips DI 2002 Insulin-like growth factor-I genotype and birthweight. Lancet 360:945–946[Medline]
  13. Binder G, Baur F, Schweizer R, Ranke MB 2006 The d3-growth hormone (GH) receptor polymorphism is associated with increased responsiveness to GH in Turner syndrome and short small-for-gestational-age children. J Clin Endocrinol Metab 91:659–664[Abstract/Free Full Text]
  14. Carrascosa A, Esteban C, Espadero R, Fernandez-Cancio M, Andaluz P, Clemente M, Audi L, Wollmann H, Fryklund L, Parodi L 2006 The d3/fl-growth hormone (GH) receptor polymorphism does not influence the effect of GH treatment (66 microg/kg per day) or the spontaneous growth in short non-GH-deficient small-for-gestational-age children: results from a two-year controlled prospective study in 170 Spanish patients. J Clin Endocrinol Metab 91:3281–3286[Abstract/Free Full Text]
  15. 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]
  16. Larsen T, Larsen JF, Petersen S, Greisen G 1992 Detection of small-for-gestational-age fetuses by ultrasound screening in a high risk population: a randomized controlled study. Br J Obstet Gynaecol 99:469–474[Medline]
  17. Larsen T, Greisen G, Petersen S 1997 Intrauterine growth correlation to postnatal growth–influence of risk factors and complications in pregnancy. Early Hum Dev 47:157–165[CrossRef][Medline]
  18. Larsen T, Petersen S, Greisen G, Larsen JF 1990 Normal fetal growth evaluated by longitudinal ultrasound examinations. Early Hum Dev 24:37–45[CrossRef][Medline]
  19. Andersen E, Hutchings B, Jansen J, Nyholm M 1982 [Heights and weights of Danish children]. Ugeskr Laeger 144:1760–1765 (Danish)[Medline]
  20. Marshall WA, Tanner JM 1970 Variations in the pattern of pubertal changes in boys. Arch Dis Child 45:13–23[Medline]
  21. Prader A 1966 Testicular size: assessment and clinical importance. Triangle 7:240–243[Medline]
  22. Bang P, Eriksson U, Sara V, Wivall IL, Hall K 1991 Comparison of acid ethanol extraction and acid gel filtration prior to IGF-I and IGF-II radioimmunoassays: improvement of determinations in acid ethanol extracts by the use of truncated IGF-I as radioligand. Acta Endocrinol (Copenh) 124:620–629[Medline]
  23. Juul A, Bang P, Hertel NT, Main K, Dalgaard P, Jorgensen K, Muller J, Hall K, Skakkebaek NE 1994 Serum insulin-like growth factor-I in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index. J Clin Endocrinol Metab 78:744–752[Abstract]
  24. Blum WF, Ranke MB, Kietzmann K, Gauggel E, Zeisel HJ, Bierich JR 1990 A specific radioimmunoassay for the growth hormone (GH)-dependent somatomedin-binding protein: its use for diagnosis of GH deficiency. J Clin Endocrinol Metab 70:1292–1298[Abstract]
  25. Juul A, Dalgaard P, Blum WF, Bang P, Hall K, Michaelsen KF, Muller J, Skakkebaek NE 1995 Serum levels of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) in healthy infants, children, and adolescents: the relation to IGF-I, IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index, and pubertal maturation. J Clin Endocrinol Metab 80:2534–2542[Abstract]
  26. Pantel J, Machinis K, Sobrier ML, Duquesnoy P, Goossens M, Amselem S 2000 Species-specific alternative splice mimicry at the growth hormone receptor locus revealed by the lineage of retroelements during primate evolution. J Biol Chem 275:18664–18669[Abstract/Free Full Text]
  27. Audi L, Esteban C, Carrascosa A, Espadero R, Perez-Arroyo A, Arjona R, Clemente M, Wollmann H, Fryklund L, Parodi LA 2006 Exon 3-deleted/full-length growth hormone receptor polymorphism genotype frequencies in Spanish short small-for-gestational-age (SGA) children and adolescents (n = 247) and in an adult control population (n = 289) show increased fl/fl in short SGA. J Clin Endocrinol Metab 91:5038–5043[Abstract/Free Full Text]
  28. Horan M, Newsway V, Yasmin, Lewis MD, Easter TE, Rees DA, Mahto A, Millar DS, Procter AM, Scanlon MF, Wilkinson IB, Hall IP, Wheatley A, Blakey J, Bath PM, Cockcroft JR, Krawczak M, Cooper DN 2006 Genetic variation at the growth hormone (GH1) and growth hormone receptor (GHR) loci as a risk factor for hypertension and stroke. Hum Genet 119:527–540[CrossRef][Medline]
  29. Mehta A, Hindmarsh PC, Stanhope RG, Turton JP, Cole TJ, Preece MA, Dattani MT 2005 The role of growth hormone in determining birth size and early postnatal growth, using congenital growth hormone deficiency (GHD) as a model. Clin Endocrinol (Oxf) 63:223–231[CrossRef][Medline]
  30. Wit JM, van Unen H 1992 Growth of infants with neonatal growth hormone deficiency. Arch Dis Child 67:920–924[Abstract]
  31. Jensen RB, Jeppesen KA, Vielwerth S, Michaelsen KF, Main KM, Skakkebaek NE, Juul A 2005 Insulin-like growth factor I (IGF-I) and IGF-binding protein 3 as diagnostic markers of growth hormone deficiency in infancy. Horm Res 63:15–21[CrossRef][Medline]
  32. Gluckman PD, Gunn AJ, Wray A, Cutfield WS, Chatelain PG, Guilbaud O, Ambler GR, Wilton P, Albertsson-Wikland K 1992 Congenital idiopathic growth hormone deficiency associated with prenatal and early postnatal growth failure. The International Board of the Kabi Pharmacia International Growth Study. J Pediatr 121:920–923[CrossRef][Medline]
  33. Woods KA, Dastot F, Preece MA, Clark AJ, Postel-Vinay MC, Chatelain PG, Ranke MB, Rosenfeld RG, Amselem S, Savage MO 1997 Phenotype: genotype relationships in growth hormone insensitivity syndrome. J Clin Endocrinol Metab 82:3529–3535[Abstract/Free Full Text]
  34. Zogopoulos G, Figueiredo R, Jenab A, Ali Z, Lefebvre Y, Goodyer CG 1996 Expression of exon 3-retaining and -deleted human growth hormone receptor messenger ribonucleic acid isoforms during development. J Clin Endocrinol Metab 81:775–782[Abstract]
  35. Chellakooty M, Vangsgaard K, Larsen T, Scheike T, Falck-Larsen J, Legarth J, Andersson AM, Main KM, Skakkebaek NE, Juul A 2004 A longitudinal study of intrauterine growth and the placental growth hormone (GH)-insulin-like growth factor I axis in maternal circulation: association between placental GH and fetal growth. J Clin Endocrinol Metab 89:384–391[Abstract/Free Full Text]
  36. Frankenne F, Alsat E, Scippo ML, Igout A, Hennen G, Evain-Brion D 1992 Evidence for the expression of growth hormone receptors in human placenta. Biochem Biophys Res Commun 182:481–486[CrossRef][Medline]
  37. Urbanek M, MacLeod JN, Cooke NE, Liebhaber SA 1992 Expression of a human growth hormone (hGH) receptor isoform is predicted by tissue-specific alternative splicing of exon 3 of the hGH receptor gene transcript. Mol Endocrinol 6:279–287[Abstract]
  38. Hujeirat Y, Hess O, Shalev S, Tenenbaum-Rakover Y 2006 Growth hormone receptor sequence changes do not play a role in determining height in children with idiopathic short stature. Horm Res 65:210–216[Medline]
  39. Kenth G, Shao Z, Cole DE, Goodyer CG 2007 Relationship of the human growth hormone receptor exon 3 genotype with final adult height and bone mineral density. J Clin Endocrinol Metab 92:725–728[Abstract/Free Full Text]
  40. Albertsson-Wikland K, Karlberg J 1994 Natural growth in children born small for gestational age with and without catch-up growth. Acta Paediatr Suppl 399:64–70[Medline]
  41. Hokken-Koelega AC, De Ridder MA, Lemmen RJ, Den Hartog H, Muinck Keizer-Schrama SM, Drop SL 1995 Children born small for gestational age: do they catch up? Pediatr Res 38:267–271[Medline]
  42. Karlberg J, Albertsson-Wikland K 1995 Growth in full-term small-for-gestational-age infants: from birth to final height. Pediatr Res 38:733–739[Medline]
  43. Boguszewski M, Rosberg S, Albertsson-Wikland K 1995 Spontaneous 24-hour growth hormone profiles in prepubertal small for gestational age children. J Clin Endocrinol Metab 80:2599–2606[Abstract]
  44. Jorge AA, Marchisotti FG, Montenegro LR, Carvalho LR, Mendonca BB, Arnhold IJ 2006 Growth hormone (GH) pharmacogenetics: influence of GH receptor exon 3 retention or deletion on first-year growth response and final height in patients with severe GH deficiency. J Clin Endocrinol Metab 91:1076–1080[Abstract/Free Full Text]
  45. Blum WF, Machinis K, Shavrikova EP, Keller A, Stobbe H, Pfaeffle RW, Amselem S 2006 The growth response to growth hormone (GH) treatment in children with isolated GH deficiency is independent of the presence of the exon 3-minus isoform of the GH receptor. J Clin Endocrinol Metab 91:4171–4174[Abstract/Free Full Text]
  46. Pilotta A, Mella P, Filisetti M, Felappi B, Prandi E, Parrinello G, Notarangelo LD, Buzi F 2006 Common polymorphisms of the growth hormone (GH) receptor do not correlate with the growth response to exogenous recombinant human GH in GH-deficient children. J Clin Endocrinol Metab 91:1178–1180[Abstract/Free Full Text]
  47. Atzmon G, Muzumdar R, Budagov T, Barzilai N, Cohen P 2006 The growth hormone receptor exon-3 deletion is a marker for exceptional longivity. Growth Horm IGF Res 16:S9–S10 (Abstract)
  48. Strawbridge R, Karvestedt L, Gu H, Li C, Brismar K 2006 Influence of exon 3-deleted growth hormone receptor variant on clinical parameters of patients with type 2 diabetes mellitus. Growth Horm IGF Res 16:S43 (Abstract)




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
92/7/2758    most recent
Author Manuscript (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jensen, R. B.
Right arrow Articles by Juul, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jensen, R. B.
Right arrow Articles by Juul, A.
Related Collections
Right arrow Metabolism
Right arrow Neuroendocrinology and Pituitary
Right arrow Pediatric Endocrinology

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals