The d3-Growth Hormone (GH) Receptor Polymorphism Is Associated with Increased Responsiveness to GH in Turner Syndrome and Short Small-for-Gestational-Age Children

Binder, Gerhard; Baur, F.; Schweizer, Roland; Ranke, Michael B.

doi:10.1210/jc.2005-1581

Cited by 155 publications

(181 citation statements)

References 25 publications

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“…The data on postnatal growth are supported by two population-based studies, where no significant association between GHR polymorphism and final height was observed (36,38). On the other hand, observations of spontaneous growth in adolescence as well as observations in children treated with GH support indicate that presence of the short-GHR isoform might have a favorable impact on postnatal growth velocity (15,16,39). Taken together, the influence of GHR genotype on pre-and postnatal growth is an area of research where controversy exists and where no consensus has been reached.…”

Section: Pre-and Postnatal Growthmentioning

confidence: 75%

Association between GH receptor polymorphism (exon 3 deletion), serum IGF1, semen quality, and reproductive hormone levels in 838 healthy young men

Andreassen

Jensen

Jørgensen

et al. 2014

European Journal of Endocrinology

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Introduction: GH activity may be involved in male reproductive function. A common genetic polymorphism in the gene encoding the GH receptor (GHR) results in deletion of the entire exon 3 sequence (GHRd3 isoform). The short GHRd3/d3 isoform seems more sensitive compared with full-length receptors (GHRfl/fl). Aim: To investigate the associations between GH activity, evaluated by exon 3 GHR polymorphism, and serum IGF1 vs reproductive hormones, semen quality, and pre-and postnatal growth in healthy young males (nZ838, mean age: 19.4 years). Results: Compared with GHRfl/fl homozygous individuals (nZ467) GHRd3/d3 homozygous individuals (nZ69) tended to have larger semen volume (3.2 (2.4-4.3) vs 3.6 (2.6-4.7) ml, PZ0.053) and higher serum inhibin-B levels (208 pg/ml (158-257) vs 227 pg/ml (185-264), PZ0.050). Semen quality, levels of gonadotropins, testosterone, estradiol, sex hormone-binding globulin, and IGF1 were not associated with GHRd3 genotype. A twofold increase in serum IGF1 was associated with a 13% (4-23) increase in calculated free testosterone (PZ0.004). By contrast IGF1 was inversely associated with serum inhibin-B (PZ0.027), but showed no associations to semen quality. GHR genotype and serum IGF1 were not associated with size at birth or final height. Conclusions: GHRd3 polymorphism seemed only to have a weak influence on male reproductive function of borderline significance. The sensitive GHRd3/d3 genotype may slightly increase testicular function, as evaluated by semen volume and levels of inhibin-B, but does not seem to influence Leydig cell steroidogenesis. GHR genotype did not influence pre-and postnatal growth.

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Section: Pre-and Postnatal Growthmentioning

confidence: 75%

Association between GH receptor polymorphism (exon 3 deletion), serum IGF1, semen quality, and reproductive hormone levels in 838 healthy young men

Andreassen

Jensen

Jørgensen

et al. 2014

European Journal of Endocrinology

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“…Apart from differences in sample sizes, the discrepancies between our data and those previously published could be due to an IGF1-independent pathway. Binder et al (25,26) published two studies on the use of recombinant human GH (rhGH) in children short for gestational age with remarkable outcomes. They observed a higher growth velocity in d3-GHR carriers during rhGH therapy, although this was not reflected by increases in IGF1 levels, and may allow cautious speculation about an IGF1 independent pathway.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Pegvisomant in combination with long-acting somatostatin analogues in acromegaly: the role of the GH receptor deletion of exon 3

Franck

Lely

Delhanty

et al. 2015

European Journal of Endocrinology

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Background: Doses of the GH receptor (GHR) antagonist pegvisomant (PEGV) that normalize insulin-like growth factor 1 (IGF1) levels vary widely among acromegaly patients. Predictors for PEGV response are baseline IGF1 levels, sex, body weight and previous radiotherapy. A GHR polymorphism lacking exon 3 (d3-GHR) is frequent in the general population. The influence of d3-GHR on PEGV responsiveness in acromegaly is unclear. Objective: To assess the influence of d3-GHR on IGF1 levels and PEGV responsiveness in acromegaly patients using combined PEGV and long-acting somatostatin receptor ligand (LA-SRIF) treatment. Design: Data were collected at the Rotterdam Pituitary Centre between 2004 and 2013. Patients with elevated IGF1 levels (O1.2 upper limit of normal; nZ112) and over 6 months of high-dose LA-SRIF treatment were co-treated with PEGV. GHR genotype was assessed using genomic DNA in 104 patients. Results: D3-GHR was observed in 51 (49.0%) of the patients (7.7% homozygous, 41.3% heterozygous) and was in Hardy-Weinberg equilibrium (PZ0.859). Baseline characteristics were similar in d3-GHR and full-length (fl)-GHR genotypes. During PEGV/LA-SRIF treatment IGF1 levels were not different between d3-carriers and non-carriers. Similarly, no difference in PEGV dose required to normalize IGF1 (PZ0.337) or PEGV serum levels (PZ0.433) was observed between the two groups. However, adenoma size decreased significantly (O20% of largest diameter) in 25.6% of the fl-GHR genotype but only in 7.5% of d3-carriers (PZ0.034, OR: 4.6 (CI: 1.1-18.9)). Conclusions: GHR genotype does not predict the IGF1 normalizing dose of PEGV in acromegaly patients using combination PEGV/LA-SRIF treatment. However, fewer d3-carriers showed significant reductions in adenoma size. IntroductionDisease activity and phenotype is diverse among patients with acromegaly. Comorbidities such as hypertension, cardiomyopathy, type 2 diabetes, sleep apnea and osteoarthritis are influenced by the severity and the duration of growth hormone (GH) hypersecretion (1). Pegvisomant (PEGV) is a competitive GH receptor (GHR) antagonist that is used in the treatment of acromegaly (2). The required dose of PEGV to achieve disease control as assessed by the normalization of insulin-like growth factor 1 (IGF1) levels differs significantly between individual patients (2). Baseline IGF1 appears to be a predictor for the required dose (3). Other factors known to influence the required dose are sex, body weight and previous radiotherapy (4). However, GHR polymorphisms seem to have an influence as well (5, 6). A polymorphism of the GHR that lacks exon 3 (d3-GHR) during splicing is common in the general population. About half of the population is homozygous for the full-length GHR (fl-GHR), 30-40% is heterozygous for d3-GHR and 10-20% is homozygous for this deletion (7,8,9). It has been reported that the d3-GHR polymorphism shows a comparable distribution between different cohorts of acromegalic patients (6,10,11,12). Multiple studies show that the fl-GHR and d3-GHR have co...

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“…Patients with at least one GHRd3 allele (GHRfl/GHRd3; GHRd3/GHRd3) had a significantly better first year response leading to an improved adult height on rhGH treatment than patients with homozygosity for GHRfl [39]. However, reported studies are not all consistent which may reflect differing populations and conditions and the high probability of false-positive results arising from post-hoc analysis particularly in small sample size populations [41][42][43][44][45][46][47][48][49].…”

Section: Polymorphism Of the Ghrmentioning

confidence: 99%

“…When comparing these findings obtained from patients with severe GHD with the previous studies focusing on GHR allele genotype and response to rhGH replacement therapy, the patients, the individual conditions, their related growth disorder as well as the rhGH doses used have to be carefully analyzed [41][42][43][44][45][46][47][48][49]. In the first report, for instance, Dos Santos et al [40] studied patients with either SGA or ISS so that in effect patients with normal GH secretion were treated with supraphysiological rhGH doses.…”

Section: Polymorphism Of the Ghrmentioning

confidence: 99%

Biological Determinants of Responsiveness to Growth Hormone: Pharmacogenomics and Personalized Medicine

Mullis¹

2010

Current Indications for Growth Hormone Therapy

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It is becoming most clear that many genes are involved in controlling the regulation of growth. Ultimately however, at the level of growth hormone (GH), the relevant question may be not whether a patient is GH-deficient, but whether he is GH-responsive. As these disturbances can be divided into two gross categories, namely alterations causing subnormal GH secretion and/or those presenting with subnormal GH sensitivity/responsiveness, the main aim of this review is to focus on genes involved in growth regulation leading to short stature caused by an alteration of GH insensitivity/GH responsiveness; in other words, clinical circumstances where individually adapted GH replacement therapy may help to increase height velocity and eventually final height.

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The d3-Growth Hormone (GH) Receptor Polymorphism Is Associated with Increased Responsiveness to GH in Turner Syndrome and Short Small-for-Gestational-Age Children

Abstract: Our data support the theory that there is increased responsiveness to high-dose rhGH in association with the d3-GHR genotype. The magnitude of this effect may depend on the primary origin of the short stature.

Cited by 155 publications

References 25 publications

Association between GH receptor polymorphism (exon 3 deletion), serum IGF1, semen quality, and reproductive hormone levels in 838 healthy young men

Association between GH receptor polymorphism (exon 3 deletion), serum IGF1, semen quality, and reproductive hormone levels in 838 healthy young men

Pegvisomant in combination with long-acting somatostatin analogues in acromegaly: the role of the GH receptor deletion of exon 3

Biological Determinants of Responsiveness to Growth Hormone: Pharmacogenomics and Personalized Medicine

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