Growth hormone receptor polymorphism and growth hormone therapy response in children: a bayesian meta-analysis

Recombinant human growth hormone (rhGH) therapy is used in the long-term treatment of children with growth disorders, but there is considerable treatment response variability. The exon 3-deleted growth hormone receptor polymorphism (GHR(d3)) may account for some of this variability. The authors performed a systematic review (to April 2011), including investigator-only data, to quantify the effects of the GHR(fl-d3) and GHR(d3-d3) genotypes on rhGH therapy response and used a recently established Bayesian inheritance model-free approach to meta-analyze the data. The primary outcome was the 1-year change-in-height standard-deviation score for the 2 genotypes. Eighteen data sets from 12 studies (1,527 children) were included. After several prior assumptions were tested, the most appropriate inheritance model was codominant (posterior probability = 0.93). Compared with noncarriers, carriers had median differences in 1-year change-in-height standard-deviation score of 0.09 (95% credible interval (CrI): 0.01, 0.17) for GHR(fl-d3) and of 0.14 (95% CrI: 0.02, 0.26) for GHR(d3-d3). However, the between-study standard deviation of 0.18 (95% CrI: 0.10, 0.33) was considerable. The authors tested by meta-regression for potential modifiers and found no substantial influence. They conclude that 1) the GHR(d3) polymorphism inheritance is codominant, contrasting with previous reports; 2) GHR(d3) genotypes account for modest increases in rhGH effects in children; and 3) considerable unexplained variability in responsiveness remains.

Association of the (CA)n repeat polymorphism of insulin-like growth factor-I and -202 A/C IGF-binding protein-3 promoter polymorphism with adult height in patients with severe growth hormone deficiency

A number of mathematical models for predicting growth and final height outcome have been proposed to enable the clinician to 'individualize' growth-promoting treatment. However, despite optimizing these models, many patients with isolated growth hormone deficiency (IGHD) do not reach their target height. The aim of this study was to analyse the impact of polymorphic genotypes [CA repeat promoter polymorphism of insulin-like growth factor-I (IGF-I) and the -202 A/C promoter polymorphism of IGF-Binding Protein-3 (IGFBP-3)] on variable growth factors as well as final height in severe IGHD following GH treatment. DESIGN, PATIENTS AND CONTROLS: One hundred seventy eight (IGF-I) and 167 (IGFBP-3) subjects with severe growth retardation because of IGHD were studied. In addition, the various genotypes were also studied in a healthy control group of 211 subjects.

Oestradiol enhances plasma growth hormone and insulin-like growth factor-I concentrations and increased the expression of their receptors mRNAs in the liver of ovariectomized cows

Many metabolic hormones, growth hormone (GH), insulin-like growth factor-I (IGF-I) and insulin affect ovarian functions. However, whether ovarian steroid hormones affect metabolic hormones in cattle remains unknown. This study aimed to determine the effect of sex steroids on the plasma profiles of GH, IGF-I and insulin and their receptors in the liver and adipose tissues of dairy cows. Ovariectomized cows (n = 14) were randomly divided into four groups: control group (n = 3) was treated with saline on Day 0; oestradiol (E2) group (n = 3), with saline and 1 mg oestradiol benzoate (EB) on Day 0 and 5, respectively; progesterone (P4) group (n = 4) with two CIDRs (Pfizer Inc., Tokyo, Japan) from Day 0; and E2 + P4 group (n = 4) with two CIDRs on Day 0 that were removed on Day 6 and were immediately injected with 1 mg EB. The animals were euthanized after the experiment, and liver and adipose tissues samples were quantitatively analysed using real-time PCR for the expression of mRNA for the GH (GHR), IGF-I (IGFR-I) and insulin (IR) receptor mRNAs. Oestradiol benzoate significantly increased the number of peaks (p < 0.05), pulse amplitude (p < 0.05) and area under the curve (AUC; p < 0.01) for plasma GH; moreover, it increased plasma IGF-I concentration (p < 0.05), but it had no effect on the plasma insulin profile. P4 significantly decreased the AUC (p < 0.01), compared with the control group, whereas it did not affect the number of peaks and the amplitude of GH pulses. P4 + E2 did not affect the GH pulse profile. E2 increased the mRNA expression of GHR, IGFR-I and IR in the liver (p < 0.05), whereas both P4 and E2 + P4 did not change their expressions. Our results provide evidence that the metabolic and reproductive endocrine axes may regulate each other to ensure optimal reproductive and metabolic function.

Anti-Müllerian hormone levels in girls and adolescents with Turner syndrome are related to karyotype, pubertal development and growth hormone treatment

In girls and adolescents with Turner syndrome (TS), is there a correlation between serum AMH levels and karyotype, spontaneous puberty and other biochemical markers of ovarian function, or growth hormone (GH) therapy? SUMMARY ANSWER: Serum anti-Müllerian hormone (AMH) correlates with karyotype, pubertal development, LH, FSH and are measurable in a higher percentage of TS patients under GH therapy. WHAT IS KNOWN ALREADY: Most girls with TS suffer from incomplete sexual development, premature ovarian failure and infertility due to abnormal ovarian folliculogenesis. Serum AMH levels reflect the ovarian reserve in females, even in childhood. STUDY DESIGN, SIZE, DURATION: Cross-sectional study investigating 270 karyotype proven TS patients aged 0-20 years between 2009 and 2010. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Studies were conducted at three University Children's hospitals in Europe. Main outcome measures were clinical data concerning pubertal development as well as laboratory data including karyotype, serum AMH, LH, FSH, estradiol (E2), inhibin B and IGF. RESULTS AND THE ROLE OF CHANCE: Serum AMH was detectable in 21.9% of all TS girls and correlated strongly with karyotypes. A measurable serum AMH was found in 77% of TS girls with karyotype 45,X/46,XX, in 25% with 'other' karyotypes and in only 10% of 45,X TS girls. A strong relationship was also observed for measurable serum AMH and signs of spontaneous puberty such as breast development [adjusted odds ratio (OR) 19.3; 95% CI 2.1-175.6; P = 0.009] and menarche (crude OR 47.6; 95% CI 4.8-472.9; P = 0.001). Serum AMH correlated negatively with FSH and LH, but did not correlate with E2 and inhibin B. GH therapy increased the odds of having measurable AMH in TS (adjusted OR 4.1; 95% CI 1.9-8.8; P < 0.001). LIMITATIONS, REASONS FOR CAUTION: The cross-sectional design of the study does not allow longitudinal interpretation of the data; for that further studies are needed. High percentage of non-measurable AMH levels in the cohort of TS require categorized analysis. WIDER IMPLICATIONS OF THE FINDINGS: Serum AMH levels are a useful marker of the follicle pool and thus ovarian function in pediatric patients with TS. These findings are in line with the published literature. The finding that GH therapy may affect AMH levels is novel, but must be confirmed by future longitudinal studies.

From endoplasmic reticulum to secretory granules: role of zinc in the secretory pathway of growth hormone

Endocrine and neuroendocrine cells differ from cells which rapidly release all their secreted proteins in that they store some secretory proteins in concentrated forms in secretory granules to be rapidly released when cells are stimulated. Protein aggregation is considered as the first step in the secretory granule biosynthesis and, at least in the case of prolactin and growth hormone, greatly depends on zinc ions that facilitate this process. Hence, regulation of cellular zinc transport especially that within the regulated secretory pathway is of importance to understand. Various zinc transporters of Slc30a/ZnT and Slc39a/Zip families have been reported to fulfil this role and to participate in fine tuning of zinc transport in and out of the endoplasmic reticulum, Golgi complex and secretory granules, the main cellular compartments of the regulated secretory pathway. In this review, we will focus on the role of zinc in the formation of hormone-containing secretory granules with special emphasis on conditions required for growth hormone dimerization/aggregation. In addition, we highlight the role of zinc transporters that govern the process of zinc homeostasis in the regulated hormone secretion.

Towards optimal treatment with growth hormone in short children and adolescents: evidence and theses

Treatment with growth hormone (GH) has become standard practice for replacement in GH-deficient children or pharmacotherapy in a variety of disorders with short stature. However, even today, the reported adult heights achieved often remain below the normal range. In addition, the treatment is expensive and may be associated with long-term risks. Thus, a discussion of the factors relevant for achieving an optimal individual outcome in terms of growth, costs, and risks is required. In the present review, the heterogenous approaches of treatment with GH are discussed, considering the parameters available for an evaluation of the short- and long-term outcomes at different stages of treatment. This discourse introduces the potential of the newly emerging prediction algorithms in comparison to other more conventional approaches for the planning and evaluation of the response to GH. In rare disorders such as those with short stature, treatment decisions cannot easily be deduced from personal experience. An interactive approach utilizing the derived experience from large cohorts for the evaluation of the individual patient and the required decision-making may facilitate the use of GH. Such an approach should also lead to avoiding unnecessary long-term treatment in unresponsive individuals.

Ectopic growth hormone-releasing hormone secretion by a metastatic bronchial carcinoid tumor: a case with a non hypophysial intracranial tumor that shrank during long acting octreotide treatment

Ectopic acromegaly represents less than 1% of the reported cases of acromegaly. Although clinical improvement is common after treatment with somatostatin (SMS) analogs, the biochemical response and tumor size of the growth hormone-releasing hormone (GHRH)-producing tumor and its metastases are less predictable. Subject A 36-year-old male was referred because of a 3-year history of acromegaly related symptoms. He had undergone lung surgery in 1987 for a "benign" carcinoid tumor. Endocrine evaluation confirmed acromegaly Plasma IGF-1: 984 ng/ml (63-380), GH: 49.8 ng/ml (<5). MRI showed a large mass in the left cerebellopontine angle and diffuse pituitary hyperplasia. Pulmonary, liver and bone metastases were shown by chest and abdominal CT scans. Ectopic GHRH secretion was suspected. Methods Measurement of circulating GHRH levels by fluorescence immunoassay levels and immunohistochemical study of the primary lung tumor and metastatic tissue with anti-GHRH and anti-somatostatin receptor type 2 (sst2A) antibodies. Results Basal plasma GHRH: 4654 pg/ml (<100). Pathological study of liver and bone biopsy material and lung tissue removed 19 years earlier was consistent with an atypical carcinoid producing GHRH and exhibiting sst2A receptor expression. Treatment with octreotide LAR 20-40 mg q. month resulted in normalization of plasma IGF-1 levels. Circulating GHRH levels decreased dramatically. The size of the left prepontine cistern mass, with SMS receptors shown by a radiolabeled pentetreotide scan, decreased by 80% after 18 months of therapy. Total regression of pituitary enlargement was also observed. No changes were observed in lung and liver metastases. After 24 months of therapy the patient is asymptomatic and living a full and active life.

Catch-up growth in autosomal dominant isolated growth hormone deficiency (IGHD type II)

OBJECTIVE: Data on the GH-induced catch-up growth of severely GH-deficient children affected by monogenetic defects are missing. PATIENTS: Catch-up growth of 21 prepubertal children (6 females, 15 males) affected with IGHD type II was analyzed in a retrospective chart review. At start of therapy, mean age was 6.2 years (range, 1.6-15.0), mean height SDS was -4.7 (-7.6 to -2.2), mean IGF-I SDS was -6.2 (-10.1 to -2.2). GH was substituted using a mean dose of 30.5microg/kg*d. RESULTS: Catch-up growth was characterized by a mean height gain of +0.92, +0.82, and +0.61 SDS after 1, 2, and 3 years of GH therapy, respectively. Mean height velocities were 10.7, 9.2 and 7.7cm/year during the first three years. Mean duration of complete catch-up growth was 6 years (3-9). Mean height SDS reached was -0.97 (-2.3 to +1.1), which was within the range of the estimated target height of -0.60 SDS (-1.20 to -0.15). The younger and shorter the children were at start of therapy the better they grew during the first year independent of the dose. Mean bone age was delayed at start by 2.1 years and progressed by 2.5 years during the first two years of therapy. Incomplete catch-up growth was caused by late initiation or irregular administration of GH in four cases. CONCLUSIONS: Our data suggest that GH-treated children with severe IGHD show a sustained catch-up growth over 6 years (mean) and reach their target height range. This response to GH is considered to be characteristic for young children with severe growth retardation due to IGHD.

Post-prandial alterations in LDL size and subclasses in patients with growth hormone deficiency

Several studies have suggested that lipoproteins generated during the post-prandial phase are highly atherogenic, with modifications in low-density lipoproteins (LDL) size and density. In the present study we assessed post-prandial variations in LDL size and subclasses in patients with growth hormone deficiency (GHD).

Atherogenic lipoprotein phenotype and low-density lipoprotein size and subclasses in patients with growth hormone deficiency before and after short-term replacement therapy

Patients with growth hormone deficiency (GHD) have increased cardiovascular risk and may show elevated triglyceride and reduced high density lipoprotein (HDL) cholesterol concentrations, two lipid abnormalities usually accompanied by increased small dense LDL in the 'atherogenic lipoprotein phenotype' (ALP). In the present study, we directly investigated (1) whether hypopituitary patients with GHD have increased small dense LDL; (2) whether growth hormone replacement therapy (GHRT) beneficially impact on such particles; (3) the prevalence of ALP in GHD and GHRT patients.

Expanding the spectrum of mutations in GH1 and GHRHR: genetic screening in a large cohort of patients with congenital isolated growth hormone deficiency

CONTEXT: It is estimated that 3-30% of cases with isolated GH deficiency (IGHD) have a genetic etiology, with a number of mutations being reported in GH1 and GHRHR. The aim of our study was to genetically characterize a cohort of patients with congenital IGHD and analyze their characteristics. PATIENTS AND METHODS: A total of 224 patients (190 pedigrees) with IGHD and a eutopic posterior pituitary were screened for mutations in GH1 and GHRHR. To explore the possibility of an association of GH1 abnormalities with multiple pituitary hormone deficiencies, we have screened 62 patients with either multiple pituitary hormone deficiencies (42 pedigrees), or IGHD with an ectopic posterior pituitary (21 pedigrees). RESULTS: Mutations in GH1 and GHRHR were identified in 41 patients from 21 pedigrees (11.1%), with a higher prevalence in familial cases (38.6%). These included previously described and novel mutations in GH1 (C182X, G120V, R178H, IVS3+4nt, a>t) and GHRHR (W273S, R94L, R162W). Autosomal dominant, type II IGHD was the commonest form (52.4%), followed by type IB (42.8%) and type IA (4.8%). Patients with type II IGHD had highly variable phenotypes. There was no difference in the endocrinology or magnetic resonance imaging appearance between patients with and without mutations, although those with mutations presented with more significant growth failure (height, -4.7 +/- 1.6 SDS vs. -3.4 +/- 1.7 SDS) (P = 0.001). There was no apparent difference between patients with mutations in GH1 and GHRHR. CONCLUSIONS: IGHD patients with severe growth failure and a positive family history should be screened for genetic mutations; the evolving endocrinopathy observed in some of these patients suggests the need for long-term follow-up.

Dyslipidaemia in Adult Growth Hormone (GH) Deficiency and the Effect of GH Replacement Therapy: A Review

Adult growth hormone (GH) deficiency is associated with a lipid profile known to be related to atherosclerosis. GH replacement therapy improves the lipid profile with the exception of lipoprotein (a) concentrations, which tend to increase after GH therapy. Plasma lipid concentrations depend on its plasma carriers, the lipoproteins. Possible mechanisms involved in the dyslipidaemia of GH-deficient patients and the effects of GH replacement therapy are discussed with a special focus on hepatic lipoprotein metabolism.