Additive effect of GHRd3 and COLIA1 polymorphisms on the GH-substitution dose in GH-deficient adults.

UNLABELLED: The exon 3-deleted/full-length growth hormone receptor (GHRd3) polymorphism and the collagen type Iα 1-specific protein 1 (COLIA1) polymorphism have each recently been linked to the responsiveness to recombinant growth hormone (GH) treatment in GH-deficient adults. In this context, one or two GHRd3 alleles and the homozygous COLIA1 TT genotype were each associated with a significantly lower GH dose. AIM: The aim of this pilot study was to test if these polymorphisms together have an additive effect on the individually required GH dose in adults with GH deficiency. PATIENTS & METHODS: The GHRd3 and COLIA1 polymorphisms were determined in 130 German adult patients (65 men, 65 women; mean age: 45.9 years ± 12.9 SD; majority Caucasian) with GH deficiency of different origin, derived from the prospective KIMS Pharmacogenetics Study. Patients received GH treatment for at least 12 months with finished dose-titration of GH and centralized IGF-1 measurements. GH dose after 1 year of treatment, IGF-1 concentrations, IGF-1 standard deviation score and anthropometric data were analyzed according to genotype group. RESULTS: Concerning etiology, gender, age, anthropometric data, IGF-1 concentrations and IGF-1 standard deviation score, study subjects demonstrated no significant differences by genotype. After 1 year of GH treatment, the GH dose in the GH-deficient patients carrying one or two alleles of the growth hormone receptor (GHR) exon 3 deletion and the TT genotype of the COLIA1 polymorphism was on average half the dose required in patients with the full-length GHR (fl/fl) and the homozygous COLIA1 GG genotype (p = 0.045). CONCLUSION: Carriers of one or two alleles of the GHR exon 3 deletion and COLIA1 TT genotype require significantly lower GH doses as compared with both homozygous fl GHR and COLIA1 GG genotype carriers. There seems to be an additive effect of both polymorphisms on the individually required GH dose in GH-deficient adults which may serve to explain part of the variability of the required amounts of exogenous GH in these patients.

Structured assessment of hypopituitarism after traumatic brain injury and aneurysmal subarachnoid hemorrhage in 1242 patients: the German interdisciplinary database.

Clinical studies have demonstrated that traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage (SAH) are frequent causes of long-term disturbances of hypothalamo-pituitary function. This study aimed to assess the prevalence and associated factors of post-traumatic hypopituitarism in a large national registry of patients with TBI and SAH. Data were collected from 14 centers in Germany and Austria treating patients for TBI or SAH and performing endocrine assessments. Data were collected using a structured, internet-based study sheet, obtaining information on clinical, radiological, and hormonal parameters. A total of 1242 patients (825 TBI, age 43.5±19.7 years; 417 SAH, age 49.7±11.8 years) were included. We studied the prevalence of hypopituitarism reported based on different definitions of laboratory values and stimulation tests. Stimulation tests for the corticotropic and somatotropic axes were performed in 26% and 22% of the patients, respectively. The prevalence of hypopituitarism in the chronic phase (at least 5 months after the event) by laboratory values, physician diagnoses, and stimulation tests, was 35%, 36%, and 70%, respectively. Hypopituitarism was less common in the acute phase. According to the frequency of endocrine dysfunction, pituitary hormone secretion was impaired in the following sequence: ACTH, LH/FSH, GH, and TSH. TBI patients with abnormal stimulation tests had suffered from more severe TBI than patients with normal stimulation tests. In conclusion, our data confirm that hypopituitarism is a common complication of TBI and SAH. It is possible that patients with a higher likelihood of hypopituitarism were selected for endocrine stimulation tests.

Association of the exon 3 deleted/full-length GHR polymorphism with recombinant growth hormone dose in growth hormone-deficient adults.

AIMS: Contradictory reports exist regarding the influence of the exon 3 deleted (d3)/full-length (fl) growth hormone receptor (GHR) polymorphism on responsiveness to recombinant human growth-hormone therapy in idiopathic short stature, small for gestational age and GH-deficient children, Turner syndrome patients and GH-deficient adults. In some of these studies, the d3 allele was associated with increased responsiveness to GH. The aim of this study was to test this association in a group of GH-deficient adult patients receiving recombinant GH treatment. MATERIALS & METHODS: Patients were derived from the prospective German Pfizer International Metabolic Study (KIMS) Pharmacogenetics Study. The GHRd3/fl polymorphism was determined in 133 German adult patients (66 men and 67 women; mean age: 45.4 years +/- 13.1 standard deviation; majority Caucasian) with a GH-deficiency of different origin. Patients received GH treatment for 12 months with a finished dose-titration of GH and standardized insulin-like growth factor (IGF)-1 measurements in one central laboratory. GH dose after 1 year of treatment, IGF-1 serum concentrations, IGF-1 standard deviation score (SDS) values and anthropometric data were analyzed by GHRd3/fl genotypes. RESULTS: After 1 year of GH treatment, the individually required GH dose was significantly lower in GH-deficient patients carrying one or two d3 alleles, compared with patients with the full-length receptor (p = 0.04). Genotype groups (d3-allele carriers vs noncarriers) showed no significant differences in IGF-1 serum concentrations (p = 0.51), IGF-1 SDS (p = 0.36) nor in gender (p = 0.53), age (p = 0.28), weight (p = 0.13), height (p = 0.53) or BMI (p = 0.15). CONCLUSION: The d3-allele carriers required approximately 25% less exogenous GH compared with the homozygous fl-allele carriers, which may express an increased responsiveness to exogenous GH. Variability of the individually required GH dose in adult GH-deficient patients may therefore be partly due to the GHRd3/fl polymorphism. Further studies are required to confirm these results.

Frequent incidental discovery of phaeochromocytoma: data from a German cohort of 201 phaeochromocytoma.

CONTEXT: Adrenal and extra-adrenal phaeochromocytoma are chromaffin cell-derived tumours that are discovered due to classical symptom triad with headache, sweating and palpitations combined with persistent or paroxysmal hypertension. However, an increasing proportion of phaeochromocytoma seems to be discovered incidentally upon abdominal imaging. OBJECTIVE: To specify the exact circumstances of discovery of adrenal and extra-adrenal phaeochromocytoma. DESIGN AND PATIENTS: Four German endocrine centres participated in this retrospective study. MEDICAL: records of 201 patients with adrenal and extra-adrenal phaeochromocytoma who were diagnosed between 1973 and 2007 were analyzed. RESULTS: The typical triad of symptoms was found only in 10% of cases. Ten percent of patients presented were without clinical symptoms and 6.1% were normotensive. Documented blood pressure peaks occurred in 44.1% of cases. In 24 patients (12.2%), phaeochromocytoma was malignant. Before 1985, <10% of cases were incidentally discovered, whereas thereafter the frequency was >25% (29.4% of the total study population). Patients with incidentally detected phaeochromocytoma were significantly older (53.1+/-1.9 vs 47.0+/-1.3 years; P<0.05) and often had less blood pressure peaks (37.0 vs 70.7%; P<0.001) than patients in whom the diagnosis was suspected on clinical grounds. Of phaeochromocytomas 94.4% were intra-adrenal tumours, of which 12.9% were bilateral. Bilateral tumours were significantly smaller than unilateral tumours (36.6+/-14.7 vs 52.5+/-34.3 mm; P<0.05), whereas extra-adrenal tumours had a mean diameter of 52.6+/-28.7 mm. CONCLUSIONS: Owing to better availability and accessibility of imaging procedures, the number of incidentally discovered phaeochromocytoma is increasing and reaches nearly 30% in our study population. Every adrenal incidentaloma should be investigated for the presence of phaeochromocytoma.

Growth hormone dose in growth hormone-deficient adults is not associated with IGF-1 gene polymorphisms.

AIMS: Several SNPs and a microsatellite cytosine-adenine repeat promoter polymorphism of the IGF-1 gene have been reported to be associated with circulating IGF-1 serum concentrations. Variance in IGF-1 concentrations due to genetic variations may affect different response to growth hormone (GH) treatment, resulting in different individually required GH-doses in GH-deficient patients. The aim of this study was to test if the IGF-1 gene polymorphisms are associated with the GH-dose of GH-deficient adults. MATERIALS & METHODS: A total of nine tagging SNPs, five additionally selected SNPs and a cytosine-adenine repeat polymorphism were determined in 133 German adult patients (66 men, 67 women; mean age 45.4 years +/- 13.1 standard deviation; majority Caucasian) with GH-deficiency (GHD) of different origin, derived from the prospective Pfizer International Metabolic Study (KIMS) Pharmacogenetics Study. Patients received GH-treatment for 12 months with finished dose-titration of GH and centralized IGF-1 measurements. GH-dose after 1 year of treatment, IGF-1 concentrations, IGF-1-standard deviation score (SDS), the IGF-1:GH ratio and anthropometric data were analyzed by genotype. RESULTS: Except for rs1019731, which showed a significant difference of IGF-1-SDS by genotypes (p = 0.02), all polymorphisms showed no associations with the GH-doses, IGF-1 concentrations, IGF-1-SDS and IGF-1:GH ratio after adjusting for the confounding variables gender, age and BMI. CONCLUSION: IGF-1 gene polymorphisms were not associated with the responsiveness to exogenous GH in GHD. Therefore, genetic variations of the IGF-1 gene seem not to be major influencing factors of the GH-IGF-axis causing variable response to exogenous GH-treatment.

Association of COLIA1 Sp1 polymorphism with the effect of subcutaneously injected recombinant hGH in GH-deficient adults.

OBJECTIVE: Collagen type I is a common structural protein in bone and skin. Similar to its association with the mechanical properties of the skeleton and, thus, bone-fracture risk, the collagen type I alpha (COLIA)-1 specific protein (Sp)-1 polymorphism may be related to variations in the collagen type I-containing subcutaneous tissue and its biological properties. In this study, we analyzed a possible influence of the COLIA1 Sp1 polymorphism on the effect of subcutaneously injected recombinant human growth hormone (hGH) in GH-deficient adults. MATERIALS & METHODS: We determined the COLIA1 Sp1 polymorphism in 122 adults with GH deficiency of different origin, who were derived from the prospective Pfizer International Growth Database (KIMS) Pharmacogenetics Study. Inclusion criteria were subcutaneous applied treatment with hGH for over 12 months, finished dose titration of hGH by following serum IGF-1 concentrations until desired levels were achieved, and centralized, standardized IGF-1 measurements. The genotypes (GG/GT/TT) were statistically related to clinical data from the KIMS database. RESULTS: The dose of injected hGH was significantly related to the COLIA1 Sp1 genotypes (p = 0.049), whereby the GG homozygotes were treated with a significantly higher dose of hGH than TT homozygotes (p = 0.03). Accordingly, the IGF-1:GH ratios were significantly lower in GG compared with TT homozygotes (p = 0.04). Both groups showed no significant differences in their IGF-1 serum concentrations (p = 0.98) and IGF-1 SDS (p = 0.79). CONCLUSION: The COLIA1 Sp1 polymorphism is related to the dose of individually required, subcutaneous injected hGH in GH-deficient adults, probably because of an alteration of the subcutaneous collagen type I structure, content and/or biological/biomechanical properties. GG homozygotism, which is related to a more stable bone structure and decreased fracture risk, may impact skin resistance to subcutaneous injected protein-based drugs, as shown for hGH in this study.

Influence of GH substitution therapy in deficient adults on the recurrence rate of hormonally inactive pituitary adenomas: a case control study.

OBJECTIVE: Several studies documented metabolic and psychological benefits of GH substitution in deficient adults, most of them suffering from benign pituitary adenomas. Since GH substitution is considered to promote tumour regrowth, adequate treatment is performed with some reservation. Therefore, we aimed to elucidate the effect of GH replacement therapy on tumour recurrence following surgery. METHODS: In patients with hormonally inactive pituitary adenomas undergoing tumour surgery, a retrospective case-control study was performed. Pre- and postoperative magnetic resonance (MR) images of GH-treated and untreated patients were matched for best fit by two independent observers. The treated patients were retrieved from the surveillance programme of the German KIMS database and the untreated from the database of the Department of Neurosurgery, University of Erlangen. A total of 55 matched pairs were followed for at least 5 years. Tumour recurrence and progression rates were determined according to the postoperative MR. RESULTS: There were 16 tumour progressions in the treatment group and 12 in the control group. Statistical analysis revealed no significant increase in either recurrence (P = 0.317) or progression (P = 0.617) within the follow-up period of 5 years when GH was adequately replaced. CONCLUSIONS: This study provides further observational data of substitution therapy in GH-deficient adults with pituitary adenomas. Comparing long-term surgical results, we found no evidence that GH substitution should be withheld in deficient patients. Even residual tumour does not constitute a contraindication to GH replacement. However, since pituitary tumours are slow growing, an observational period of 5 years may not have been long enough to verify any absolute influence on recurrence potential.

Multicenter study on the diagnostic value of a new RIA for the detection of free plasma metanephrines in the work-up for pheochromocytoma.

Available laboratory test methods for the detection of elevated concentrations of catecholamines and their metabolites in urine and/or plasma are not always sensitive enough for the detection of pheochromocytoma. High-quality immunoassays for these compounds appear to be as accurate as high-pressure liquid chromatography (HPLC) or gas chromatography/mass spectrometry (GC-MS). Therefore, the current project aims to establish a new sensitive radioimmunoassay (RIA) for the measurement of free metanephrines in the plasma of patients in the work-up for pheochromocytoma. We report first results of an ongoing multicenter clinico-chemical evaluation study in hypertensive patients and normotensive volunteers. After an overnight fast plasma samples were collected on ice in EDTA- and heparin-coated tubes after insertion of an indwelling venous line and resting in the supine (patients) or sitting position (normal volunteers) for 30 min. Plasma metanephrines were measured by a newly developed RIA from IBL, Hamburg, Germany. Good agreement of the assay with the tandem mass spectrometry (LC-MS/MS) method for normetanephrine (r2=0.975) and for metanephrine (r2=0.985) could be demonstrated. Both specimens, EDTA and heparin plasma, can be used with the same results. The RIA has a good precision of <15% in the normal range and of <10% in the elevated concentration range. Our preliminary data suggest a high validity of the newly developed RIA for measuring free metanephrine and normetanephrine in hypertensive subjects in both EDTA and heparin plasma. Further work is required to determine the accuracy of the test in larger patient populations and in patients with pheochromocytoma.