Ulrich Tuschy

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.

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.

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.

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.

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.

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.

Verminderte Inzidenz von Nebenwirkungen einer Wachstumshormonsubstitution bei 404 Patienten mit Hypophyseninsuffizienz

Zusammenfassung□ HintergrundDie Substitutionstherapie bei hypophyseninsuffizienten Patientten mit rekombinantem, menschlichen Wachstumshormon (rhGH) zusätzlich zur konventionellen Substitution mit Glucocorticoiden, L-Thyroxin und Geschlechtshormonen ist seit 1995 zugelassene Indikation mit der Auflage der Zulassungsbehörden, Anwendungsbeobachtungen zur Dokumentation der Langzeitsicherheit durchzuführen.□ Patienten und MethodeEs wird über die ersten deutschen Ergebnisse der Kabi-International-Metabolic-Study-(KIMS-) Anwendungsbeobachtung von Pharmacia & Upjohn, Erlangen, berichtet. In KIMS eingeschlossen wurden 404 Patienten aus 35 Zentren (227 Männer=56% und 177 Frauen=44%). 32 Patienten (8%) beendeten die Therapie. 25% der Patienten hatten einen Wachstumshormonmangel (GHD), der in der Kindheit aufgetreten war.□ Ergebnisse24% aller Patienten waren im zweiten Jahr ihrer Therapie, 15% in ihrem vierten Jahr, die längste Behandlung dauerte sechs Jahre. Bei der Altersverteilung wurden zwei Spitzen beobachtet: 30 bis 39 Jahre (24%) und 50 bis 59 Jahre (24%). Die Ursachen der Hypophyseninsuffizienz waren wie folgt: Hypophysenadenome (47%), idiopathisch (16%), Kraniopharyngeome (16%) und andere (21%). Die mittlere GH-Dosis lag bei 1,5 IU/Tag (0,4 bis 4 IU/Tag). Hierunter stieg das Serum-IGF-1 (insulinähnlicher Wachstumsfaktor) um 159 bis 192% bei Frauen bzw. Männern nach sechs Monaten Behandlung signifikant an. Der Taillenumfang nahm bei Männern um 2% ab, das Serumcholesterin wurde um 5,5% gesenkt. Bei zwei Patienten wurde während des Beobachtungszeitraums ein neues Karzinom diagnostiziert, eine Patientin verstarb, ein Patient entwickelte einen Diabetes mellitus II. Die Inzidenz unerwünschter Ereignisse (AEs) in KIMS wurde mit der Inzidenz in den Verum-(GH-) Gruppen bzw. Placebo-(Pl-) Gruppen früherer Zulassungsstudien verglichen (in Prozent): Ödeme: KIMS 10, GH 37, Pl3; Arthralgien: KIMS 8, GH 19, Pl 2; Muskelschmerzen: KIMS 2, GH 3, Pl 2; andere: KIMS 2, GH 22, Pl 13. Die angegebene Inzidenz an AEs in KIMS war signifikant niedriger als in den vorangegangenen Zulassungsstudien. Hierfür gibt es drei Gründe: 1. AEs, die scheinbar nicht mit einer GH-Therapie in Zusammenhangstehen, werden weniger häufig gemeldet. 2. Die verwendeten Dosen lagen in KIMS um die Hälfte niedriger als in den Zulassungsstudien. 3. In KIMS erfolgte eine Dosistitrierung für jeden individuellen Patienten.□ SchlußfolgerungDie Daten zeigen, daß Anwendungsbeobachtungen gut geeignet sind, um die Langzeitwirkungen und -sicherheit einer GH-Therapie zu dokumentieren. Eine dosistitrierte GH-Substitution bei hypophyseninsuf fizienten Patienten führt zu einer geringeren Nebenwirkungsrate.Abstract□ BackgroundSubstitution of pituitary insufficient patients with recombinant human growth hormone (rhGH) in addition to the conventional substitution with glucocorticoids, L-thyroxine and sex hormones has been approved by the regulatory authorities in 1995 with the imposition to conduct surveillance studies to monitor drug safety.□ Results24% of all patients were within their 2nd treatment year, 15% within their 4th year, maximum treatment period was 6 years. There were 2 peaks within the patients age distribution: 30 to 39 years (24%) and 50 to 59 years (24%). The causes for pituitary disease were as follows: pituitary adenomas (47%), idiopathic (16%), craniopharyngeomas (16%) and others (21%). Mean GH dose was 1.5 IU/ds. c. (range 0.4 to 4 IU/d). Serum-IGF-1 increased by 159 and 192% in females and males. Waist circumference decreased by 2% and serum cholesterol was lowered by 5.5% in males. There were 2 cases with new carcinomas, 1 diabetes mellitus II and 1 death. Adverse events (AEs) within KIMS were compared to those of the treatment (GH) and placebo (Pl) groups of the previous admission trials (in percent): edema: KIMS 10, GH 37, Pl 3; arthralgia: KIMS 8, GH 19, Pl 2; muscle pain: KIMS 3, GH 16, Pl 3; dizziness: KIMS 2, GH 1, Pl 3; headache: KIMS 2, GH 3, Pl 2; others: KIMS 2, GH 22, Pl 13. The reported incidence of AEs in KIMS was lower than in previous clinical trials. There might be 3 reasons for this: 1. under-reporting, particularly those AEs not likely to be related to GH treatment; 2. doses used in trials were 2-fold higher than in KIMS; 3. dose titration for individual patients.□ ConclusionSurveillance programs are important for monitoring of drug long-term efficacy and safety.BACKGROUND Substitution of pituitary insufficient patients with recombinant human growth hormone (rhGH) in addition to the conventional substitution with glucocorticoids, L-thyroxine and sex hormones has been approved by the regulatory authorities in 1995 with the imposition to conduct surveillance studies to monitor drug safety. RESULTS 24% of all patients were within their 2nd treatment year, 15% within their 4th year, maximum treatment period was 6 years. There were 2 peaks within the patients age distribution: 30 to 39 years (24%) and 50 to 59 years (24%). The causes for pituitary disease were as follows: pituitary adenomas (47%), idiopathic (16%), craniopharyngeomas (16%) and others (21%). Mean GH dose was 1.5 IU/d s.c. (range 0.4 to 4 IU/d). Serum-IGF-1 increased by 159 and 192% in females and males. Waist circumference decreased by 2% and serum cholesterol was lowered by 5.5% in males. There were 2 cases with new carcinomas, 1 diabetes mellitus II and 1 death. Adverse events (AEs) within KIMS were compared to those of the treatment (GH) and placebo (PI) groups of the previous admission trials (in percent): edema: KIMS 10, GH 37, Pl 3; arthralgia: KIMS 8, GH 19, Pl 2; muscle pain: KIMS 3, GH 16, Pl 3; dizziness: KIMS 2, GH 1, Pl 3; headache: KIMS 2, GH 3, Pl 2; others: KIMS 2, GH 22, Pl 13. The reported incidence of AEs in KIMS was lower than in previous clinical trials. There might be 3 reasons for this: 1. under-reporting, particularly those AEs not likely to be related to GH treatment; 2. doses used in trials were 2-fold higher than in KIMS; 3. dose titration for individual patients. CONCLUSION Surveillance programs are important for monitoring of drug long-term efficacy and safety.

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.