levels did not differ (patients vs. controls: 701±87 vs. 572±33mg/l, P =0.17), whereas bioactive IGF-I tended to be lower in patients (5.37±0.55 vs. 6.63±0.25mg/l, P < 0.06). Conclusion: The baseline findings of elevated free GH and low bioactive IGF-I support the concept of GH resistance in uremic hemodialysis patients. Using high dose rhGH treatment it was possible to obtain normal responses in total and bioactive IGF-I levels, showing that the GH resistance may be overcome. Nevertheless, our data imply that the response of bioactive IGF-I to GH is subnormal in hemodialysis patients.

Pivotal studies have demonstrated that pharmacotherapy with pegvisomant (Somavert) is a highly effective treatment for acromegaly. Since clinical experience with the drug was very limited, the Pegvisomant Observational Study was launched in Germany immediately with the drug becoming commercially available to patients early in 2004. Its purpose was to record safety and efficacy data on as many patients as possible. As of 12th August 2008 a total of 371 patients (185 males, 186 females) had been included in the study. They were on pegvisomant therapy for an average of 118 weeks. Median and mean doses of pegvisomant were 15 and 16.4 mg/day respectively. Treatment efficacy was monitored by IGF1 levels and the patients symptoms were evaluated by completion of a questionnaire (patient-assessed acromegaly symptom questionnaire). Safety data included liver function tests, fasting glucose, HbA1c measurements, and tumor size monitoring by repeated magnetic resonance imaging. Normalization of IGF1 ranged from 55.7% of the 273 patients assessed after 6 months to 71.3% of 202 patients assessed after 24 months of treatment. It was 70.7% after 36 months (133 patients), 64.8% at 48 months (71 patients), and 58.4% after 60 months (24 patients). In 39 patients (10.9%) treatment was discontinued due to serious adverse events or adverse events with 25 (6.7%) of these patients having a potential causal relationship with the pegvisomant treatment. Liver function tests became abnormal in 20 patients and another three patients were recorded to have hepatobiliary disorders. Tumor size increase was reported in 20 patients, but only confirmed in nine patients by careful revision of all available images. Local injection site reactions were observed in 12 patients. In conclusion, in this large group of pegvisomant-treated patients, long-term data for up to 5 years of treatment are now available. In 71.3% of patients with previously not sufficiently treatable acromegaly, IGF1 levels were normalized by pegvisomant therapy. Elevated transaminases usually normalized after discontinuation but in half of the affected patients also despite continuation of treatment without dose alteration. Tumor progression was a rare event. It did not exceed the expected rate in patients with acromegaly not treated with pegvisomant. As from this presently largest database of acromegalic patients treated with pegvisomant, long-term results are encouraging. The German data are now merged into the global ACROSTUDY and will constitute a major portion of the international ACROSTUDY project as a continuing global web-based observational study.

OBJECTIVES:Sleep apnoea has been consistently reported to occur in acromegaly. In uncontrolled patients, the severity of sleep apnoea influences physical activity in the daytime. We investigated the influence of disease activity on tongue volume and sleep apnoea treated with the GH receptor antagonist pegvisomant in poorly controlled patients with acromegaly under octreotide.DESIGN AND METHODS:A total of 12 patients with active acromegaly (six females; six males; mean age 57+/-15 years; body mass index 29.4+/-4.2 kg/m(2); mean+/-S.D.) were treated with pegvisomant (13.5+/-5.0 mg/die) for 6 months. Tongue volume was examined by magnetic resonance imaging, and sleep apnoea was characterized by polysomnography before and after 6 months of treatment with pegvisomant. The mandibular length was determined by lateral X-ray films.RESULTS:IGF1 levels decreased after 6 months in all patients (407+/-114 to 199+/-23 microg/l; P=0.0001). The tongue volume decreased (105+/-33 to 83+/-33 ml; P=0.007) as well as the apnoea-hypnoea index (23+/-22 to 18+/-18/h; P=0.0066). The mandibular length correlated with the initial tongue volume (r(2)=0.6072, P=0.0028).CONCLUSION:In conclusion, successful treatment with pegvisomant can decrease tongue volume, which has benefits for coexisting sleep disordered breathing.

Objective The estimated prevalence of acromegaly is 40-125 per million. The diagnosis of acromegaly is often delayed due to deficits in recognizing the signs of the disease. It is not known how many subjects with increased IGF-1 levels have acromegaly. We aimed to assess the prevalence of acromegaly in primary care by screening for elevated IGF-1 levels.Design A cross-sectional, epidemiological study (the DETECT study).Patients A total of 6773 unselected adult primary care patients were included.Measurements We measured IGF-1 in all patients and recommended further endocrine evaluation in all patients with elevated IGF-1 levels (> 2 age-dependent SDS).Results Of 125 patients with elevated IGF-1 levels, 76 patients had indeterminate results and acromegaly could be excluded in 42 patients. One patient had known florid acromegaly. Two patients had newly diagnosed acromegaly and pituitary adenomas. Four patients had biochemical acromegaly but refused further diagnostics. This corresponds to a prevalence of 1034 per million patients.Conclusions Our study shows a high prevalence of undiagnosed acromegaly in primary care. These results imply that acromegaly is underdiagnosed and stress the importance of detecting acromegaly.

Background Several studies have reported a high prevalence of hypopituitarism after traumatic brain injury (TBI). Risk stratification is a prerequisite for cost-effective hormonal screening of these patients. However, it is still unclear which risk factors predispose patients to develop anterior hypopituitarism after TBI.Objective To assess clinical and radiological risk factors for post-traumatic hypopituitarism.Patients and methods Seventy-eight consecutive patients (52 men, 26 women; mean age 36.0 years, range 18-65 years) with mild, moderate or severe TBI were studied. Endocrine and clinical parameters were assessed 3 and 12 months after TBI.Results We found diffuse axonal injury, basal skull fracture and older age to be major risk factors of post-traumatic hypopituitarism.Conclusions We have defined specific risk factors for the development of post-traumatic hypopituitarism that are consistent with pathophysiological considerations. These findings might help to identify at-risk patients.

Aims: Recent studies show that traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage (SAH) are frequent causes of long-term disturbances of hypothalamo-pituitary function. Still, little is known about risk factors and clinical characteristics of pituitary impairment after brain damage. This study aims to address these questions on a larger scale by establishing a national registry of these patients. Methods: Several large trauma centers in Germany treating patients with TBI or SAH and performing endocrine assessments include patients in this on-going investigation. Data are collected using a structured, internet-based study sheet, obtaining information on clinical, radiological and hormonal parameters. Results: To date, 1112 patients (725 TBI, age 43.5±19.7 years; 378 SAH, 49.7±11.8 years) have been included. Stimulation tests for the corticotropic and somatotropic axes were performed in 26% and 22% of the patients, respectively. In patients with known pituitary function, hypopituitarism was reported in 28% and 27% after TBI and SAH, respectively. According to the frequency of impairment, pituitary hormone secretion was impaired the following sequence: ACTH, LH/FSH, GH, and TSH. Conclusions: Our data confirm that hypopituitarism is a common complication of TBI and SAH, also when using data obtained from a large and unselected patient cohort. However, we can not exclude a certain selection bias for performing endocrine stimulation tests only in more severely traumatized patients.

Background: The diagnosis of growth hormone (GH) deficiency (GHD) in adults is based on provocative testing of GH secretion. The insulin tolerance test (ITT), currently the test of choice, has been criticised for inconvenience, potential side effects, and resources consumption. Since the GHRH plus Arginine (GARG) test has been proposed to be as reliable as the ITT, our aim was to establish normative data for this test, especially with regard to BMI and age.

Introduction: The aim of this study is to analyze thyroid hormone parameters in large homogenous patient cohorts with preterminal (stage 4) and terminal (stage 5) renal failure in an area of low iodine intake.Patients and Methods: Thyroid parameters were measured in healthy controls (n=48), patients with preterminal renal failure (n=48) and patients with terminal renal failure undergoing hemodialysis (n=288). All patients were assessed by measurement of TSH, T4, T3, fT4, rT3, Tg and TPO-antibodies.Results: There was a significant decrease of T4 and fT4 from healthy controls to patients with preterminal renal failure and to patients with terminal renal failure. T3 showed a decrease from healthy controls to patients with preterminal renal failure and to patients with terminal renal failure (1.54 +/- 0.06 mu g/l vs. 1.05 +/- 0.05 mu g/l vs. 1.09 +/- 0.23 mu g/l, p < 0.001 vs. controls). rT3 was significantly decreased in patients with terminal renal failure (0.24 +/- 0.01 mu g/l vs. 0.25 +/- 0.02 mu g/l vs. 0.16 +/- 0.01 mu g/l, p < 0.001). The rT3/T3 ratio was significantly elevated in patients with preterminal renal failure (p < 0.01). TSH concentrations were in the normal range in all groups.Conclusion: Our data suggest different T4 degradation pathways in patients with preterminal and terminal renal failure.

The German Pegvisomant Observational Study is at present the largest database of patients with acromegaly (n=229) treated with pegvisomant (Somavert). 90.4% pts underwent pituitary surgery, 43.2% received radiation therapy, and previous medical therapy included dopamine agonists (48.1%), octreotide (89.1%) and/or lanreotide (10%). Most relevant concomitant diseases at baseline were gallstone disease (24.4%), diabetes mellitus (28.9%) and heart failure (10.0%). Efficacy analysis was performed in 177 pts with a follow-up after 6 months, in 128 pts after 12 months and in 61 pts after 2yrs. Mean duration of treatment was 51.8±35.8 wks. IGF-I was normalized in 64.4% at 6 months with a median dose of 15.0mg/d and in 76.3% of pts treated for at least 2yrs. IGF-I levels expressed in relation to the individual reference rage decreased from 1.75±0.91 fold at baseline to 1.05±0.62 after 6 months and to 0.89±0.41 after 2yrs. Fasting glucose levels improved significantly from 150±68mg/dl to 119±46mg/dl after 12 months and 104±21mg/ml after 24 months, respectively. Additionally, antidiabetic medication of these patients could be reduced. Elevated liver function tests (LFTs) >3 times above normal occurred in 12 pts receiving octreotide before. In 7/12 pts LFTs spontaneously normalized during continued treatment. In all other pts levels normalized after discontinuation. ALT was the enzyme most prominently elevated with exception of 2 pts and elevation occurred dose independently. Progression of remnant pituitary adenoma was reported in a total of 12 pts. All cases were re-evaluated by a blinded investigator. In 5 pts tumor progression could not be verified at re-evaluation. In 3 pts, the tumor continuously grew on somatostatin analogues. 2 pts had a slight increase in tumor size without clinical relevance and 2 pts showed a tumor expansion after somatostatin treatment was stopped. In conclusion, Pegvisomant is well tolerated with a safety profile similar to that reported in clinical trials, and can effectively reduce IGF-I in pts refractory to conventional therapy.

OBJECTIVE:The GH receptor antagonist pegvisomant is a highly effective new treatment option in acromegaly. The German Pegvisomant Observational Study (GPOS) was started to monitor long-term safety and efficacy of pegvisomant as prescribed in clinical practice. DESIGN:GPOS is an observational, multi-center, surveillance study, which comprises non-interventional data collection. METHODS:Of the 229 patients included in the study, 90.4% had previous pituitary surgery, 43.2% were treated by radiation therapy, and 94.3% had previous medical therapy for acromegaly that had been discontinued mainly due to persistent IGF-I elevation or side effects. The intention-to-treat population included 177 patients with at least one post-baseline efficacy measurement. RESULTS:IGF-I levels decreased from 1.75+/-0.91-fold the upper limit of normal at baseline to 1.05+/- 0.62 at the 6-month visit, 0.96+/-0.60 at the 12-month visit, and to 0.89+/-0.41-fold after 24 months (P<0.0001). Mean duration of pegvisomant therapy was 51.8+/-35.8 weeks (median=51.9 weeks). IGF-I was normalized in 64.4% at 6 months with a median dose of 15.0 mg/day, in 70.9% at 12 months, and in 76.3% at 24 months. Fasting glucose levels improved from 114.4+/-45.9 to 101.5+/- 42.8 mg/dl after 6 months (P<0.01) and to 100.6+/-33.2 mg/ml after 12 months (P<0.01). General physical condition measured by specific signs and symptoms score improved significantly. Adverse events occurring in >1% were injection site reactions in 7.4%, elevated liver enzymes (>3 times of normal) in 5.2% (3.1% spontaneously normalized during continued treatment), reported increase of pituitary tumor volume in 5.2% (which was verified in 3.1%), and headache in 1.7%. CONCLUSIONS:Pegvisomant is generally well tolerated with a safety profile similar to that reported in clinical trials and can effectively reduce IGF-I in patients with acromegaly refractory to conventional therapy.

OBJECTIVE:Cross-sectional studies report a high prevalence of hypopituitarism after traumatic brain injury (TBI); however, no longitudinal studies on time of manifestation and reversibility exist. This study was conducted to assess hypopituitarism 3 and 12 months after TBI. DESIGN:This was a prospective, longitudinal, diagnostic study. METHODS:Seventy-eight patients (52 men, 26 women, mean age 36.0 years) with TBI grades I-III and 38 healthy subjects (25 men, 13 women, mean age 36.4 years) as a control group for the GHRH + arginine test were studied. The prevalence of hypopituitarism was assessed 3 and 12 months after TBI by GHRH + arginine test, short adrenocorticotropic hormone (ACTH) test, and basal hormone measurements in patients. RESULTS:After 3 months, 56% of all patients had impairments of at least one pituitary axis with axes being affected as follows: gonadotropic 32%, corticotropic 19%, somatotropic 9% and thyrotropic 8%. After 12 months, fewer patients were affected, but in some cases new impairments occurred; 36% still had impairments. The axes were affected as follows after 12 months: gonadotropic 21%, somatotropic 10%, corticotropic 9% and thyrotropic 3%. CONCLUSIONS:Hypopituitarism occurs often in the post-acute phase after TBI and may normalize later, but may also develop after the post-acute phase of TBI.

OBJECTIVE:The new GH receptor antagonist pegvisomant is the most effective medical therapy to normalize IGF-I levels in patients with acromegaly. Based on currently available data pegvisomant is well tolerated; however, treatment-induced elevation of transaminases has been reported and led to the necessity for drug discontinuation in some patients in the pivotal studies. The aim of this study was to evaluate and characterize the prevalence of elevated transaminases and to describe in detail the findings in a single case who required drug discontinuation because of elevation of transaminases which emerged during treatment and who underwent liver biopsy.DESIGN AND METHODS:Retrospective safety analyses were carried out on 142 patients with acromegaly receiving pegvisomant treatment in Germany between March 2003 and the end of 2004. Of these patients, 123 were documented in a post-marketing surveillance study, one case of elevated transaminases was reported spontaneously and the other patients were treated in a clinical study.RESULTS:Mean treatment duration with pegvisomant in the ongoing observational study at the end of 2004 was 28.3 +/- 19.9 (S.D.) weeks. Twelve out of the 142 patients had elevated transaminases above three times the upper limit of normal, likely caused by biliary obstruction in five of the patients. All patients but one affected by elevated transaminases had been previously treated with somatostatin analogues. In six out of 142 (4%) of patients, pegvisomant was permanently withdrawn because of elevated transaminases. The same number of patients showed a transient increase of transaminases with either spontaneous remission without dose modification (n = 4) or no re-increase of transaminases after temporary discontinuation and re-exposure (n = 2). The liver biopsy of one patient who was permanently withdrawn showed a chronic mild hepatitis with a mixed portal inflammation including eosinophilic granulocytes.CONCLUSIONS:Liver function tests should be regularly followed on pegvisomant treatment. Biliary complications, which may arise from restitution of normal gall bladder motility after cessation of somatostatin analogue treatment, need to be differentiated from pegvisomant-induced abnormalities. The histological pattern of the liver biopsy performed in one of the patients showed a mild chronic active hepatitis. The lack of dose dependency and rather low frequency of elevated transaminases in those cases where a biliary disorder was excluded render this reaction an idiosyncratic drug toxicity.

The approval of pegvisomant (Somavert) has augmented the therapeutic options in acromegaly. Between Jan 04 and Jul 05, 184 pts were enrolled in the German Acrostudy. Pts age was 49.2±13.5yrs. 91% pts underwent pituitary surgery, 45% received radiation therapy, and previous medical therapy included dopamine agonists (56%), octreotide (90%) and/or lanreotide (10%). Efficacy analysis was performed in 134 pts with a follow-up after 6 months, in 99 pts after 12 months and in 22 pts after 2 years. Mean duration of pegvisomant therapy was 42.2±30.0 wks. During pegvisomant therapy with dose titration not escalated to normalize IGF-I in some, IGF-I was normalized in 65.4% at 6 months with a mean dose of 16.8mg/d and a median dose of 15.0mg/d. IGF-I levels were normalized in 90.2% of pts treated for at least 2 years. Elevated liver function tests (LFT) >3 times above normal occurred in 9 pts receiving octreotide before. In 6/9 pts, LFTs spontaneously normalized during continued treatment, in the other 3 pts (1.6%), levels normalized after treatment discontinuation. With the exception of one patient with transient LFT elevation obviously due to a singular alcohol excess, ALT was the enzyme most prominently elevated. Progression of remnant pituitary adenoma was reported in a total of 9 pts. 7 cases were re-evaluated by a independent neurosurgeon. In 3 pts tumor progression could not be verified at re-evaluation. In 2 pts, the tumor had continuously grown already before pegvisomant therapy, while on somatostatin analogues. In one case, a slight and clinically non-significant growth was seen during pegvisomant therapy and one pt showed a tumor growth due to rebound from somatostatin-induced shrinkage. Pegvisomant is generally well tolerated with a safety profile similar to that reported in clinical trials, and can effectively reduce IGF-I in pts refractory to conventional therapy. In conclusion, the German Acrostudy is at present the globally larges database on patients treated with pegvisomant. It provides important information on safety and efficacy on these treatment.

Several studies report a high prevalence of hypopituitarism after traumatic brain injury (TBI). However, it is still not clear which risk factors predispose patients to develop anterior hypopituitarism after TBI. In this study we wanted to assess clinical and radiographical risk factors for the development of hypopituitarism. Seventy-eight patients (52 men, 26 women, mean age 36.0 years) with TBI °I-III were studied prospectively. We evaluated initial CT scans and clinical status and complications from clinical records. Additionally, we assessed endocrine and clinical parameters 3 and 12 months after TBI. To this end, basal hormone values, a GHRH+arginine and an ACTH test were done and the modified Rankin Scale was assessed in all patients. We evaluated the association of several potential clinical and radiological predictors with the presence of pituitary impairment at different time points. The rate of hypopituitarism (impairment of at least one pituitary axis) at at least one time point was significantly higher in patients with diffuse axonal injury (DAI). Secondary hypogonadism was significantly more common in patients with severe TBI, DAI, history of transient diabetes insipidus, hypoxia, external ventricular drain, and polytrauma. Impairment of at least one of the hormones ACTH, GH, TSH was significantly more frequent in patients with basal skull fracture. Logistic regression analysis showed DAI and higher age to be associated with hypopituitarism and basal skull fracture to be associated to presence of ACTH, GH, or TSH deficiency. Cranial vault fracture was associated with a decreased frequency of hypopituitarism. DAI and basal skull fractures are independent predictors of post-traumatic hypopituitarism. Particular care should be taken to screen for hormone deficiencies in these patients. Unlike the other pituitary hormone axes, the gonadotropic axis is associated with the severity of TBI.

Several recent studies have pointed to a substantial prevalence of hypopituitarism in defined groups of patients with traumatic brain injury (TBI) and aneurysmal subarachnoid hemorrhage (SAH). However, epidemiological data on the prevalence and incidence of hypopituitarism after TBI and SAH in the general population do not exist. Moreover, very little is known about risk factors and clinical characteristics of pituitary impairment after brain damage. To address these questions we are establishing a multi-center, structured data assessment to create a national registry of these patients. It is planned to include 600–1000 patients per year. Data will be collected using a structured, internet-based study sheet, collecting information on clinical, radiological and hormonal parameters. The study aims to connect clinical information on trauma and presence and type of hypopituitarism.