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ObjectiveHypopituitarism is associated with an increased mortality rate but the reasons underlying this have not been fully elucidated. The purpose of this study was to evaluate mortality and associated factors within a large GH-replaced population of hypopituitary patients.DesignIn KIMS (Pfizer International Metabolic Database) 13 983 GH-deficient patients with 69 056 patient-years of follow-up were available.MethodsThis study analysed standardised mortality ratios (SMRs) by Poisson regression. IGF1 SDS was used as an indicator of adequacy of GH replacement. Statistical significance was set to PResultsAll-cause mortality was 13% higher compared with normal population rates (SMR, 1.13; 95% confidence interval, 1.04–1.24). Significant associations were female gender, younger age at follow-up, underlying diagnosis of Cushing's disease, craniopharyngioma and aggressive tumour and presence of diabetes insipidus. After controlling for confounding factors, there were statistically significant negative associations between IGF1 SDS after 1, 2 and 3 years of GH replacement and SMR. For cause-specific mortality there was a negative association between 1-year IGF1 SDS and SMR for deaths from cardiovascular diseases (P=0.017) and malignancies (P=0.044).ConclusionsGH-replaced patients with hypopituitarism demonstrated a modest increase in mortality rate; this appears lower than that previously published in GH-deficient patients. Factors associated with increased mortality included female gender, younger attained age, aetiology and lower IGF1 SDS during therapy. These data indicate that GH replacement in hypopituitary adults with GH deficiency may be considered a safe treatment.

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.

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 ofhypopituitarism 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.

OBJECTIVE: Several studies have suggested that iodine may influence thyroid hormone status, and perhaps antibody production, in patients with autoimmune thyroid disease. To date, studies have been carried out using large amounts of iodine. Therefore, we evaluated the effect of small doses of iodine on thyroid function and thyroid antibody levels in euthyroid patients with Hashimoto's thyroiditis who were living in an area of mild dietary iodine deficiency. METHODS: Forty patients who tested positive for anti-thyroid (TPO) antibodies or with a moderate to severe hypoechogenic pattern on ultrasound received 250 microg potassium iodide daily for 4 months (range 2-13 months). An additional 43 patients positive for TPO antibodies or with hypoechogenicity on ultrasound served as a control group. All patients were TBII negative. RESULTS: Seven patients in the iodine-treated group developed subclinical hypothyroidism and one patient became hypothyroid. Three of the seven who were subclinically hypothyroid became euthyroid again when iodine treatment was stopped. One patient developed hyperthyroidism with a concomitant increase in TBII titre to 17 U/l, but after iodine withdrawal this patient became euthyroid again. Only one patient in the control group developed subclinical hypothyroidism during the same time period. All nine patients who developed thyroid dysfunction had reduced echogenicity on ultrasound. Four of the eight patients who developed subclinical hypothyroidism had TSH concentrations greater than 3 mU/l. In 32 patients in the iodine-treated group and 42 in the control group, no significant changes in thyroid function, antibody titres or thyroid volume were observed. CONCLUSIONS: Small amounts of supplementary iodine (250 microg) cause slight but significant changes in thyroid hormone function in predisposed individuals.

ObjectiveWe studied whether the severity of GH deficiency (GHD) defined as i) GH-peak on stimulation tests (insulin tolerance test (ITT), arginine, and glucagon), ii) number of additional pituitary deficits, or iii) baseline IGF1 SDS could impact the response to GH treatment. We further explored whether iv) IGF1 SDS after 24 months of GH replacement or v) ΔIGF1 SDS from baseline to 24 months was related to the phenotypic response to GH treatment.Design, patients, and measurementsThe patient cohort (n=1752; 50% women) was obtained from KIMS (Pfizer International Metabolic Database). The patients were divided into three groups of approximately equal size (tertiles) according to the stimulated GH-peak values and baseline IGF1 SDS and were studied at baseline, 12, and 24 months of GH therapy.ResultsLower baseline IGF1 SDS predicted better response in weight, BMI, total cholesterol, and triglycerides, while IGF1 SDS after 24 months was associated with reduction in waist/hip ratio, total cholesterol, and improved quality of life (QoL). Age-correlated negatively with the response in body weight, BMI, waist, IGF1 SDS, and total and LDL-cholesterol.Response in weight and BMI was greater in men than in women, whereas women showed greater improvement in QoL than men. Patients with more severe GHD as assessed by lower GH-peaks and more pituitary hormone deficiencies had a greater increase in IGF1 SDS. The increase in IGF1 SDS was associated with a reduction in waist/hip ratio and an increase in weight, BMI, and triglycerides. There was no correlation with other lipids, blood pressure, or glucose.ConclusionOur findings indicate that baseline and 24 months, IGF1 and its degree of increase during GH replacement were more important than stimulated peak GH to predict the phenotypic response.

ObjectiveWe aimed at investigating the association of age-dependent IGF-I SDS with diabetes, dyslipidemia, hypertension, and heart diseases, in a large patient sample.BackgroundIGF-I has been suggested to be associated with several diseases and a prognostic marker for the development of cardiovascular diseases and risk factors. The findings, though, have been inconsistent possibly due to the methodological factors.MethodsWe studied 6773 consecutive primary care patients, aged 18+ years, in a cross-sectional, epidemiological study in primary care, Diabetes Cardiovascular Risk-Evaluation: Targets and Essential Data for Commitment of Treatment study. All patients underwent a standardized clinical diagnostic and laboratory assessment. IGF-I levels were measured with an automated chemiluminescence assay system. We calculated the odds ratios (OR) for diseases in quintiles of IGF-I, and additionally analyzed the association of age-dependent IGF-I SDS with these conditions.ResultsAfter multiple adjustments for confounders, we found increased ORs for coronary artery disease in patients with high IGF-I. Women, but not men, with low IGF-I also showed increased ORs for coronary artery disease. Dyslipidemia was positively associated with IGF-I. Type 2 diabetes showed a curvilinear association with IGF-I SDS.ConclusionsThe findings suggest the existence of multiple and complex interactions between IGF-I and several health conditions. The complex nature of disease- and subgroup-specific associations along with the methodological factors can be held responsible for divergent findings in previous studies.

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 (PPP1% 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: This study set out to determine the change in quality of life (QoL) and healthcare utilization during 2 years of growth hormone (GH) replacement therapy in adults with GH deficiency. Data were compared from three European countries. Design: Analysis was made from KIMS, the Pfizer International Metabolic Database on adult GH deficiency. Methods: QoL and healthcare utilization were measured at baseline and after 1 and 2 years of GH replacement in patient cohorts from Sweden (n = 302), The Netherlands (n = 103) and Germany (n = 98). QoL was assessed by the QoL-Assessment in Growth Hormone Deficient Adults (QoL-AGHDA) questionnaire, and the KIMS Patient Life Situation Form was used to evaluate healthcare utilization. Results: QoL improved significantly (P < 0.0001) and comparably in all three cohorts. The improvement was seen during the first year of treatment and QoL remained improved during the second year. The number of days in hospital was reduced by 83% (P < 0.0001) during GH replacement. There were no country-specific differences either at baseline or during follow-up. The same was true for the number of days of sick leave (reduction of 63%; P = 0.0004). Significant reductions were recorded in the number of doctor visits in each of the three cohorts after 2 years of GH replacement (P < 0.05). Conclusions: This study provides a detailed comparative analysis of GH replacement therapy in GHD patients in three European countries. Despite some differences in treatment strategies, the beneficial effects on QoL, patient-reported outcomes and healthcare utilization are essentially similar in the healthcare environment of Western European countries.

Objective: Insulin-like growth factor-I (IGF-I) has been suggested to be a prognostic marker for the development of cancer and, more recently, cardiovascular disease. These diseases are closely linked to obesity, but reports of the association of IGF-I with measures of obesity are divergent. In this study, we assessed the association of age-dependent IGF-I standard deviation scores with body mass index (BMI) and intra-abdominal fat accumulation in a large population. Design: A cross-sectional, epidemiological study. Methods: IGF-I levels were measured with an automated chemiluminescence assay system in 6282 patients from the DETECT study. Weight, height, and waist and hip circumference were measured according to the written instructions. Standard deviation scores (SDS), correcting IGF-I levels for age, were calculated and were used for further analyses. Results: An inverse U-shaped association of IGF-I SDS with BMI, waist circumference, and the ratio of waist circumference to height was found. BMI was positively associated with IGF-I SDS in normal weight subjects, and negatively associated in obese subjects. The highest mean IGF-I SDS were seen at a BMI of 22.5–25 kg/m2 in men (+0.08), and at a BMI of 27.5–30 kg/m2 in women (+0.21). Multiple linear regression models, controlling for different diseases, medications and risk conditions, revealed a significant negative association of BMI with IGF-I SDS. BMI contributed most to the additional explained variance to the other health conditions. Conclusions: IGF-I standard deviation scores are decreased in obesity and underweight subjects. These interactions should be taken into account when analyzing the association of IGF-I with diseases and risk conditions.

Mann K, Rendl J, Busley R, Sailer B, Seybold S, Hoermann R, Sauerbruch T, Börner W. Systemic iodine absorption during endoscopic application of radiographic contrast agents for endoscopic retrograde cholangiopancreaticography. Eur J Endocrinol 1994;130:498–501. ISSN 0804–4643 Hyperthyroidism induced by contrast agents is a major problem in patients with pre-existing thyroid disease, particularly in patients with functional thyroid autonomy. The present study was undertaken to evaluate whether contrast media applied during endoscopic retrograde cholangiopancreaticography (ERCP) may result in a significant increase of serum iodine levels and thus may be associated with the risk of iodine-induced hyperthyroidism. The courses of serum concentrations of total iodine and free iodide, as well as of urinary iodine excretion, were measured in 15 patients before and up to 21 days after ERCP. During ERCP, the non-ionic contrast medium iopamidol was instilled in amounts resulting in a total iodine load of 57.4 ± 22.8 mmol (7.3 ± 2.9 g). In all patients, ERCP resulted in a highly significant increase in serum levels of total iodine from 0.8±0.5 to 85.2 ± 116.9 μmol/l 4 h after application of the contrast agent. In parallel, serum iodide levels were raised from 0.06 ± 0.04 to 5.42 ± 6.09 μmol/l and urinary iodine excretion from 71.1 ± 35.7 μmol/mol creatinine to 621 620.9 ± 636 492.2 μmol/mol creatinine. Peak concentrations of serum iodine are well related to the total amount of iodine applied (p < 0.05). During follow-up, iodine levels returned to preexposure levels within 2–3 weeks. Levels of thyrotropin, free thyroxine, and free triiodothyronine remained unchanged during the follow-up period. In conclusion, endoscopic application of iodinated contrast agents during ERCP leads to significant increases of serum levels of total iodine and free iodide and of urinary iodine excretion. Therefore, patients with underlying thyroid disease may be at risk to develop iodine-induced hyperthyroidism. Klaus Mann, Dept. of Internal Medicine II. Klinikum Grosshadern, Marchionistr. 15, 81377 Munich, Germany