European proficiency study with control serum for the tumor marker CA 19-9 measured on different test systems.

BACKGROUND: Reliable and precise CA 19-9 testing is required for the long-term follow-up of patients with pancreatic carcinoma during therapy. The aim of this longitudinal proficiency study was to evaluate the comparability, linearity, and precision of CA 19-9 determinations performed in different laboratories using currently available test systems under routine conditions. METHODS: During the one year study period, 15 laboratories applied 7 different tests and included a liquid BIOREF control serum with pancreatic carcinoma derived CA 19-9 in their routine testing and quality control procedures. The results were collected centrally and evaluated statistically. RESULTS: The comparability of CA 19-9 results is limited especially when different tests are used, albeit, some tests show a good correlation: The CA 19-9 values obtained by different laboratories using different test systems vary up to a factor of 2. The precision of CA 19-9 determinations was acceptable in most laboratories with coefficients of variation ranging between very low 3.2% and high 17.8%. The imprecision was slightly increased when automatic dilution procedures of the analysers were used. CONCLUSIONS: The comparability of CA 19-9 test results must be improved. The precision is acceptable in most cases. In order to monitor key performance parameters, every laboratory should participate in external quality assessment schemes and should perform a routine internal quality control with a control serum independent from the test kit manufacturer.

Discrepant results in the diagnosis of GH deficiency with the insulin-tolerance test and the GHRH plus arginine test in patients with traumatic brain injury.

OBJECTIVE: Patients with traumatic brain injury (TBI) are at moderate risk of GH deficiency (GHD), requiring a diagnostic test with high specificity. The GHRH + arginine (GHRH + ARG) test has been recommended as a reliable alternative to the insulin-tolerance test (ITT) as a standard test with a cutoff level of 9 ng/ml. However, it has recently been questioned for its low specificity in obese subjects, and now BMI-dependent cut-off levels are available. In this study, we compared the ITT and GHRH + ARG test in patients with TBI. DESIGN: A cross-sectional study METHODS: We performed an ITT and a GHRH + ARG test in 21 patients with TBI (6 women, 15 men; mean age 40.2 +/- 12.1 years; BMI 30.7 +/- 6.2). The number of patients classified discordantly as GH deficient by the ITT and the GHRH + ARG test with both classical and BMI-dependent cut-off levels was assessed. RESULTS: Using the GHRH + ARG test with the classical cut-off ( 3 ng/ml), and one patient as GH sufficient who had a blunted GH response to ITT (discordance rate 61.9%). All patients discordantly classified as GH deficient by the GHRH + ARG test had a BMI of >or= 28. With the BMI-dependent cut-offs (4.2, 8.0, and 11.5 ng/ml in obese, overweight, and lean subjects respectively), only 3 of the 21 patients were discordantly classified (discordance rate 14.3%). CONCLUSIONS: Our results discourage the use of a cut-off level of 9 ng/ml for the GHRH + ARG test in obese subjects. The diagnostic reliability of this test is improved with the BMI-dependent cut-offs.

Hypopituitarism following severe traumatic brain injury.

Although hypopituitarism is a known complication of traumatic head injury, it may be under-recognized due to its subtle clinical manifestations. To address this issue, we determine the prevalence of neuroendocrine abnormalities in patients rehabilitating from severe traumatic brain injury (Glasgow Coma Scale < or = 8). 76 patients (mean age 39 +/- 14 yr; range 18-65; 53 males and 23 females; BMI 25.8 +/- 4.2 kg/m2; mean +/- SD) with a severe traumatic brain injury, an average of 22 +/- 10 months before this study (median, 20 months), underwent a series of standard endocrine tests, including TSH, free T4, T4, T3, prolactin, testosterone (males), estradiol (females), cortisol, ACTH, GH, and IGF-I. All subjects also underwent GH response to GHRH + arginine. Growth hormone deficiency (GHD) was defined as a GH response < 9 microg/L to GHRH + arginine and was confirmed by ITT (< 3 microg/L). Pituitary deficiency was shown in 24% of the patients (18/76). 8% (n = 6) had GHD (GH-peak range [GHRH + arginine]: 2.8-6.3 microg/L; GH-peak range [ITT]: 1.5-2.2 microg/L; IGF-I range: 62-174 microg/L). 17% (n = 13) had hypogonadism (total testosterone < 9.5 nmol/L and low gonadotropins in 12 males; low estradiol, and low gonadotropins in 1 female). Total testosterone levels did not correlate with BMI or age. 2 males with hypogonadism also showed a mild hyperprolactinemia (33 and 41 ng/ml). 3% (n = 2) patients had partial ACTH-deficiency (cortisol-peak [ITT] 392 and 417 nmol/L) and 3% (n = 2) had TSH-deficiency. In summary, we have found hypopituitarism in one-fourth of patients with predominantly secondary hypogonadism and GHD. These findings strongly suggest that patients who suffer head trauma must routinely include neuroendocrine evaluations.

Effects of octreotide on sleep apnoea and tongue volume (magnetic resonance imaging) in patients with acromegaly.

OBJECTIVES: Sleep apnoea has been consistently reported to occur in acromegaly. Both obstructive apnoeas, in which apnoeas are due to intermittent obstruction of the upper airways, as well as central apnoeas are known to occur. Because the relationship between disease activity and severity of sleep apnoea is currently unclear, we have performed a prospective study to address this issue. DESIGN AND METHODS: In 14 newly diagnosed patients with active acromegaly (eight females and six males; mean age 57+/-4 years; IGF-I 583+/-48 microg/l; GH 13.5+/-7.0 microg/l (means+/-s.e.m.)), tongue volume and signal intensity of the tongue were examined by magnetic resonance imaging and sleep apnoea was characterised by polysomnography before and after 6 months of treatment with octreotide acetate (Sandostatin LAR 10-30 mg every 4 weeks i.m.). RESULTS: The initial tongue volume was significantly higher in patients with acromegaly (151+/-9 ml; females 133+/-10 ml; males 172+/-10 ml) in comparison with the body mass index (BMI)- and age-matched healthy control group (97+/-5 ml, P<0.001; females 75+/-1 ml, P<0.001; males 120+/-3 ml, P<0.003). After treatment with octreotide, IGF-I was normalised within the age-adjusted normal range in 50% of the patients. In these patients, tongue volume significantly decreased (120+/-14 ml, P<0.05) in comparison with the persistent uncontrolled group of acromegalics (137+/-10 ml, P=not significant). Overall, tongue volume (128+/-8 ml, P<0.05) and the signal intensity ratio of the tongue decreased significantly after treatment with octreotide acetate (120+/-3 vs 105+/-3, P=0.003). The BMI-adjusted tongue volume correlated with IGF-I levels (r=0.60, P<0.002) and the disease duration (r=0.71, P=0.006). At baseline, 50% had obstructive sleep apnoea with a mean respiratory disturbance index (RDI) of >20/h (range 5.1-91.5) and no patient had central sleep apnoea. After 6 months of octreotide treatment, there was a 28+/-10% decrease in RDI. However, RDI did not correlate with IGF-I or GH levels, but correlated positively with BMI (r=0.58, P=0.001) and age (r=0.46, P=0.02). CONCLUSIONS: Obstructive sleep apnoea but not central sleep apnoea frequently occurs in patients with active acromegaly. Successful treatment with octreotide can decrease tongue volume, which may have benefits for coexisting sleep-disordered breathing.

Primary malignant fibrous histiocytoma of the lung: IGF-II producing tumor induces fasting hypoglycemia.

Augmented glucose utilisation or secretion of insulin-like-growth-factor II (IGF-II) are discussed as important pathogenetic factors in tumor-associated hypoglycemia (Doege-Potter Syndrome) with suppressed insulin and C-peptide levels. Primary malignant fibrous histiocytoma of the lung is an uncommon neoplasia and its association with hypoglycemia is rare and the causal relationship remains unclear. - We report a 57-year-old male with spontaneous hypoglycemia (1.67 mmol/l) due to a primary malignant fibrous histiocytoma of the lung, secreting IGF-II. Insulin (0.10 nmol/l; normal range 0.33-1.2) and C-peptide (3.0 mIU/l; 5-25) levels were suppressed in combination with low levels of growth hormone (<0.5 ng/ml; <7 ng/ml) and IGF-I (<66.0 ng/ml; 70-246). The elevated IGF-II level (787 ng/ml; 300-500) and decreased IGF-binding protein 3 (1.6 mg/l; 2-5) indicated a high free IGF-II activity. After surgery (resection of the right upper lobe), glucose (4.4 mmol/l), insulin (9.0 mIU/L) and C-peptide (0.84 nmol/l) levels returned to normal. Serum IGF-I (289 ng/ml) and the IGF-I/IGF-II ratio (<0.08 preoperative vs. 0.41 postoperative; >0.20) increased to the normal reference range. - In conclusion, malignant fibrous histiocytoma (MFH) is rarely described presenting as tumor-induced hypoglycemia. Doege-Potter Syndrome in MFH seems to be related to tumor-associated IGF-II production.

Impact of disease activity on thyroid diseases in patients with acromegaly: basal evaluation and follow-up.

In patients with acromegaly, the exact incidence of thyroid disorders is still controversial and less is known about the impact of disease activity and successful treatment. To address this issue, we investigated 73 acromegalic patients (age 55 +/- 13 yr; mean +/- SD) by ultrasonography in comparison to an age-matched control group (54 +/- 1 yr) in the same moderate iodine deficient area (retrospective study). These non-acromegalic volunteers (n = 199) were examined in the same clinic during a thyroid screening test. At the time of examination, 52 (71.2 %) of the acromegalic patients were active, 17 (23.3 %) were cured, and 4 (5.5 %) were controlled with somatostatin analogues. The prevalence of goiter (normal range < 18 ml female, < 25 ml male) was significantly higher (82.2 %) in the mixed group of acromegalics (active, well controlled, cured; n = 73) and in the active group (90.4 %) than in the control group (n = 199, 18.1 %, p < 0.001). Thyroid nodules were found in 63.0 % of the mixed group of acromegalics and in 71.2 % of patients with active disease (33.1 % in controls, p < 0.001). (99 m)Tc scintigraphy revealed thyroid autonomy in 9/73 (12.3 %) and cold nodules in 19/73 (26.0 %) patients. Thyroid cancer was diagnosed in 4 (5.5 %) of acromegalic patients (3 papillary and 1 follicular carcinoma). We found a weak correlation between the disease duration and the initial thyroid volume (r = 0.54, p < 0.0056). Thirty-seven newly diagnosed acromegalics were followed over a period of 7.3 +/- 4.1 years. 5 (13.5 %) of these patients remained active, 8 (21.6 %) were controlled with somatostatin analogues, and 24 (64.9 %) were cured. The mean age, sex distribution, disease duration, prevalence of TSH-deficiency, and initial thyroid volume (46 +/- 11 ml in active, 42 +/- 7 ml in controlled, and 45 +/- 5 ml in cured patients) did not differ statistically between the three groups. In patients with active acromegaly, thyroid volume increased by 19.5 +/- 8.1 %. In contrast, thyroid volume decreased in the group of medically controlled and cured acromegalics (- 21.5 +/- 7.1 %; p < 0.005 and - 24.2 +/- 5.7 %; p < 0.002, respectively). No correlation was found between thyroid volume and TSH levels, levothyroxine and/or iodide administration neither in TSH sufficient nor in TSH insufficient patients. In conclusion, successful treatment of patients with active acromegaly decreases thyroid volume. Cold nodules and thyroid cancer frequently occur in acromegalic patients.

[Continuous blood glucose monitoring: the acute effect of acarbose on blood glucose variations]. / Kontinuierliche Blutglucosemessungen: Der Akuteffekt von Acarbose auf die Blutglucoseschwankungen.

BACKGROUND: Acarbose, a pseudo-tetrasaccharid, inhibits intestinal alpha-glucosidases, effects a reduction of postprandial hyperglycemia and is particularly used in the treatment of patients with type-2 diabetes mellitus. The aim of the study is to analyse by a continuous blood glucose measurement the acute effect of acarbose after a carbohydrate loading and during a 12 hours period. PATIENTS AND METHODS: We examined 10 patients with type-2 diabetes mellitus (mean age 59.2 +/- 3.79, HbA1 9.2 +/- 0.26%) treated with sulfonylureas and/or insulin after a carbohydrate meal and 12 hours during daytime, to test whether the first application of acarbose influences the mean blood glucose or the blood glucose amplitudes. Four measurements were enrolled using a portable continuous blood glucose sensor (Glucosensor, unitec Ulm). A measurement after a carbohydrate loading (Fresubin, 500 kcal, 69 g carbohydrate) with 100 mg acarbose (Glucobay) was followed by a 12-hour measurement during daytime with 3 x 100 mg acarbose and standard diet. These measurements were repeated without acarbose. RESULTS: After a carbohydrate loading, the mean blood glucose level (AUC 44,320 +/- 10,660 with acarbose vs. 61,390 +/- 12,590 without acarbose; mean + SD; p = 0.004) decreased by 28%. During daytime blood glucose levels were not significantly decreased (165.7 +/- 50.3 mg/dl vs 183.7 + 67.4 mg/dl; p = 0.1) although the postprandial blood glucose amplitudes after the 3 meals were reduced significantly (85.90 +/- 24.6 mg/dl vs 106.5 +/- 20.5 mg/dl; p = 0.02). CONCLUSIONS: Continuous blood glucose monitoring indicated that acarbose diminished mean blood glucose levels after a carbohydrate loading in patients with type-2 diabetes mellitus, but not during 12 hours of standard diet, although blood glucose amplitudes decreased. Long-term improvements of metabolism by acarbose may therefore be related to the reduction of blood glucose amplitudes which is likely to reduce toxic effects of glucose on islet cell function.

Comparison of insulin aspart vs. regular human insulin with or without insulin detemir concerning adipozytokines and metabolic effects in patients with type 2 diabetes mellitus.

BACKGROUND: In type 2 diabetes mellitus, treatment with insulin is initiated when HbA1c is reduced inadequately with oral antidiabetic drugs or incretin mimetics. Whether insulin analogues vs. regular human insulin have favorable effects in terms of efficacy and metabolism is under discussion. PATIENTS: 29 patients with type 2 diabetes mellitus (19 males, 10 females) with a mean age 59±11(mean±SD) years (range 24-75) and treated with oral drugs for at least 6 months and a HbA1c >7.0% were included in an open, randomised, prospective, controlled, multicenter parallel-group study over a period of 24 months. METHODS: 11 patients were randomized in the regular human insulin-group (RHI-group) and 18 patients in the insulin aspart group (IA-group). Insulin aspart or regular human insulin should be treated to <140 mg/dl postprandial and insulin detemir should be treated to <110 mg/dl in the morning (fasting) after a previous dose titration of insulin aspart or regular human insulin over 6 months of treatment. Adiponectin, HbA1c, fasting plasma glucose, BMI, triglycerides and cholesterol levels were determined every 3 months. RESULTS: 7/11 of the RHI-group received additional insulin detemir and 13/18 of the IA-group. HbA1c levels decreased significantly in both groups (8.7±1.6 to 7.2±0.9 in the RHI-group (p<0.05) vs. 8.7±1.6 to7.3±0.9 in the IA-group (p<0.05)) without significant difference between the groups. No significant changes were seen between the 2 groups during the 24 months period in terms of BMI, fasting plasma glucose, lipids. Adiponectin serum levels decreased over the time without difference between the groups (7.9±4.0 to 5.0±2.0 in the RHI-group (p<0.03) vs. 7.3±3.4 to 4.8±2.8 in the IA-group (p<0.0001)). During the first 9 months, the insulin dosage to reach the postprandial blood glucose <140 mg/dl, were significantly lower in the IA-group, but approached the following the RHI-group without significant changes after 24 months. CONCLUSION: After stopping oral antidiabetic drugs in type 2 diabetes mellitus, insulin aspart in comparison to human regular insulin decreased effectively HbA1c levels without significant difference. Moreover, insulin aspart in comparison to human regular insulin does not have any substantial benefits concerning metabolic effects and adipocytokines in type 2 diabetes mellitus over a 24 months treatment period.

Acromegaly: a cross-sectional analysis of the oral and maxillofacial pathologies.

CONTEXT: It is well established that clinical features of acromegaly concern the teeth and the jaw, but less is known about the degree of oral and maxillofacial pathologies. PATIENTS: 28 acromegalics (13 females, 15 males) with a mean age 49±11 (mean±SD) years (range 31-70) were included in the study. 32% had active disease, 68% were well-controlled under the somatostatin analogue octreotide, the dopamine agonist cabergoline, and the GH receptor antagonist pegvisomant, or were cured after pituitary surgery and/or radiation. METHODS: All subjects undergone intensive and complex examinations of a plaster model and facial arch with articulator, an intra-oral bracket-pen registration, analysis of a digital picture, panoramic and lateral radiographs with cephalometry in comparison with a reference group (n=201). RESULTS: 42% had a diastema mediale (0.9±1.1 mm). Overbite and overjet (vertical overbite) correlated with the disease duration (r²=0.2237; p=0.011 respectively r²=0.3364; p=0.015). 96% had an asymmetric movement of the mandible. 57% had a prognathism. The protrusion of the mandible correlated significantly with the disease duration (r²=0.1784; p=0.028). The degree of the mandibular prognathism (SNB-angle) was higher in the acromegalic group (84°±7° vs. 81°±3°, p<0.05). The ANB-angle indicates the relation between maxilla and mandible and was negative in the acromegalic group and positive in the controls (-0.3°±5.0° vs. 1.6°±2.1°, p=<0.05) and correlated negative with the disease duration (r²=0.2553; p=0.0061). The mandibular angle was significantly greater in the acromegalic group (126°±9° acromegalic group vs. 121°±7°control group, p=0.003). The length of the mandible correlated with the disease duration (r²=0.2801; p=0.0038). 86% had an asymmetric face. The high of the midface was in the acromegalic group higher (6.1±0.7 vs. 5.5±0.4 cm, p=0.0009) as well as the lower bony high of the face (9.5±1.0 acromegalics vs. 6.9±0.5 cm controls, p=0.0009). The high of the lower bony face correlated with as well with the disease duration (r²=0.3224; p=0.0016). CONCLUSIONS: Patients with acromegaly suffer not only from cardiovascular, metabolic and neoplastic complications, but also from dental and jaw disorders. The high incidence of these manifestations and its relation to the disease duration requires a carefully work-up of oral and maxillofacial examinations in close collaboration with endocrinologists, dentists and dental surgeons.

Calcitonin screening and pentagastrin testing: predictive value for the diagnosis of medullary carcinoma in nodular thyroid disease.

CONTEXT: Serum calcitonin (hCT) measurement may be useful for detecting medullary thyroid carcinoma (MTC), but the routine use of hCT after pentagastrin stimulation to screen patients with nodular thyroid disease remains controversial. PATIENTS: A total of 1007 patients (567 females and 440 males) with nodular thyroid disease and a mean age of 55+/-14 (mean+/-S.D.) years were included in the study. All patients did not have impaired renal function, bacterial infection, alcohol and drug abuse, pseudohypoparathyroidism, or proton-pump inhibitor therapy. Individuals referred with known elevation of hCT, Graves' disease, or autoimmune thyroid disease were not considered or included in this investigation. METHODS: Serum hCT levels were determined under basal conditions, and when basal values were >or=10 and <100 pg/ml, testing was repeated after pentagastrin stimulation. Patients with basal or stimulated levels >100 pg/ml were referred for surgery. RESULTS: hCT levels >10 pg/ml were increased in 17 patients (1.7%). One patient had a basal hCT level of 4400 pg/ml with a histological confirmation of a MTC. In this patient, pentagastrin test was not performed. Sixteen patients with basal hCT between 10 and 100 pg/ml underwent pentagastrin-stimulated hCT measurement. Of 16 patients, 4 had stimulated hCT>100 pg/ml. Of 17 patients with hCT>10 pg/ml, 2 had MTC, and of 17 patients, 3 had C-cell hyperplasia. In total, two patients (0.20%) had a histologically verified MTC. CONCLUSIONS: Basal hCT measurement together with pentagastrin-stimulated hCT measurement in cases of basal hCT>10 pg/ml detects MTC in 0.20% of patients with nodular thyroid disease. Whether this high incidence of MTC has major implications or not has to be discussed, but it should be considered as a useful and recommended tool for early detection of MTC and to save patients' life.

Prevalence of anterior pituitary dysfunction in patients following traumatic brain injury in a German multi-centre screening program.

INTRODUCTION: We determined the prevalence of anterior pituitary dysfunction in a multi-centre screening program across five German endocrine centres in patients rehabilitating from TBI (GCS<13). PATIENTS & METHODS: 246 patients (39+/-14 yrs; 133 males, 12+/-8 months after TBI) underwent a series of baseline endocrine tests with central assessment of TSH, free T4, prolactin, LH, FSH, testosterone (m), estradiol (f), cortisol, GH, and IGF-I. If IGF-I was <-2 SDS dynamic testing was performed. GHD was defined according to BMI-dependent cut-off values for GH response to GHRH+arginine of <4.2, <8.0 and <11.5 ng/ml in obese, overweight and lean subjects, respectively, or <3 micro g/l in ITT. Hypocortisolism was suggested when basal cortisol was <200 nmol/l and confirmed by ITT (peak<500 nmol/l). RESULTS: In TBI patients some degree of impaired pituitary function was shown in 21% (n=52/246). Total, multiple and isolated deficits were present in 1%, 2% and 18%, respectively. 19% had an IGF-I of <-1 SDS, 9% of <-2 SDS. In 5% GHD was confirmed. 9% had hypogonadism. 4% had hypocortisolism and 1% of patients had confirmed ACTH-deficiency. 12% had TSH-deficiency. SUMMARY: In summary, in this large series carried out on an unselected group of TBI survivors we have found hypopituitarism in every fifth patient with predominantly secondary hypogonadism and hypothyreosis. Regarding somatotrope insufficiency IGF-I is decreased in 50% of GHD patients. CONCLUSION: These findings strongly suggest that patients who suffer head trauma should routinely undergo endocrine evaluation.

Impact of disease duration on coronary calcification in patients with acromegaly.

It is well established, that the increased mortality in patients with acromegaly is due to cardiac diseases. Cardiomyopathy is the predominant cardiac alteration in patients with acromegaly. There are less data about coronary heart disease or coronary calcifications. Electron beam computed tomography (EBCT) is the standard imaging modality for identification of coronary artery calcifications (CAC) and can determine the extent and severity of coronary atherosclerosis. Coronary risk was evaluated by the Framingham risk score (FRS). The prospective study included 30 patients with acromegaly (mean age 53+/-14 year; 16 females, 14 males; BMI 28.1+/-3.6 kg/m (2); mean+/-SD), 12 patients had active disease (IGF-1 751+/-338 microg/L; GH 25.6+/-36.4 microg/L), 9 were well-controlled (IGF-1 157+/-58 microg/L; GH 1.8+/-1.1 microg/L) under somatostatin analogue octreotide (n=5), dopamine agonists (n=2), and the GH receptor antagonist pegvisomant (n=2; GH levels were not determined in this subgroup) and 9 were cured IGF-1 (148+/-57 microg/L; GH 0.5+/-0.2 microg/L). Increased left ventricular muscle mass index (LVMI >132 g/m (2)) was focused in 53%, hypercholesterinemia in 63%, hypertension in 43%, diabetes mellitus/impaired glucose tolerance in 27%, and smokers in 53% (pack per year 9+/-15 yr). For quantification of CAC the EBCT was used and the Agatston calcium score was determined. Results were composed to established age and sex adjusted percentile distribution of CAC. CAC was present in 53%, high CAC score (75 (th) percentile) in 37% and were categorized as cardiovascular high risk patients. FRS was related to the CAC score (p=0.008, r (2)=0.22) and the disease duration (p=0.002, r (2)=0.29). The CAC score correlated with LVMI (p=0.02, r (2)=0.17), the disease duration of acromegaly (p=0.004, r (2)=0.36), and the FRS (p=0.008, r (2)=0.22). Patients with a high CAC score had a longer disease duration of 9.6+/-4.7 versus 5.4+/-2.8 years with CAC<75 (th) percentile (p=0.02). In summary, the disease duration and consequently the accompanying metabolic disorders appear to influence the degree of CAC in patients with acromegaly. The observations underline the importance of early and sufficient treatment of acromegaly in high risk patients.

Influence of disease control with pegvisomant on sleep apnoea and tongue volume in patients with active acromegaly.

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.

Effects of estrogen replacement therapy on bone and glucose metabolism in a male with congenital aromatase deficiency.

Little is known about the impact of estrogen replacement therapy for bone formation, glucose metabolism and hormonal parameters on males with aromatase deficiency. Transdermal estrogen (TE) replacement was initiated at 100 microg/week in months 0-3, 50 microg/week in months 3-6, 25 microg/week in months 6-12, 75 microg/week in months 12-24, and 25 microg/week in months 24-36 to substitute for the deficiency in a 27-year-old homozygous male with a mutation on the CYP19 gene. Estradiol levels increased from<10 at baseline to 45, 12, 27 and 17 pg/ml (normal range 10-50) after 6, 12, 24 and 36 months, and inversely correlated to LH and FSH levels. Testosterone levels changed from 31.2 nmol/l at baseline to 3.8, 22.1, 7.1 and 22.0 nmol/l (9.5-30) after 6, 12, 24 and 36 months, respectively, and correlated closely to basal and stimulated LH and FSH levels at 100 microg GnRH. Bone maturation progressed, and metacarpal and phalangeal epiphysis closed after 12 months. Spongiosa-hydroxyapatite of the radius assessed by quantitative computed tomography changed from 52 to 83, 51, 69 and 71 mg/cm3 (120-160); bone mineral density of the lumbar spine assessed by dual energy X-ray-absorptiometry (normal value>1.150) increased from 0.971 (T-Score -2.24) to 1.043 (-1.64), 1.065 (-1.46), 1.128 (-0.93) g/cm2 and 1.021 (-1.82) after 6, 12, 24 and 36 months of TE, respectively. Osteocalcin as a bone formation parameter and aminoterminal collagen type I telopeptide as a bone resorption parameter increased during high-dose estrogen supplementation, and then decreased during the lower doses. Lipoprotein (a) increased from 20 mg/dl at baseline to 60 and 62 mg/dl after 6 and 12 months, and then decreased to 24 and 25 mg/dl after 24 and 36 months, respectively, while total cholesterol, HDL, LDL and triglycerides did not change. AUC glucose decreased continuously after oral glucose load, and HOMA IR reached its lowest value the 75 microg weekly estradiol dose. This study confirms the role of estrogens in achieving bone mineralization and maturation in human males. Additionally, estradiol has dual negative feedback sites that on the hypothalamus to decrease GnRH pulse frequency, and on the pituitary to decrease responsiveness to GnRH. The improvement in glucose metabolism after estrogen replacement therapy suggests a probable role of sex steroids in insulin sensitivity. The optimal weekly dose of transdermal estrogen replacement for normalizing estrogen levels and maintain bone mass in adult males with aromatase deficiency may be 50-75 microg spread over two doses.

Effects of a combination of rhGH and metformin on adiponectin levels in patients with metabolic syndrome.

Adiponectin is a recently discovered adipocytokine that correlates negatively with body mass index and body fat. In patients with GH deficiency, treatment with recombinant human growth hormone (rhGH) reduces body fat mass and thus may also have a favorable effect in patients with metabolic syndrome, and would also be expected to increase adiponectin levels. However, due to its diabetogenic effect, rhGH treatment also bears an increased risk for the development of type 2 diabetes mellitus. We conducted a 18-month randomized, double-blind, placebo-controlled study to assess the effect of rhGH in combination with metformin (MGH) in 14 obese men (7 MGH; 7 Metformin+Placebo, 54 +/- 2 years, BMI 33.0 +/- 1.2 kg/m(2)) with mildly elevated fasting plasma glucose (FPG) at screening (6.1-8.0 mmol/l). All patients received metformin (850 mg twice daily) for treatment of type 2 diabetes mellitus/impaired glucose tolerance, either alone or in combination with rhGH (daily dose 9.5 mug/kg body weight). Glucose disposal rate (GDR) was measured using the euglycemic hyperinsulinemic clamp technique, and body composition was measured by DEXA at 0 and 18 months. After 18 months, the mean adiponectin concentration increased by 32 +/- 11 % (p = 0.018) in the MGH group and did not change in the MP group (- 10 +/- 13 %; p = n. s.). The difference in relative changes in adiponectin levels between the two groups after 18 months was statistically significant (p = 0.026). Improvement in insulin sensitivity (GDR) correlated positively with adiponectin levels (r = 0.73; p = 0.004). In conclusion, the additional administration of rhGH increased adiponectin levels in patients with metabolic syndrome, indicating its potential role in adiponectin-associated insulin sensitivity alterations.

Clinical and biochemical characterization of women with polycystic ovary syndrome in North Rhine-Westphalia.

Polycystic ovary syndrome (PCOS), defined as the combination of oligoanovulation and hyperandrogenism, affects more than 5% of women of reproductive age. Insulin resistance and hyperinsulinemia appear to play an important role in its pathogenesis. Here, we will present a characterization of a PCOS cohort from North Rhine-Westphalia in Germany. Clinical features, family history as well as endocrine and metabolic parameters were prospectively recorded from 200 successive patients. All patients were evaluated for insulin resistance and beta-cell-function by oral glucose tolerance test. Patient data were compared with those of 98 age-matched control women. PCOS patients showed significantly higher BMI, body fat mass and androgen levels as well as impaired glucose and insulin metabolism. A positive family history of PCOS and diabetes was more frequent in PCOS patients. Insulin resistance (71%) was the most common metabolic abnormality in PCOS patients followed by obesity (52%) and dyslipidemia (46.3%), with an incidence of 31.5% for the metabolic syndrome. C-reactive protein and other cardiovascular risk factors were frequently elevated even in young PCOS patients. While the clinical characteristics and endocrine parameters of this German PCOS cohort were heterogeneous, they were comparable to those from other Caucasian populations.

[Hypophyseal coma]. / Das hypophysäre Koma.

Pituitary coma is a rare case of emergency and primarily due to ACTH and TSH deficiency. Pituitary coma occurs more often in patients with well-known pituitary deficiency than in patients with intrasellar tumor. Clinical manifestations are hypotonia, bradycardia, decreased skin and nipple pigmentation, muscle weakness, vomitus, nausea, obstipation, hypothermia, and hypoventilation. A postpartal agalactia is often the first sign of Sheehan's syndrome. Unlike primary adrenal insufficiency (Addison's disease) ACTH deficiency does not cause hyperpigmentation, hyperkalemia, or salt loss. The suspicion of pituitary coma requires replacement with 100 mg hydrocortisone iv, 200 mg hydrocortisone iv/24 h, 500 micro g levothyroxine iv and fluid substitution. Since thyroxine accelerates the degradation of cortisol and can precipitate adrenal crisis in patients with limited pituitary reserve, hydrocortisone replacement should always precede levothyroxine therapy. ACTH stimulation test, CRH stimulation test and insulin tolerance test (optional) should be performed after therapeutic compensation to determine pituitary function.

[Rhabdomyolysis, hyponatremia and fever in a patient with Schmidt's syndrome]. / Rhabdomyolyse, Hyponatriämie und Fieber bei einem Patienten mit Schmidt-Syndrom.

HISTORY: A 38-year-old man had fever (40 degrees C) and a swollen right leg. Two weeks before admission he had received non-steroid anti-inflammatory drugs (paracetamol and ibuprofen) after a tooth extraction. Some weeks before he had noticed a rough voice and a dry skin. INVESTIGATIONS: The patient had a sinus tachycardia of 145/min (blood pressure of 130/80 mm Hg). Laboratory data revealed a CK of 16,650 U/l (< 80 U/l), myoglobin of 2420 U/l (< 90 microg/l) and LDH of 1250 U/l (<240 U/l), leukocyte count of 12,000 / microl and C-reactive protein of 3.0 mg/dl (<0.5 mg/dl). Sodium was markedly decreased (110 mmol/l (135 - 145 mmol/l)). Determination of thyroid hormone showed primary hypothyroidism with an elevated TSH of 62.6 mU/l (0.3 - 4.0 mU/l); T4 of 38 nmol/l (58 - 154 nmol/l), T3 1.17 of nmol/l (1.23 - 3.08 nmol/l) and fT4 of 6 pmol/l (10 - 25 pmol/l). The thyroid autoantibodies were increased (thyroxine peroxidase antibodies of 684 U/l (<35 U/l) and thyroglobulin antibodies of 173 U/l (<40 U/l)). Ultrasound of the thyroid revealed an nonhomogeneous structure. Cortisol at 8.00 a. m. was reduced by 63 mmol/l (180 - 640 mmol/l) and did not increase after administration of ACTH (60 min. cortisol at 90 mmol/l (>550 mmol/l)). ACTH was increased (141 pg/ml; normal range 17 - 52 pg/ml). TREATMENT AND COURSE: The initial therapy consisted of hydrocortisone (100 mg i.v as bolus and 100 mg during the next 24 hours) and levothyroxine replacement (200 micro g) was initiated. During the following 8 days clinical symptoms regressed. Values of sodium, myoglobin and LDH decreased. After therapy with cephalosporin (Ceftriaxon) and penicillin (Flucloxacillin) fever and inflammation parameters decreased. CONCLUSION: This is a rare case of a rhabdomyolysis and hyponatriaemia due to hypothyroidism and Addison's disease (Schmidt's syndrome).

Effects of a combination of recombinant human growth hormone with metformin on glucose metabolism and body composition in patients with metabolic syndrome.

Abdominal obesity and insulin resistance are central findings in metabolic syndrome. Since treatment with recombinant human growth hormone (rhGH) can reduce body fat mass in patients with organic GH deficiency, rhGH therapy may also have favourable effects on patients with metabolic syndrome. However, due to the highly increased risk for type 2 diabetes in these patients, strategies are needed to reduce the antagonistic effect of rhGH against insulin. We conducted a 18-month randomised, double-blind, placebo-controlled study to assess the effect of rhGH in combination with metformin (Met) in patients with metabolic syndrome. 25 obese men (55 +/- 6 years, BMI 33.4 +/- 2.9 kg/m (2)) with mildly elevated fasting plasma glucose (FPG) levels at screening (6.1-8.0 mmol/l) were included. All patients received metformin (850 mg twice daily) either alone or in combination with rhGH (daily dose 9.5 microg/kg body weight). An oGTT was performed at baseline, after 6 weeks, and after 3, 6, 12, and 18 months of therapy. Glucose disposal rate (GDR) was measured by euglycemic hyperinsulinemic clamp at 0 and 18 months and body composition was measured by DEXA every 6 months. In the Met + GH group, IGF-I increased from 146 +/- 56 microg/l to 373 +/- 111 microg/l (mean +/- SD) after 3 months and remained stable after that. BMI did not change significantly in either group during the study. Total body fat decreased by -4.3 +/- 5.4 kg in the Met + GH group and by -2.7 +/- 2.9 kg in the Met + Placebo group (differences between the two groups: p = n. s.). Waist circumference decreased in both groups (Met + GH: 118 +/- 8 cm at baseline, 112 +/- 10 cm after 18 months; Met + Placebo: 114 +/- 7 cm vs. 109 +/- 8 cm; differences between the two groups: p = 0.096). In the Met + GH group, FPG increased significantly after 6 months (5.9 +/- 0.7 vs. 6.7 +/- 0.4 mmol/l; p = 0.005), but subsequently decreased to baseline levels (18 months: 5.8 +/- 0.2 mmol/l). FPG remained stable in the Met + Placebo group until 12 months had elapsed, and then slightly decreased (baseline: 6.2 +/- 0.3, 18 months: 5.5 +/- 0.6 mmol/l, p = 0.02). No significant changes were seen in either group regarding glucose and insulin AUC during oGTT or HbA (1c) levels. GDR at 18 months increased by 20 +/- 39% in Met + GH-group and decreased by -11 +/- 25% in the Met + Placebo group (differences between the two groups: p = 0.07). In conclusion, treatment of patients with metabolic syndrome and elevated FPG levels did not cause sustained negative effects on glucose metabolism or insulin sensitivity if given in combination with metformin. However, since our data did not show significant differences between the two treatment groups with respect to body composition or lipid metabolism, future studies including larger numbers of patients will have to clarify whether the positive effects of rhGH on cardiovascular risk factors that have been shown in patients with GH deficiency are also present in patients with metabolic syndrome, and are additive to the effects of metformin.

[Transsphenoidal hypophysectomy of a patient with an ACTH-producing pituitary adenoma and an "empty sella" after pretreatment with etomidate]. / Transsphenoidale Hypophysektomie bei einer Patientin mit einem ACTH-produzierenden Hypophysenadenom und einer "empty Sella" nach Vorbehandlung mit Etomidat.

HISTORY AND ADMISSION FINDINGS: A seventy-year-old woman was admitted to our hospital under suspicion of an adrenal Cushings's syndrome. Initial laboratory values showed elevated cortisol (834 nmol/l; normal: 180-640) which could not be suppressed after administration of 2 mg dexamethasone (632 nmol/l). Computed tomography of the abdomen showed a 19 x 34 mm mass in the region of the left adrenal gland. INVESTIGATIONS: ACTH levels were normal (42 ng/ml; 17-52). Serum cortisol remained high at 1021 nmol/l after administration of 8 mg dexamethasone. Four more doses of 2 mg dexamethasone were applied on 3 consecutive days, leading to a mild suppression of serum cortisol to 705 nmol/l, with urine cortisol levels dropping from 1915 to 101 nmol/l/24 h. The CRH-test produced a rise of serum cortisol from 895 to 1475 nmol, with ACTH rising from 42 to 68 pg/ml, a laboratory constellation consistent with the diagnosis of centrally located Cushing's syndrome (Cushing's disease). MRI failed to show an adenoma of the pituitary gland so that sinus petrosus sampling was done to confirm the diagnosis (ACTH central/peripheral 7:1; normal range < 2:1). TREATMENT AND COURSE: Serum cortisol rose to 1070 nmol/l and the patient developed pneumonia and contracted tinea. Prior to surgery we lowered the excessive cortisol levels with etomidate and successfully treated the pneumonia with antibiotics. Postoperatively clinical symptoms of Cushing's syndrome disappeared. The patient now presented with total insufficiency of the anterior pituitary. CONCLUSION: Exact hormone testing that may involve sinus petrosus sampling is necessary in diagnosing Cushing's syndrome. Even if radiological procedures cannot show an adenoma of the pituitary, transsphenoidal resection should be considered. Etomidate can lower excessive cortisol levels in seriously ill patients.