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Otto Wegelius and B.-A. Lamberg

ABSTRACT

The localization of 35S-labelled sulphate in the retrobulbar connective tissue and Harder's glands of untreated and thyrotrophin stimulated guinea-pigs was autoradiographically determined. Uptake of sulphate was observed in the mast cells, in the metachromatic connective tissue ground substance, in the cells of Harder's gland, and in the secretion of the latter of untreated as well as of stimulated animals. The secretory activity seemed to be due to thyrotrophic hormone stimulation.

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Otto Wegelius, G. Asboe-Hansen and B.-A. Lamberg

The histological changes in the retrobulbar connective tissue of patients with malignant exophthalmos have been thoroughly investigated. Most authors are in agreement about the character of the changes (Aird, 1940, Brain & Turnbull, 1938, Dobyns, 1946 a, b, Falconer & Alexander, 1952, Friedenwald, 1932, Merrill & Oakes, 1933, Mulvany, 1944, Naffziger, 1933, Smelser, 1937, 1939), but the cause and genesis of the tissue changes have been matters of dispute. Smelser (1937) pointed out the resemblance between the picture in malignant exophthalmos in man and in the thyrotrophin-induced changes in the guinea pig. It is evident (Paulson, 1937) that the water-binding properties of the retrobulbar tissue are increased in exophthalmos. These augmented water-binding properties could be explained by the investigations of Asboe-Hansen & Iversen (1951) and Ludwig et al. (1950). These investigators showed that the ground substance of the retrobulbar connective tissue, and especially the mucopolysaccharide hyaluronic acid, was definitely increased

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B Otto, M Tschop, W Heldwein, AF Pfeiffer and S Diederich

OBJECTIVE: The orexigenic and adipogenic peptide hormone ghrelin is predominantly produced and secreted by the stomach and seems to transduce changes in food intake to specific neuronal circuits in the brain. The activity of ghrelin also includes stimulatory effects on the corticotropic system. However, little is known about the influence of glucocorticoids on ghrelin levels. We therefore studied human plasma ghrelin levels in the presence and absence of elevated glucocorticoid levels of either endogenous or exogenous origin. METHODS: Plasma ghrelin levels were measured in five patients with chronic hypercortisolism (aged 29-58, median 46 years) due to Cushing's syndrome before and after successful surgery for the adenoma, and in eight healthy controls (aged 24-39, median 27.5 years) before and after 30 mg prednisolone (for 5 days) once a day in the morning (median body mass index (BMI) 22.7 kg/m(2)). Plasma ghrelin levels were measured with a commercially available radioimmunoassay. RESULTS: In patients with Cushing's syndrome, plasma ghrelin levels were low (median 363.2 pg/ml, range 161.9-525.7 pg/ml) and significantly increased by 26.6% (P=0.04) after successful surgery, while BMI decreased (median 26.2-24.0 kg/m(2), P=0.04). A strong negative correlation (r=-0.9, P=0.04) between changes in BMI and plasma ghrelin was observed. In healthy controls, plasma ghrelin levels (median 288.7 pg/ml, range 119.6-827.8 pg/ml) were significantly suppressed by 18.3% (P=0.04) after prednisolone treatment. CONCLUSIONS: We have shown for the first time that plasma ghrelin levels are decreased under endogenously or exogenously induced hypercortisolism, making ghrelin an unlikely candidate for causing the changes in energy balance or body composition characteristic of Cushing's disease. However, the reduced ghrelin secretion could reflect a compensation mechanism in reaction to the metabolic consequences of chronic hypercortisolism.

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Jens Otto L. Jørgensen, Werner F. Blum, Niels Møller, Michael B. Ranke and Jens S. Christiansen

Abstract.

Knowledge of the circadian patterns of serum IGF-I I and the large molecular weight IGF binding protein, IGFBP-3 might, apart from its physiological relevance, be of clinical interest, inasmuch as measurements of these parameters are being introduced into the evaluation of GH deficiency. We therefore evaluated the 24-h (08.00-08.00 h) patterns of serum IGF-II and IGFBP-3 in 8 GH-deficient patients who were studied during three periods when receiving 1. GH (2 IU) at 20.00 h; 2. GH (2 IU) at 08.00 h and 3. no GH. For comparison, 10 age- and sex-matched untreated healthy subjects were studied once under similar conditions. The serum IGF-II levels of the patients were relatively stable over the 24-h periods, yielding mean levels which were significantly lower during no GH: 553±78 (evening GH), 554±54 (morning GH), and 429±65 μg/l (no GH). The mean IGF-II level in the normal subjects was 635±29 μg/l, which was significantly higher than in either patient study. Similarly, stable 24-h levels of IGFBP-3 were recorded in all studies. The mean IGFBP-3 level of the patients was significantly lower when they received no GH, and the mean level in the healthy subjects was higher than in any of the patient studies: 1853±301 (no GH), 2755 ± 317 (evening GH), 2904±269 (morning GH), and 3856±186 μg/l (healthy subjects). However, minute but significant changes over time, characterised by slight decrements at night, were observed for both parameters in several of the studies. Nevertheless, since both IGF-II and IGFBP-3 display rather stable 24-h levels in the individual, it is concluded that measurements of these parameters in evaluation of growth retardation can be based on a single daytime sample.

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J Roemmler, B Otto, A M Arafat, M Bidlingmaier and J Schopohl

Introduction

Pegvisomant (peg) is a GH receptor antagonist. In de novo acromegalic patients with high GH levels, ghrelin and leptin levels are reduced, suggesting a direct GH-mediated effect. The aim of our study was to evaluate whether peg treatment in acromegalic patients may abolish the GH impact on ghrelin and leptin levels.

Methods

Ghrelin, leptin and endogenous GH were measured in ten peg-treated acromegalic patients (three females/seven males, 47 years (28–57)), ten patients with active (act) and ten patients with inactive disease (inact) as well as in ten gender-, age- and body mass index (BMI)-matched healthy volunteers (controls). Endogenous GH was measured using a special in-house assay without interference by peg; total ghrelin and leptin were determined using a commercial RIA and an immunofluorometric in-house assay respectively.

Results

Age and BMI did not differ significantly between groups. Endogenous GH was significantly higher in peg (6.3 μg/l (1.5–41)) and act (9.3 μg/l (1.7–70)) compared with controls (0.1 μg/l (0.1–3.1)) and inact (0.35 μg/l (0.1–2.0), P<0.001). Ghrelin was significantly higher in peg (232 ng/l (96–351)) compared with act (102 ng/l (33–232), P<0.01), whereas ghrelin was not significantly different between the other groups. Leptin was highest in controls (19 μg/l (4–57)) and lowest in act (6 μg/l (2–21)), but this difference did not reach significance.

Conclusion

Treatment with peg seems to disrupt the feedback loop of ghrelin and GH, leading to elevated ghrelin levels. Furthermore, peg therapy appears not to have a strong impact on leptin levels, as acromegalic patients with and without peg treatment showed similar leptin levels.

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Lars-Eric Edqvist, Lars Ekman, Börje Gustafsson, Sten-Olof Jacobsson, Elof D. B. Johansson and Jan-Otto Lindell

ABSTRACT

Eight pregnant cows of the Swedish Red and White Breed were used. Four cows at 248–250 days of pregnancy received 10 or 20 mg of dexamethasone1) intramuscularly and a second dose equal to the first 3 to 6 days later. Two cows at day 75 and two cows at days 147 and 150 of pregnancy received daily injections of 40 mg of dexamethasone for 7 to 12 days. All late pregnant cows delivered living calves 12 to 68 hours after the second injection. One cow at day 150 of pregnancy aborted on the 6th day from the start of treatment. In all the other cows dead foetuses were found.

An increase in oestrone and a decrease in progesterone in peripheral blood plasma were observed in all late pregnant cows after the dexamethasone treatment. The increase in oestrone preceded the decrease in progesterone. The cow pregnant for 150 days which aborted showed decreased plasma levels of progesterone before abortion. No pronounced changes in the levels of progesterone were observed in the other three early pregnant cows. The peripheral plasma levels of oestrone showed no increase in any of the early and mid-term pregnant cows.

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John F. Dymling, Otto Ljungberg, Carmel J. Hillyard, Peter B. Greenberg, Imogen M. A. Evans and lain MacIntyre

ABSTRACT

Oral whisky is a potent stimulus of calcitonin secretion. Peak increments of immunoreactive calcitonin are observed within 15 min after the ingestion of 50 ml of whisky; the magnitude of the response is similar to that observed during a four-hour calcium infusion. This procedure has several advantages over standard methods of stimulating calcitonin release in patients at risk of developing medullary carcinoma of the thyroid, and this is shown by a study in a large family with familial chromaffinomatosis.

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B Otto, U Cuntz, E Fruehauf, R Wawarta, C Folwaczny, RL Riepl, ML Heiman, P Lehnert, M Fichter and M Tschop

OBJECTIVE: Ghrelin is a new gastric hormone that has been identified as an endogenous ligand for the growth hormone (GH) secretagogue receptor subtype 1a (GHS-R1a). Ghrelin administration however not only stimulates GH secretion but also induces adiposity in rodents by increasing food intake and decreasing fat utilization. We hypothesized that impaired ghrelin secretion in anorexia nervosa may be involved in the pathogenesis of this eating disorder. To examine this hypothesis and to further investigate the role for ghrelin in regulating energy homeostasis, we analyzed circulating ghrelin levels in patients with anorexia nervosa and examined possible correlations with clinical parameters before and after weight gain. METHODS: Plasma ghrelin levels were measured in overnight fasting plasma samples from 36 female patients with anorexia nervosa (age: 25.0+/-1.2 years, BMI: 15.2+/-0.2 kg/m(2)) before and after weight gain following psychotherapeutic treatment intervention in a psychosomatic institution. Plasma ghrelin levels were also measured in fasting plasma samples from 24 age-matched female controls (31+/-1.4 years, BMI: 22.9+/-0.45 kg/m(2)). For quantification of ghrelin levels a commercially available radioimmunoassay (Phoenix Pharmaceuticals, USA) was used. RESULTS: Fasting plasma ghrelin levels in anorectic patients were significantly higher (1057+/-95 pg/ml) than in normal age-matched female controls (514+/-63 pg/ml n=24, P=0.02). Therapeutic intervention in a psychosomatic institution caused an BMI increase of 14% (P<0.001) leading to a significant decrease in circulating ghrelin levels of 25%, (P=0.001). A significant negative correlation between Deltaghrelin and DeltaBMI was observed (correlation coefficient: -0.47, P=0.005, n=36). CONCLUSION: We show for the first time that fasting plasma levels of the novel appetite-modulating hormone ghrelin are elevated in anorexia nervosa and return to normal levels after partial weight recovery. These observations suggest the possible existence of ghrelin resistance in cachectic states such as caused by eating disorders. Future studies are necessary to investigate putative mechanisms of ghrelin resistance such as a possible impairment of intracellular ghrelin receptor signaling in pathophysiological states presenting with cachexia.

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J Roemmler-Zehrer, V Geigenberger, S Störmann, M Losa, V Crippa, B Otto, M Bidlingmaier, C Dimopoulou, G K Stalla and J Schopohl

Introduction

Patients with craniopharyngioma (CP) have disturbances of the hypothalamic–pituitary axis and serious comorbidities such as obesity. We hypothesized that the secretion of hormones regulating the nutritional status is altered in adult patients with CP compared with patients with non-functioning pituitary adenoma (NFPA).

Methods

We included 40 CP (50% males, mean age: 49.6±14.3 years) and 40 NFPA (72.5% males, mean age: 63.4±9.8 years) patients. We measured glucose, insulin, leptin, total ghrelin, peptide-YY (PYY) and cholecystokinin (CCK) during oral glucose tolerance test (OGTT). Fat mass (FM) was determined by dual X-ray absorptiometry.

Results

Gender distribution was not significantly different, but CP patients were significantly younger (P<0.001). CP patients had significantly higher BMI and FM than NFPA patients (BMI 32±8 vs 28±4 kg/m2, P=0.009 and FM 37±9 vs 33±9%, P=0.02). Fasting glucose level (84±12 vs 78±11 mg/dl, P=0.03), leptin (27.9±34.2 vs 11.9±11.6 μg/l, P=0.008) and leptin levels corrected for percentage FM (0.66±0.67 vs 0.32±0.25 μg/l%, P=0.005) were significantly higher in CP than in NFPA patients, whereas ghrelin was significantly lower (131±129 vs 191±119 ng/l, P=0.035). Insulin, PYY and CCK did not differ significantly between groups. After glucose load, leptin decreased significantly in CP patients (P=0.019). In both groups, ghrelin decreased significantly during OGTT (both P<0.001). The percentage decline was significantly smaller for CP. PYY and CCK increased equally after glucose in both groups.

Conclusion

Our patients with CP have more metabolic complications than our patients with NFPA. The levels of leptin and ghrelin at fasting status and after glucose seem to be altered in CP, whereas changes in insulin, PYY and CCK do not seem to be responsible for the metabolic changes in these patients.

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M A Arafat, B Otto, H Rochlitz, M Tschöp, V Bähr, M Möhlig, S Diederich, J Spranger and A F H Pfeiffer

Objective: It is well known that i.m. glucagon administration stimulates GH and cortisol release in humans, although the mechanisms are unclear. These effects are similar to those described for ghrelin on somatotroph and corticotroph function. The aim of the present study was to investigate the role of ghrelin in mediating the stimulatory effects of glucagon and to evaluate the effect of glucagon on ghrelin secretion.

Design and methods: We studied the endocrine and metabolic response to i.m. glucagon administration in 24 subjects (14 men, 10 women; age 19–65 years; body mass index, 25.3 ± 1 kg/m2), who were shown to have an intact anterior pituitary function as evaluated before enclosure.

Results: Serum ghrelin concentrations fell significantly at 30, 60, 120 and 180 min after glucagon administration (means ± s.e.m.; baseline, 377.9 ± 34.5 pg/ml; nadir, 294.6 ± 28.3 pg/ml (60 min); P < 0.01). Conversely, i.m. glucagon elicited an increase in GH (baseline, 1.5 ± 0.4 μg/l; peak, 14.2 ± 2.7 μg/l (180 min); P < 0.01) and cortisol concentrations (baseline, 452.6 ± 35.2 nmol/l; peak, 622.1 ± 44 nmol/l (180 min); P < 0.01). The changes in ghrelin concentration at both 120 and 180 min were still significant after correction for glucose and insulin (P < 0.05).

Conclusions: We show that i.m. glucagon decreases ghrelin significantly. Therefore, the already known stimulatory effects of i.m. glucagon on cortisol and GH are not mediated by a change in ghrelin concentrations. The mechanisms underlying the ghrelin suppression after i.m. glucagon are unlikely to include glucose or insulin variations and need to be further elucidated.