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Ulrich Renner, Uberto Pagotto, Eduardo Arzt, and Günter Karl Stalla

Renner U, Pagotto U, Arzt E, Stalla GK. Autocrine and paracrine roles of polypeptide growth factors, cytokines and vasogenic substances in normal and tumorous pituitary function and growth: a review. Eur J Endocrinol 1996;135:515–32. ISSN 0804–4643

In addition to the classical hormones, the production of numerous polypeptide growth factors, cytokines, vasogenic substances and neuropeptides by pituitary cells has been demonstrated. Expression of the corresponding receptors on pituitary cells enables these factors to influence growth and function of the pituitary by auto- or paracrine mechanisms. Thus, in addition to the external endocrine control of pituitary growth and function, an intrinsic intercellular communication network seems to be involved in the control of pituitary homeostasis. The cell-to-cell communication may be of importance for the pre- and postnatal differentiation of the pituitary, for the regulation of the cellular composition of the gland (by balancing mitosis and apoptosis and controlling angiogenesis) and for the adaption of pituitary function to altered physiological conditions (i.e. stress, pregnancy and diseases). Differences in the expression of or the response to the above-mentioned factors in pituitary adenomas indicate that these substances are of importance for pituitary tumorigenesis. Disturbances of auto-/paracrine mechanisms may not necessarily be involved in the tumor initiation processes, but they may play a crucial role in tumor progression. After the initial transformation, the clonal expansion of the tumor cell is dependent on its ability to escape either from the inhibitory action of growth suppressing factors or to develop an autocrine mechanism that allows autonomous growth. In summary, therefore, this review outlines the potential role of polypeptide growth factors, cytokines and vasogenic peptides as auto-/paracrine-acting substances in normal pituitary and pituitary adenomas.

Ulrich Renner, Max-Planck-Institute of Psychiatry, Clinical Institute, Department of Endocrinology, Kraepelinstr. 10, D-80804 Munich, Germany

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Günter K Stalla, Steffi J Brockmeier, Ulrich Renner, Chris Newton, Michael Buchfelder, Johanna Stalla, and O Albrecht Müller

Stalla GK, Brockmeier SJ, Renner U, Newton C, Buchfelder M, Stalla J, Müller OA. Octreotide exerts different effects in vivo and in vitro in Cushing's disease. Eur J Endocrinol 1994;130:125–31. ISSN 0804–4643

The effect of the long-acting somatostatin analog octreotide (SMS 201-995) on adrenocorticotropin (ACTH) secretion was studied in five patients with untreated Cushing's disease in vivo and in six human corticotropic adenoma cell cultures in vitro. For the in vivo study, 100 μg of octreotide sc was given 30 and 180 min after cannulation of the cubital vein and 100 μg of corticotropin-releasing hormone (CRH) was injected iv at 210 min. Serum ACTH and cortisol levels were measured for 390 min. In vivo, octreotide had no significant effect either on basal or CRH-stimulated ACTH levels and did not influence cortisol levels. The in vitro studies were conducted with corticotropic adenoma cell cultures derived from adenoma tissue obtained from six patients with Cushing's disease. In four of six cell cultures, octreotide (1 nmol/l–1 μmol/l) inhibited basal ACTH secretion in a dose-dependent manner. The inhibition ranged from 70 to 92% for 1 nmol/l octreotide to 14–46% for 1 μmol/l octreotide as compared to controls (100%). In three of three octreotide-responsive adenoma cell cultures investigated, CRH-stimulated ACTH secretion was suppressed by octreotide. Hydrocortisone pretreatment in vitro abolished the inhibitory effect of octreotide on ACTH secretion in one octreotide-responsive corticotropic adenoma cell culture. In conclusion, we showed that octreotide in most cases could inhibit the ACTH release from human corticotropic adenoma cells in vitro but had no suppressive effect on ACTH levels of patients with Cushing's disease in vivo. This discrepancy could be due to a somatostatin receptor down-regulation by cortisol at the hypercortisolemic state in vivo.

Günter K Stalla, Max-Planck-Institute of Psychiatry, Clinical Institute, Kraepelinstr. 10, D-80804 Munich, Germany

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Marco Losa, Lilian Bock, Jochen Schopohl, Günter K. Stalla, O. Albrecht Müller, and Klaus von Werder

Abstract. To evaluate the dynamics of GH-secretion after infusion of growth hormone releasing factor, human pancreatic growth hormone releasing factor (hpGRF1-44) was infused over 2 and 5 h at a dosage of 100 μg hpGRF1-44/h into 11 healthy subjects. The infusion was started and terminated with a 50 μg hpGRF1-44 bolus injection. In 5 subjects 200 μg TRH was given 4 h after starting the infusion. In addition, 4 healthy subjects received 50 μg hpGRF1-44 bolus injection every 2 h. GRF, somatostatin, GH, Prl, and TSH were measured by radioimmunoassay.

The initial 50 μg GRF bolus increased GH-levels in all 11 subjects with a maximum at 30 min (24.1 ± 5.1 ng/ml ± se). However, though hpGRF1-44 was continuously infused and GFR-levels remained elevated, GH decreased to a minimum 270 min after start of infusion (2.6 ± 0.6 ng/ml). The GH-response to the second bolus at the end of the infusion was lower compared to the first response (14.6 ± 3.4 ng/ml after 2 h and 7.6 ± 2.5 ng/ml after 5 h). TRH did not lead to a GH-increase during hpGRF1-44 infusion though Prl and TSH rose normally. The intermittent bolus injection of 50 μg hpGRF1-44 led to continuously decreasing GH-responses to the same GRF-dosage (I. bolus: 16.5 ± 1.6 ng/ml; II. bolus: 4.2 ± 0.8 ng/ml; III. bolus: 3.4 ± 0.5 ng/ml). No change in somatostatin levels was observed.

These findings show that GRF infusion or bolus injection in short intervals does not sustain elevated GH-levels. Pituitary GH is either not readily available for continuous GRF-stimulation or GH-secretion may be antagonized by increasing portal somatostatin levels which are not reflected in the peripheral circulation.

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Ulrich Renner, Juri Mojto, Manfred Lange, O Albrecht Müller, Klaus von Werder, and Günter K Stalla

Renner U, Mojto J, Lange M, Albrecht Müller O. von Werder K, Stalla GK. Effect of bromocriptine and SMS 201-995 on growth of human somatotrophic and non-functioning pituitary adenoma cells in vitro. Eur J Endocrinol 1994;130:80–91. ISSN 0804–4643

The effect of the dopamine agonist bromocriptine and the somatostatin analog SMS 201-995 on growth of 12 human somatotrophic and 13 non-functioning adenoma cell cultures was investigated. When adenoma cells were maintained in medium supplemented with 5% fetal calf serum. cell counts of 10 of 12 somatotrophic cultures increased to 145±6 and 171 ±9% (mean±sd) and in 12 of 13 non-functioning cell cultures up to 125±12 and 217±15% after 3 days of incubation. In most cases bromocriptine and SMS 201-995 dose dependently (1 nmol/l to 10 μmol/l) inhibited adenoma cell growth but there was only (1.10 μmol/l) a significant inhibitory effect at high doses of both drugs. A 1 μmol/l concentration of bromocriptine decreased cell counts of 5 of 12 somatotrophic cell cultures (range 84±3 to 76±6% vs control = 100%) and in 5 of 13 non-functioning cell cultures (range 85±4 to 71 ± 7%). A 10 μmol/l concentration of bromocriptine decreased cell counts in all 12 somatotrophic (range 87±1 to 61 ±8%) and in 12 of 13 non-functioning adenoma cultures (range 87±6 to 57±3%). Bromocriptine specifically inhibited growth because its effect could be reversed by the dopamine D2-receptor antagonist haloperidol. Both 1 and 10 μmol/l SMS 201-995 significantly decreased cell counts in three of six somatotrophic (87± 3 to 38 ±3%) cell cultures. In two of five cases growth of non-functioning adenoma cultures was suppressed by 1 μmol/ISMS 201-995, and in four of five cases by 10 μmol/l(86± 3 to 74 ±4%). The growth inhibitory effect of both bromocriptine and SMS 201-995 was not just due to an effect on growth of fibroblasts contaminating the adenoma cell cultures, because it could be observed also when adenoma cells were maintained in a d-valine-supplemented medium that suppresses fibroblast growth. In summary, both bromocriptine and SMS 201-995 at high doses were able to inhibit cell growth of cultured somatotrophic and non-functioning adenomas in vitro. However, the mechanism of this inhibitory effect is not yet well understood.

Ulrich Renner, Max-Planck-Institute of Psychiatry, Clinical Institute, Kraepelinstr. 10, D-80804 Munich, Germany

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Bernhard Mayr, Rolf Buslei, Marily Theodoropoulou, Günter K Stalla, Michael Buchfelder, and Christof Schöfl

Objective

GH-producing pituitary adenomas display two distinct morphological patterns of cytoplasmic GH-containing secretory granules, namely the densely and sparsely granulated somatotroph adenoma subtype. It is unknown whether these morphological variants reflect distinct pathophysiological entities at the molecular level.

Methods

In 28 GH-producing adenoma tissues from a consecutive set of patients undergoing pituitary surgery for acromegaly, we studied the GH granulation pattern, the expression of somatostatin receptor subtypes (SSTR) as well as the calcium, cAMP and ZAC1 pathways in primary adenoma cell cultures.

Results

The expression of GSP oncogene was similar between densely and sparsely granulated somatotroph adenoma cells. There were no differences in the calcium, cAMP and ZAC1 pathways as well as in their regulation by SSTR agonists. SSTR2 was exclusively expressed in densely but not in sparsely granulated tumours (membrane expression 86 vs 0%; cytoplasmic expression 67 vs 0%). By contrast, expression of SSTR5 was only found in sparsely but not in densely granulated somatotroph adenomas (membrane expression 29 vs 0%; cytoplasmic expression 57 vs 0%).

Conclusions

Our results indicate that different granulation patterns in GH-producing adenomas do not reflect differences in pathways and factors pivotal for somatotroph differentiation and function. In vitro, the vast majority of both densely and sparsely granulated tumour cells were responsive to SSTR activation at the molecular level. Sparsely granulated adenomas lacking SSTR2, but expressing SSTR5, might be responsive to novel SSTR agonists with increased affinity to SSTR5.

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Michael Droste, Julia Domberg, Michael Buchfelder, Klaus Mann, Anja Schwanke, Günter Stalla, and Christian J Strasburger

Objective

Acromegaly is associated with an increased prevalence of glucose metabolism disorders. Clinically confirmed diabetes mellitus is observed in approximately one quarter of all patients with acromegaly and is known to have a worse prognosis in these patients.

Design

Of 514 acromegalic patients treated with pegvisomant and recorded in the German Cohort of ACROSTUDY, 147 had concomitant diabetes mellitus. We analysed these patients in an observational study and compared patients with and without concomitant diabetes.

Results

Under treatment with pegvisomant, patients with diabetes mellitus rarely achieved normalisation (64% in the diabetic cohort vs 75% in the non-diabetic cohort, P=0.04) for IGF1. Diabetic patients normalised for IGF1 required higher pegvisomant doses (18.9 vs 15.5 mg pegvisomant/day, P<0.01). Furthermore, those diabetic patients requiring insulin therapy showed a tendency towards requiring even higher pegvisomant doses to normalise IGF1 values than diabetic patients receiving only oral treatment (22.8 vs 17.2 mg pegvisomant/day, P=0.11).

Conclusions

Hence, notable interdependences between the acromegaly, the glucose metabolism of predisposed patients and their treatment with pegvisomant were observed. Our data support recent findings suggesting that intra-portal insulin levels determine the GH receptor expression in the liver underlined by the fact that patients with concomitant diabetes mellitus, in particular those receiving insulin therapy, require higher pegvisomant doses to normalise IGF1. It is therefore important to analyse various therapy modalities to find out whether they influence the associated diabetes mellitus and/or whether the presence of diabetes mellitus influences the treatment results of an acromegaly therapy.

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Michael Droste, Julia Domberg, Michael Buchfelder, Klaus Mann, Anja Schwanke, Günter Stalla, and Christian J Strasburger

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Martin Reincke, Katrin Ritzel, Andrea Oßwald, Christina Berr, Günter Stalla, Klaus Hallfeldt, Nicole Reisch, Jochen Schopohl, and Felix Beuschlein

Objective

Our aim was to review short- and long-term outcomes of patients treated with bilateral adrenalectomy (BADx) in ACTH-dependent Cushing's syndrome.

Methods

We reviewed the literature and analysed our experience with 53 patients treated with BADx since 1990 in our institution.

Results

BADx is considered if ACTH-dependent Cushing's syndrome is refractory to other treatment modalities. In Cushing's disease (CD), BADx is mainly used as an ultima ratio after transsphenoidal surgery and medical therapies have failed. In these cases, the time span between the first diagnosis of CD and treatment with BADx is relatively long (median 44 months). In ectopic Cushing's syndrome, the time from diagnosis to BADx is shorter (median 2 months), and BADx is often performed as an emergency procedure because of life-threatening complications of severe hypercortisolism. In both situations, BADx is relatively safe (median surgical morbidity 15%; median surgical mortality 3%) and provides excellent control of hypercortisolism; Cushing's-associated signs and symptoms are rapidly corrected, and co-morbidities are stabilised. In CD, the quality of life following BADx is rapidly improving, and long-term mortality is low. Specific long-term complications include the development of adrenal crisis and Nelson's syndrome. In ectopic Cushing's syndrome, long-term mortality is high but is mostly dependent on the prognosis of the underlying malignant neuroendocrine tumour.

Conclusion

BADx is a relatively safe and highly effective treatment, and it provides adequate control of long-term co-morbidities associated with hypercortisolism.

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Harald Jörn Schneider, Bernhard Saller, Jens Klotsche, Winfried März, Wolfgang Erwa, Hans-Ullrich Wittchen, and Günter Karl Stalla

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.

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Matthias K. Auer, Dorothea Gebert, Sarah V Biedermann, Laura Bindila, Günter Stalla, Nicole Reisch, Anna Kopczak, and Johannes Fuss

Objective

Patients with craniopharyngioma (CP) frequently suffer from morbid obesity. Endocannabinoids (ECs) are involved in weight gain and rewarding behavior but have not been investigated in this context.

Design

Cross-sectional single-center study.

Methods

Eighteen patients with CP and 16 age- and sex-matched controls were included. Differences in endocannabinoids (2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)) and endocannabinoid-like molecules (oleoyl ethanolamide (OEA), palmitoyl ethanolamide (PEA), and arachidonic acid (AA) were measured at baseline and following endurance exercise. We further explored ECs-dynamics in relation to markers of HPA-axis activity (ACTH, cortisol, copeptin) and hypothalamic damage.

Results

Under resting conditions, independent of differences in BMI, 2-AG levels were more than twice as high in CP patients compared to controls. In contrast, 2-AG and OEA level increased in response to exercise in controls but not in CP patients, while AEA levels decreased in controls. As expected, exercise increased ACTH and copeptin levels in controls only. In a mixed model analysis across time and group, HPA measures did not provide additional information for explaining differences in 2-AG levels. However, AEA levels were negatively influenced by ACTH and copeptin levels, while OEA levels were negatively predicted by copeptin levels only. There were no significant differences in endocannabinoids depending on hypothalamic involvement.

Conclusion

Patients with CP show signs of a dysregulated endocannabinoid system under resting conditions as well as following exercise in comparison to healthy controls. Increased 2-AG levels under resting conditions and the missing response to physical activity could contribute to the metabolic phenotype of CP patients.