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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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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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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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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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Caroline Sievers, Jens Klotsche, Lars Pieper, Harald J Schneider, Winfried März, Hans Ulrich Wittchen, Günter K Stalla, and Christos Mantzoros

Objective

Although associations between testosterone and cardiovascular (CV) morbidity in women have been proposed, no large prospective study has evaluated potential associations between testosterone and mortality in women. The objective was to determine whether baseline testosterone levels in women are associated with future overall or CV morbidity and mortality.

Design

Prospective cohort study with a 4.5-year follow-up period.

Methods

From a representative sample of German primary care practices, 2914 female patients between 18 and 75 years were analyzed for the main outcome measures: CV risk factors, CV diseases, and all-cause mortality.

Results

At baseline, the study population was aged 57.96±14.37 years with a mean body mass index of 26.71±5.17 kg/m2. No predictive value of total testosterone for incident CV risk factors or CV diseases was observed in logistic regressions. Patients with total testosterone levels in the lowest quintile Q1, however, had a higher risk to die of any cause or to develop a CV event within the follow-up period compared to patients in the collapsed quintiles Q2–Q5 in crude and adjusted Cox regression models (all-cause mortality: Q2–Q5 versus Q1: crude hazard ratios (HR) 0.49, 95% confidence interval (CI) 0.33–0.74; adjusted HR 0.62, 95% CI 0.42–0.939; CV events: Q2–Q5 versus Q1: crude HR 0.54, 95% CI 0.38–0.77; adjusted HR 0.68, 95% CI 0.48–0.97). Kaplan–Meier curves revealed similar data.

Conclusions

Low baseline testosterone in women is associated with increased all-cause mortality and incident CV events independent of traditional risk factors.

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Massimo Terzolo, Soraya Puglisi, Giuseppe Reimondo, Christina Dimopoulou, and Günter K Stalla

The literature on an association between acromegaly and cancer is particularly abundant on either colorectal cancer or thyroid cancer, and an endless debate is ongoing whether patients with acromegaly should be submitted to specific oncology screening and surveillance protocols. The aim of the present work is to review the most recent data on the risk of either colorectal cancer or thyroid cancer in acromegaly and discuss the opportunity for specific screening in relation to the accepted procedures in the general population.

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Sarah M Leistner, Jens Klotsche, Christina Dimopoulou, Anastasia P Athanasoulia, Josefine Roemmler-Zehrer, Lars Pieper, Jochen Schopohl, Hans-Ulrich Wittchen, Günter K Stalla, Stephany Fulda, and Caroline Sievers

Objectives

Several studies reported decreased quality of life (QoL) and sleep as well as increased rates of depression for patients with pituitary adenomas. Our aim was to explore to what extent differences in depression and sleep quality contribute to differences in QoL between patients with pituitary adenomas and controls.

Design

A cross-sectional case–control study.

Setting

Endocrine Outpatient Unit of the Max Planck Institute of Psychiatry, Munich, Department of Internal Medicine, Ludwig-Maximilians-University, Munich, and the Institute of Clinical Psychology and Psychotherapy, Technical University, Dresden.

Participants

Patients with pituitary adenomas (n=247) and controls (from the DETECT cohort, a large epidemiological study in primary care patients) matched individually by age and gender (n=757).

Measurements

Sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and QoL was measured by the generic EQ-5D and calculated by the time trade-off- and VAS-method. Depression was categorized as ‘no depression’, ‘subclinical depression’, and ‘clinical depression’ according to the Beck Depressions Inventory for patients and the Depression Screening Questionnaire for control subjects.

Statistical analyses

General linear and generalized, logistic mixed models as well as proportional odds mixed models were calculated for analyzing differences in baseline characteristics and in different subgroups.

Results

Patients with pituitary adenomas showed decreased QoL (VAS index: 0.73±0.19) and sleep (PSQI score: 6.75±4.17) as well as increased rates of depression (subclinical or clinical depression: 41.4%) compared with their matched control subjects (VAS index: 0.79±0.18, PSQI score: 5.66±4.31, subclinical or clinical depression: 25.9%). We have shown that a substantial proportion of the reduced QoL (48% respectively 65%) was due to the incidence of depression and reduced sleep quality.

Conclusions

These findings emphasize the importance of diagnosing depressive symptoms and sleep disturbances in patients with pituitary disease, with the ultimate goal to improve QoL in patients with pituitary adenomas.

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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), palmitoylethanolamide (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.

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Günter K Stalla, Christina Dimopoulou, Caroline Jung-Sievers, Eduardo Arzt, Marcelo Paez Pereda, Marily Theodoropoulou, Denis Ciato, and Ulrich Renner

Although effective treatment regimens (surgical resection, drug treatment with dopamine agonists or somatostatin analogues, radiotherapy) have been established for the therapy of most pituitary tumours, a considerable proportion of affected patients cannot completely cured due to incomplete resection or drug resistance. Moreover, even if hormone levels have been normalized, patients with hormone-secreting tumours still show persistent pathophysiological alterations in metabolic, cardiovascular or neuropsychiatric parameters and have an impaired quality of life. In this review reasons for the discrepancy between biochemical cure and incomplete recovery from tumour-associated comorbidities are discussed and the clinical management is delineated exemplarily for patients with acromegaly and Cushing’s disease. In view of the development of additional treatment concepts for the treatment of pituitary adenomas we speculate about the relevance of RSUME as a potential target for the development of an anti-angiogenic therapy. Moreover, the role of BMP-4 which stimulates prolactinoma development through the Smad signalling cascade is described and its role as putative drug target for the treatment of prolactinomas is discussed. Regarding the well-known resistance of a part of somatotropinomas to somatostatin analogue treatment, recently identified mechanisms responsible for the drug resistance are summarized and ways to overcome them in future treatment concepts are presented. Concerning novel therapeutic options for patients with Cushing’s disease the impact of retinoic acid, which is currently tested in clinical studies, is shown, and the action and putative therapeutic impact of silibinin to resolve glucocorticoid resistance in these patients is critically discussed.

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Christina M Berr, Mareike R Stieg, Timo Deutschbein, Marcus Quinkler, Ralf Schmidmaier, Andrea Osswald, Nicole Reisch, Katrin Ritzel, Christina Dimopoulou, Julia Fazel, Stefanie Hahner, Günter K Stalla, Felix Beuschlein, and Martin Reincke

Background

Cushing’s syndrome (CS) is characterized by an excessive secretion of glucocorticoids that results in a characteristic clinical phenotype. One feature of clinical hypercortisolism is breakdown of protein metabolism translating into clinical consequences including glucocorticoid-induced myopathy. While surgery is effective in control of cortisol excess, the effect of biochemical remission on muscular function is yet unclear.

Methods

In a cross-sectional study we analyzed 47 patients with CS during the florid phase (ActiveCS). 149 additional patients were studied 2–53 years (mean: 13 years) after surgery in biochemical long-term remission (RemissionCS). Also, 93 rule-out CS patients were used as controls (CON). All subjects were assessed for grip strength using a hand grip dynamometer and underwent the chair rising test (CRT).

Results

Hand grip strength (85% vs 97% of norm, P = 0.002) and the CRT performance (9.5 s vs 7.1 s, P = 0.001) were significantly lower in ActiveCS compared to the CON group. Six months after treatment grip strength further decreased in CS (P = 0.002) and CRT performance remained impaired. The RemissionCS group (mean follow-up 13 years) had reduced hand grip strength (92% compared to normal reference values for dominant hand, P < 0.001). The chair rising test performance was at 9.0 s and not significantly different from the ActiveCS group (P = 0.45).

Conclusion

CS affects muscle strength in the acute phase, but functional impairment remains detectable also during long-term follow-up despite biochemical remission.