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Biomedical subjects

O A Müller

Publications and source records attributed to O A Müller.

At least 19 recordsLinked to original sources
PubMed1992

Ectopic production of ACTH and corticotropin-releasing hormone (CRH).

The most common ectopic production of a pituitary hormone is the one of ACTH leading to Cushing's syndrome. Ectopic ACTH-hypersecretion is the cause of Cushing's syndrome in 10-15% of all cases. The ACTH-secreting tumours are often oat-cell carcinomas of the lung, less frequently pancreatic cancers, hypernephromas, or C-cell carcinomas of the thyroid. Some of these tumours may be benign or semi-benign as the rare carcinoid tumours and cause great problems in the differential diagnosis of ACTH-dependent hypercortisolism. Out of 173 of our patients with Cushing's syndrome observed in the last 12 years 21 were caused by ectopic ACTH-production. Of these 21 patients 13 have a small cell carcinoma of the lung. The ectopic ACTH-syndrome often has typical clinical features caused by the levels of ACTH and cortisol leading to hypocalcemic alkalosis with muscle weakness and wasting, carbohydrate intolerance, and hypertension with oedema. The survival time in many of these patients is not long enough to allow them to develop typical signs of Cushing's syndrome though they are often highly pigmented. These patients are easily diagnosed. However, patients with small tumours which do not cause very elevated ACTH-levels and who have the more typical clinical signs of full-blown Cushing's syndrome are difficult to recognize. For the differential diagnosis of ACTH-dependent Cushing's syndrome the corticotropin-releasing hormone (CRH) stimulation test and dexamethasone suppression test with high doses are helpful. In special cases the venous sampling procedure for ACTH-measurements is necessary, also CT or NMR is helpful. Ectopic CRH-production is a rare cause of ACTH-dependent Cushing's syndrome. Patients with ectopic CRH-production and consecutive ACTH-hypersecretion from the pituitary have not been studied extensively. There are especially no well documented results of the use of the CRH-stimulation test in vivo in this group of patients with Cushing's syndrome. On the other hand, in the documented cases, not only CRH-, but also ACTH-production was found in the tumours. So far, this rare cause of ACTH-dependent Cushing's syndrome has to be excluded or confirmed by the measurement of endogenous CRH-levels. But until now we have not been able to detect one single case of ectopic CRH-production using a sensitive homologous CRH-radioimmunoassay over a period of more than 8 years in which we have seen nearly 120 newly diagnosed patients with ACTH-dependent Cushing's syndrome. Only in the plasma and tumour tissue of two patients of other groups have we found high CRH-levels.

ACTH Syndrome, Ectopic↗
PubMed1992

The early mineralocorticoid effector mechanism, the sodium-proton exchanger, is sensitized in lymphocytes from patients with Cushing's syndrome.

OBJECTIVE: In-vitro binding of aldosterone to mineralocorticoid receptors on human mononuclear leucocytes and its effects on the intracellular sodium and potassium concentrations, the sodium-proton exchanger and cell volume of human mononuclear leucocytes have been described for normals. In the present paper this easily accessible human cell model was studied in Cushing's syndrome to detect abnormalities of the mineralocorticoid effector mechanism. DESIGN: The rate of cell swelling in isotonic sodium propionate reflecting the activity of the sodium-proton exchanger and the stimulatory activity of 1.4 nM aldosterone were determined in a Coulter Channelyzer. PATIENTS: Nine female patients with pituitary-dependent (7) and adrenal hypercortisolism (2) were included in the study. MEASUREMENTS: Compared with controls from matched normals, the cell volume of human mononuclear leucocytes in a physiological buffer was significantly increased in the patients. The increment of cell size in isotonic sodium propionate was elevated in the presence of 1.4 nM aldosterone only. RESULTS: These findings are equivalent to an excess stimulation of the sodium-proton exchanger by aldosterone in these patients. Plasma cortisol was inversely correlated with the cell swelling in propionate. CONCLUSIONS: These data indicate that the early mineralocorticoid effector mechanism in human mononuclear leucocytes from patients with Cushing's syndrome has an increased sensitivity to aldosterone compared with that from normals. This could reflect an adaptation of the cellular electrolyte metabolism to the decreased mineralocorticoid activity balancing the increased glucocorticoid activity. If representative of other cell systems, e.g. renal tubular cells, these findings would identify accompanying electrolyte disorders in these patients not as a side-effect of glucocorticoids, but as a result of an increased sensitivity to endogenous mineralocorticoids.

Adolescent↗
PubMed1992

Interleukin-2 and interleukin-2 receptor expression in human corticotrophic adenoma and murine pituitary cell cultures.

The production of IL-1 and IL-6 by pituitary cells has recently been demonstrated. In this study we investigated the expression of IL-2 and its receptor (IL-2R) by pituitary cells of different species. In Northern blots, a single hybridizing band of 1 kb, identical to that in normal stimulated lymphocytes, was obtained with specific IL-2 probes. In the mouse AT-20 pituitary tumor cell line, IL-2 mRNA expression was detected after stimulation with corticotropin-releasing hormone or phorbol myristate acetate. In human corticotrophic adenoma cells, basal IL-2 mRNA expression as well as IL-2 secretion were further stimulated by phorbol myristate acetate. Both adenoma and AtT-20 cells showed detectable amounts of IL-2R mRNA and by immunofluorescence, IL-2R membrane expression. In addition, dual immunofluorescence studies in rat anterior pituitary cells demonstrated colocalization of IL-2R with ACTH-positive cells and other cell types expressing the receptor. In addition to the action of lymphocyte-produced IL-2, this cytokine may have a paracrine or autocrine regulatory role within the pituitary. It remains to be established whether IL-2 production occurs in the normal pituitary or is intrinsic to the process of tumor development of these cells. IL-2 may be involved in the growth control of pituitary cells.

Adenoma↗
PubMed1992

Effects of loperamide on the human hypothalamo-pituitary-adrenal axis in vivo and in vitro.

Loperamide, an opiate agonist of high specificity for mu-receptors, was recently reported to suppress ACTH and cortisol levels in normal subjects, but not in patients with proven ACTH-dependent Cushing's disease. However, there is little information on the site of action of loperamide in the hypothalamo-pituitary-adrenal axis of man. We investigated the effect of loperamide on pituitary hormone secretion in vivo and in vitro. In seven normal subjects, basal ACTH plasma levels were significantly suppressed 3 h after loperamide administration (16 mg, orally) from 5 +/- 1 to 2 +/- 0 pmol/L (P less than 0.0001). After the combined pituitary stimulation test (100 micrograms human CRH, 100 micrograms GnRH, 100 micrograms GH-releasing hormone, and 200 micrograms TRH), the ACTH peak (maximum increase at 30 min) was significantly blunted by loperamide from 9 +/- 1 to 4 +/- 1 pmol/L (P less than 0.001) and the area under the curve of ACTH from 0-120 min was reduced from 35 +/- 5 to 23 +/- 4 pmol/L.2 h (P less than 0.05). In the insulin-hypoglycemia test (0.15 IU/kg BW), neither the ACTH peak nor the area under the curve of ACTH was affected by loperamide. In six patients with Cushing's disease and one patient with secondary adrenal insufficiency due to hypothalamic failure, neither basal ACTH and cortisol levels nor CRH-stimulated levels were influenced by loperamide. In four cultured human corticotropic adenomas, loperamide was not able to reduce basal and CRH-induced ACTH secretion. In summary, loperamide is able to reduce basal and CRH-induced ACTH and cortisol levels in normal subjects, but not in patients with Cushing's disease or secondary adrenal failure of hypothalamic origin. Loperamide has no significant effect on insulin-hypoglycemia-induced ACTH and cortisol levels and, therefore, no effect on stress-induced elevation of cortisol levels. Loperamide might act at a suprapituitary site in man in vivo, but, nevertheless, a pituitary site cannot be excluded.

Adenoma↗
PubMed1992

[Adrenal gland disorders].

Adrenal diseases are generally rare but of variable manifestation and high diagnostic expenditure for definitive conformation of the disease in the individual case; therefore, the definitive diagnosis is often made by the specialist. On the other hand the supposed diagnosis, based on the knowledge of clinical symptoms, is frequently made by the nonspecialist who also initiates the first diagnostic steps in order to confirm or exclude the diagnosis. It is the aim of this survey to discuss not only the clinical symptoms of the most important adrenal diseases, but also the essential diagnostic steps in order to at least narrow down the diagnosis with as little expenditure as possible and to avoid a diagnostic maze.

Adrenal Cortex Function Tests↗
PubMed1991

Disturbed glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressives pretreated with metyrapone.

We studied glucocorticoid receptor autoregulation and corticotropin response to dexamethasone in depressed patients and controls, attempting to control for the confounding effect of endogenous glucocorticoids. After depletion of endogenous cortisol, depressed patients showed an attenuated suppressibility of corticotropin by dexamethasone in the face of unchanged dexamethasone plasma levels. Beta-endorphin levels were strongly correlated with adrenocorticotropic hormone (ACTH) concentrations. Although metyrapone administration resulted in a marked rise of glucocorticoid receptor sites per cell in controls, this effect was not present in depressives. These data support the hypothesis of a decreased glucocorticoid receptor plasticity and a partial steroid resistance in depression.

Adolescent↗
PubMed1991

Long-term treatment with SMS 201-995 in resistant acromegaly: effectiveness of high doses and continuous subcutaneous infusion.

Seventeen patients (8 women and 9 men) resistant to all other forms of therapy were treated with the somatostatin analogue SMS 201-995 (octreotide, Sandostatin). The duration of treatment ranged from 1 to 5 years. Mean GH levels of only 4 patients were suppressed under 5 micrograms/L during an 8 h serum profile with the standard dose of 0.1 mg 2 or 3 times daily. This standard dose suppressed mean GH levels in 10 other patients more than 50% of baseline, but for optimal effect higher doses up to 1.5 mg, 4 daily injections or continuous subcutaneous infusion (CSI) were needed. Octreotide had no influence on GH secretion in 3 patients. Suppression of mean GH levels under 5 micrograms/L was achieved in 10 patients. Normalization of insulin-like growth factor I (IGF-I) occurred in only 5 patients. Altogether, therapy with SMS 201-995 reduced GH levels from 23.8 +/- 32.2 micrograms/L (mean +/- SD) to 6.7 +/- 5.0 micrograms/L by 71.8% and IGF-I levels from 7.9 +/- 3.1 U/ml to 3.2 +/- 1.6 U/ml by 59.5%. We conclude that 1) treatment with SMS 201-995 in patients resistant to other forms of therapy may be less successful than previously reported for heterogenous groups of patients; 2) the dose regimen must be adapted to the individual patient for optimal effect and most of our patients needed higher doses than 300 micrograms daily; 3) 4 or maybe more daily injections or CSI seem to be most effective; and 4) in a minority of patients SMS has no influence on GH-secretion.

Acromegaly↗
PubMed1991

In vivo and in vitro effects of glucocorticoids on lymphocyte proliferation in depression.

Twelve severely depressed patients and 13 healthy controls were studied under baseline, metyrapone and metyrapone plus dexamethasone pretreated conditions. Lymphocyte proliferation data were obtained by concanavalin A, phytohaemagglutinin and pokeweed mitogen (PWM) stimulation. There was a decrease in PWM-induced B-cell proliferation and an increase in inhibition of spontaneous leucocyte proliferation by dexamethasone added in vitro following metyrapone administration in vivo, in healthy controls, which was not present in the depressed patients. These data support the concept of a decreased functional plasticity of the glucocorticoid receptor in depression also at the cellular level.

Adolescent↗
PubMed1991

Plasma growth hormone (GH)-releasing hormone levels in patients with lung carcinoma.

OBJECTIVE: The aim was to investigate the serum levels of growth hormone releasing hormone and GH in patients with lung carcinoma. DESIGN After an overnight fast a plasma sample was collected for determination of growth hormone releasing hormone and GH. PATIENTS: The investigation was performed in 28 patients with non small cell lung carcinoma, in 44 patients with small cell lung carcinoma, and 10 patients with non malignant lung disease. A group of 37 normal subjects served as control. MEASUREMENTS: Growth hormone releasing hormone and GH were determined by radioimmunoassay. RESULTS: Patients with small cell lung carcinoma showed higher plasma growth hormone releasing hormone levels (49 +/- 9.4 ng/l) than control subjects (16.3 +/- 2.1 ng/l; P less than 0.05), patients with non small cell lung carcinoma (23.9 +/- 8.8 ng/l; P less than 0.05), and patients with non malignant lung disease (12.7 +/- 5.5; P less than 0.05). Basal GH level was lower than 5 micrograms/l in all patients except five patients with small cell lung carcinoma and one patient with non small cell lung carcinoma. CONCLUSIONS: The higher plasma growth hormone releasing hormone levels in patients with small cell lung carcinoma compared to normal controls and patients with non small cell lung carcinoma and patients with non malignant lung disease, confirm the frequent neuroendocrine activity of this particular tumour.

Adult↗
PubMed1991

Multihormonal response to dexamethasone. A study in atopic dermatitis and normal controls.

Although minor disturbances of the circadian serum cortisol rhythm and diminished excretion of steroid metabolites have been reported in patients with atopic dermatitis, test assays regarding subtle neuroendocrine alterations have not been employed so far. We therefore studied the serum concentrations of cortisol, prolactin and adrenocorticotropin under baseline conditions, after 1 mg dexamethasone and after a defined methylprednisolone treatment in 15 patients with atopic dermatitis, in comparison with 10 healthy controls. The assessment of the hormones revealed no remarkable differences between either group at any of the blood sampling time points. However, in 3 patients and 2 control subjects, though exhibiting no concomitant disease, we could find no suppression of endogenous cortisol to below 5 micrograms/dl after oral intake of 1 mg dexamethasone. These cortisol non-suppressors showed lower dexamethasone serum concentrations in the morning after its administration, as compared with the suppressors. Acute (1 mg dexamethasone) or prolonged (40 mg methylprednisolone over 6 days) intake of glucocorticoids suppressed prolactin levels in both groups, demonstrating that the effect of glucocorticoids on the hormone system is not restricted to the hypothalamic-pituitary-adrenal axis. Our results indicate an intact feedback response of this hormonal axis to 1 mg dexamethasone and the ability of long-term as well as acute glucocorticoid administration to influence the prolactin secretion in patients with atopic dermatitis.

Adolescent↗
PubMed1990

The influence of psychotropic drugs and releasing hormones on anterior pituitary hormone secretion in healthy subjects and depressed patients.

Pharmacoendocrinological studies have shown that psychotropic drugs with different actions have different effects on anterior pituitary hormone secretion in man. Substances with different effects on the central nervous system are characterized by a different pharmacoendocrinological profile. Studies with various receptor blockers have shown varying influences on the DMI-induced growth hormone, prolactin, and ACTH/cortisol secretion. Growth hormone stimulation was shown to be mediated by alpha 2-receptors and inhibited by beta-receptors. Investigations in male and female endogenous depressive patients demonstrated a significantly blunted growth hormone response to DMI compared with age- and sex-matched healthy subjects. A comparative study in male endogenous depressive patients showed a significantly diminished growth hormone stimulation both after DMI and after growth hormone-releasing hormone compared to healthy male subjects. In further tests a simultaneous application of four releasing hormones (GHRH, CRH, GnRH, TRH) was used. These investigations showed a significantly lower GH stimulation in endogenous depressive patients compared with age- and sex-matched healthy subjects, but not in neurotic depressive or schizophrenic patients. Cortisol stimulation was similar in all groups of patients and healthy subjects. TSH stimulation was significantly lower in endogenous depressive and schizophrenic patients than in healthy subjects. Somatomedin-C concentrations were significantly elevated in endogenous depressed patients compared with healthy subjects. The blunted growth hormone response in endogenous depression could be explained by inhibitory influences such as increased somatomedin-C concentrations or a hyperactivity of central beta-adrenergic-receptors.

Depressive Disorder↗
PubMed1990

Observations on the pathophysiology of Nelson's syndrome: a report of three cases.

Nelson's syndrome is generally regarded as an unusual sequela of primary bilateral adrenalectomy when performed for Cushing's disease. It is classically defined by cutaneous hyperpigmentation, considerably elevated adrenocorticotropic hormone (ACTH) levels, and an enlarged sella turcica. In this report, we present three cases initially treated by transsphenoidal sellar exploration for Cushing's disease. In two of these cases, remission of hypercortisolism did not occur after the initial pituitary exploration. A microadenomectomy was performed in one case and, in the other, no microadenoma was found. In both, Nelson's syndrome occurred after adrenalectomy. A second transsphenoidal operation and radiotherapy were required to control tumor growth. In another case, transsphenoidal adenomectomy of an ACTH-secreting tumor initially led to a remission of hypercortisolism for 4 years, but recurrent Cushing's disease necessitated adrenalectomy, and again Nelson's syndrome occurred. The documentation of a pre-existing ACTH-secreting basophilic pituitary microadenoma before adrenalectomy, as seen in two of our cases, has not been previously reported, and these observations of "non-classical" courses have major implications for the pathophysiology of Nelson's syndrome.

Adenoma↗
PubMed1990

Presence of growth hormone-releasing hormone-like immunoreactivity in human tumors: characterization of immunological and biological properties.

The distribution and physical and biological properties of GH-releasing hormone-like immunoreactivity (GHRH-IR) in human tissues and tumors was investigated using a specific GHRH RIA, gel chromatography, immunoaffinity chromatography, and bioassay with cultured rat anterior pituitary cells. Variable concentrations of GHRH-IR, ranging from 1.4-39.0 ng/g wet wt, were found in normal liver, lung, placenta, and pancreas. In the latter tissue, however, a different chromatographic profile and a marked decrease in GHRH-IR after immunoaffinity occurred, suggesting that GHRH-IR in pancreatic extracts is not native GHRH. In all tumors examined (n = 35) GHRH-IR could be detected, and four tumors (three carcinoids and one jejunal carcinoma) contained a very high amount of GHRH-IR (greater than 1000 ng/g wet wt). Affinity chromatography of tumor extracts led to a significant loss (greater than 50%) of GHRH-IR in nine tumors. The four tumors containing large amounts of GHRH-IR were obtained from two patients with active acromegaly and two patients who had no clinical evidence of acromegaly. Using antibodies with different specificities for GHRH-(1-44) and GHRH shortened at the C-terminus, varying concentrations of GHRH-(1-44) in these tumors were found, ranging from 10-87% of the total GHRH-IR. The biological activity of GHRH in the four tumor extracts was similar to that of synthetic GHRH alone or GHRH added to control tissue subjected to extraction. These results demonstrate the presence of GHRH-IR in the majority of normal tissues and tumors, which, though they may produce large amounts of biologically active GHRH, do not always lead to acromegaly.

Adolescent↗
PubMed1990

[Diagnosis of multiple endocrine neoplasms type IIa using DNA analysis].

The gene causing MEN IIa has recently being assigned to the pericentromeric region of chromosome 10. We performed linkage analysis using DNA-markers closely related to the chromosomal locus at chromosome 10: MCK II, retinol binding protein cDNA and cTBIRBP-9. Available for the study were EDTA blood from two families. The analysis was positive in two asymptomatic offsprings in one family (B), whereas the markers were not informative in the other family (A). Genetic distance of the informative marker of family A to MEN IIa gene is 2 cM, i.e. a likelihood of 98% (95% up a confidence limit with 5%) for the gene carrier status of two children aged 11 and 7 y old. The following clinical investigation including pentagastrin test, plasma catecholamines and 24 hour urine catecholamines and parathormone was negative until now. We recommend early linkage analysis for establishing the genetic status in offspring of MEN IIa families to focus further screening to those, who are predicted to be gene carrier.

DNA, Neoplasm↗