The stress response to laparoscopic cholecystectomy: investigation of endocrine parameters.

Laparoscopic cholecystectomy, as a typical example of minimal invasive surgery, is associated with low complication rates and minimal patient discomfort, and provides the same safety as conventional cholecystectomy. In the present prospective observational study, endocrine parameters as indicators for stress response were measured. We investigated 53 patient with laparoscopy cholecystectomy and 12 patients with conventional cholecystectomy. Blood samples were taken pre-, peri-, and postoperatively for measurement of ACTH, cortisol, prolactin, and growth hormone. General anesthesia followed a standardized protocol. The increase in all stress hormones did not differ between patients in the two groups, and was comparable with that reported in the literature and the findings of our own previous studies in patients undergoing conventional cholecystectomy and elective colon resection. We conclude that laparoscopic cholecystectomy is associated with a pronounced endocrine stress response that does not account for the observed differences in the peri- and postoperative complication rate or patient comfort.

Cardiac function in endocrine diseases: I. Acromegaly.

The aim of our echocardiographic study was to characterize cardiac function and anatomy of 14 acromegalics (A: 9 women, 5 men; mean age: 42.4 yrs) more closely. The duration of acromegaly in 4 of these patients was between 3 and 12 years; the disease was diagnosed for the first time in the other patients. Double M-mode echocardiography was performed in all patients and the results compared with data obtained from a control group of 24 healthy volunteers (N: 22 men, 2 women; mean age: 23 yrs). The mean left ventricular diameter at end-diastole was greater in the acromegalics than in the controls (A: 55 +/- 6 mm, N: 50 +/- 4 mm; p less than 0.005, means +/- SD). After correction for age and body surface area, it, however, was outside the 95% confidence interval in 5 patients. Left ventricular hypertrophy was present in 3 patients, one of whom had coexistent arterial hypertension. A total of 3 patients were hypertensive. Significantly higher values for the maximal velocity of systolic wall thickening (A: 6.1 +/- 0.6 cm/s, N: 4.2 +/- 0.6 cm/s, p less than 0.001) and diameter change (A: 12.4 +/- 2.0 cm/s, N: 10.6 +/- 1.0 cm/s, p less than 0.005) indicate increased contractility with concurrently increased relaxation; fractional shortening did not differ significantly (A: 38 +/- 5%, N: 37 +/- 5%, ns). The isovolumetric relaxation period at diastole was slightly longer in the acromegalics (A: 70 +/- 17 ms, N: 61 +/- 13 ms, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

[Diagnosis and therapy of asymptomatic adrenal tumors]. / Diagnostik und Therapie asymptomatischer Nebennierentumoren.

Adrenal tumours had been discovered incidentally (since 1981) in 32 patients (23 females and nine males; mean age 54 [25-73] years) who had had computed tomography (CT) or ultrasonography for other reasons: none had a history or symptoms of such tumour. Tumours were bilateral in eight, right or left-sided in 12 each: all had been confirmed by CT. Average tumour size was 3 cm (1-9 cm). Three patients had cortisol-producing adrenal tumours, and there was one benign phaeochromocytoma (abnormally high adrenaline and noradrenaline excretion). Fine-needle biopsies in two patients revealed a benign histology. An adrenalectomy was performed in eight patients (the one phaeochromocytoma, six adenomas and one ganglioneuroma). Follow-up CT in 11 of the non-operated patients 6-48 months later (mean of 14 months) did not demonstrate any increase in tumour size so that a waiting attitude seems justified: benign tumours are clearly much more frequent than malignant ones. However, if the tumour diameter is greater than 6 cm, an adrenalectomy is indicated because of the danger of malignancy.

The effect of sodium valproate in Cushing's disease, Nelson's syndrome and Addison's disease.

UNLABELLED: We investigated the effect of sodium valproate on plasma ACTH and serum cortisol concentrations in different pathological states of ACTH hypersecretion. Five patients with pituitary dependent Cushing's syndrome, two patients with Nelson's syndrome and five patients with Addison's disease were studied. Neither a single dose nor long term administration of sodium valproate resulted in a significant decrease of plasma ACTH levels in patients with Cushing's disease and Nelson's syndrome. Furthermore, the response of ACTH and cortisol to stimulation with lysine-vasopressin was unaffected during acute and chronic treatment. Patients with Addison's disease showed a slight attenuation of the ACTH response to lysine-vasopressin as compared to placebo but the difference was not statistically significant. IN CONCLUSION: sodium valproate does not appear to be effective in controlling ACTH hypersecretion in pituitary dependent Cushing's syndrome.

Nonhypnotic low-dose etomidate for rapid correction of hypercortisolaemia in Cushing's syndrome.

We determined the adrenostatic potential of low-dose nonhypnotic etomidate in six patients with Cushing's syndrome (ectopic Cushing's syndrome, n = 2; Cushing's disease, n = 3; bilateral adrenal adenoma, n = 1). Etomidate was given as a continuous infusion for 32 h in a dose of 2.5 mg/h (n = 5) or 0.3 mg/kg/h (n = 3), respectively. Saline was given during a control period. The responsiveness to exogenous ACTH was studied during placebo and 7 and 31 h after commencing etomidate by administration of 250 micrograms 1-24 ACTH i.v. Etomidate (2.5 mg/h) led to a consistent decrease in serum cortisol in all patients from a mean of 39.4 +/- 13.3 to 21.1 +/- 5.7 micrograms/dl after 7 h (P less than 0.05 compared with placebo). After 24 h cortisol was reduced further to a mean steady state concentration of 12.3 +/- 5.7 micrograms/dl (P less than 0.05). At the end of the infusion period the cortisol increase in response to ACTH was reduced but not abolished. In contrast, a dose of 0.3 mg/kg/h etomidate induced unresponsiveness of serum cortisol to exogenous ACTH within 7 h. However, sedation was observed in two out of three patients at this dose, while during etomidate in a dose of 2.5 mg/h no side effects were seen. We conclude that low-dose nonhypnotic etomidate reduces serum cortisol to within the normal range in patients with Cushing's syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

A pituitary adenoma secreting high molecular weight adrenocorticotropin without evidence of Cushing's disease.

We report a patient with hypersecretion of a high mol wt ACTH from an aggressive corticotropic pituitary tumor who did not have hypercortisolism. Basal plasma ACTH levels were clearly elevated (26-121 pmol/L), whereas basal and stimulated serum cortisol levels were in the normal range. The pituitary source of the ACTH hypersecretion was confirmed by selective venous catheterization. Gel chromatography of the patient's plasma showed two peaks of ACTH immunoreactivity, one major peak eluting near the void volume (high mol wt form of ACTH), accounting for more than 95% of the ACTH detected, and a very small peak at the expected position of ACTH-(1-39). Plasma ACTH levels were not altered by metyrapone or bromocriptine. During high dose dexamethasone administration plasma ACTH decreased, but was not fully suppressed. Immunohistochemical evaluation of tumor tissue demonstrated ACTH immunoreactivity in 40% of the tumor cells. The patient died from postoperative complications after a second operation performed after tumor recurrence. This patient's course confirms the observations of relatively rapid growth and high recurrence rate in clinically silent corticotropic pituitary adenomas.

[Adrenostatic treatment of ACTH-dependent Cushing syndrome using metyrapone and aminoglutethimide]. / Adrenostatische Therapie mit Metyrapon und Aminoglutethimid beim ACTH-abhängigen Cushing-Syndrom.

The adrenostatic effect of metyrapone (Metopiron) and aminoglutethimide (Orimeten) was assessed retrospectively in ten patients with ACTH-dependent Cushing's syndrome, four of them with the ectopic form. Five patients received metyrapone only, the other five both metyrapone and aminoglutethimide. Persistent lowering of the serum cortisol level was achieved in all, after an observation period of two weeks to four years. The intended therapeutic level of below 16 micrograms/100 ml was achieved in seven patients. In the course of treatment there was a rise in mean plasma ACTH concentration, but without an "escape" phenomenon. The adrenostatic treatment had to be limited, if at all, only because of side effects, which in two patients required that the drug administration be terminated. It is concluded that adrenostatic treatment with metyrapone and aminoglutethimide is effective and practical. It is suitable not only in the management of florid Cushing's syndrome, but also for long-term treatment when complete cure is not possible.

Naloxone in treatment of circulatory shock resistant to conventional therapy.

The effect of naloxone (4.4-5.9 mg i.v.) was evaluated in 10 patients with circulatory shock (sepsis, n = 7; intoxication, n = 1; cardiogenic shock, n = 2) not responding to full conventional therapy. In addition, we measured plasma ACTH and immunoreactive beta-endorphin before and 60 min after administration of naloxone and compared the results with hormone concentrations in 10 intensive care patients without shock. Only in two patient with septic shock a transient increase (duration 15 min and 60 min, respectively) of systolic blood pressure was observed, while naloxone was ineffective in the remaining eight patients. No adverse effects of naloxone were found. Plasma ACTH and immunoreactive beta-endorphin concentrations in patients with shock were not different from those in controls (ACTH, 79 +/- 28 vs 120 +/- 60 pg/ml; immunoreactive beta-endorphin, 952 +/- 262 vs 1,070 +/- 378 pg/ml). Our findings suggest that naloxone in a single dose of 4.4-5.9 mg i.v. does not improve the management of circulatory shock unresponsive to conventional treatment. beta-endorphin seems to play no major role in the hypotension of shock.

FK 33-824, a met-enkephalin analog, blocks corticotropin-releasing hormone-induced adrenocorticotropin secretion in normal subjects but not in patients with Cushing's disease.

To further elucidate the site of action of opioids on the pituitary-adrenal axis, we studied the effect of D-Ala2,MePhe4,met-(O)enkephalin-ol (Sandoz, FK 33-824) on plasma ACTH and beta-endorphin immunoreactivity and serum cortisol in 7 normal subjects and 11 patients with Cushing's syndrome (Cushing's disease, n = 7; adrenal adenoma, n = 2; ectopic Cushing's syndrome, n = 2) after administration of human corticotropin-releasing hormone (hCRH). hCRH (0.1 mg; Bachem) was injected iv after pretreatment with 0.5 mg FK 33-824, im, or 0.9% saline. In normal subjects, the hCRH-induced ACTH, beta-endorphin, and cortisol increases were almost completely abolished by pretreatment with FK 33-824. Mean peak (+/- SEM) hormone concentrations were significantly reduced (ACTH, 16.7 +/- 3.5 vs. 45.3 +/- 7.8 pg/ml; beta-endorphin, 151 +/- 25 vs. 277 +/- 51 pg/ml; cortisol, 8.1 +/- 1.2 vs. 19.5 +/- 2.6 micrograms/dl; P less than 0.02), as were secretory areas (P less than 0.02). These results indicate a direct pituitary action of the synthetic met-enkephalin. In contrast, in patients with Cushing's disease, FK 33-824 did not inhibit hCRH-induced hormone release. Instead, maximum ACTH and beta-endorphin concentrations were slightly but not significantly higher after the administration of FK 33-824 (ACTH, 292 +/- 143 vs. 131 +/- 32 pg/ml; beta-endorphin, 2409 +/- 763 vs. 1921 +/- 600 pg/ml). These findings indicate a defect in inhibitory opiodergic control of ACTH secretion in patients with Cushing's disease, which may contribute to the pathological ACTH hypersecretion. In patients with Cushing's syndrome due to an adrenal adenoma or ectopic ACTH secretion, neither hCRH nor FK 33-824 altered hormone concentrations.

Effects of high-dose and low-dose naloxone on plasma ACTH in patients with ACTH hypersecretion.

The effect of a high (5.4 mg/h) and a low (0.8 mg/h) dose of naloxone (i.v. over a period of 90 min) on ACTH secretion was compared with placebo in patients with Addison's disease, congenital adrenal hyperplasia, Cushing's disease or Nelson's syndrome. In seven patients with primary adrenal insufficiency the high dose of naloxone provoked a significant increase of plasma ACTH concentrations (P less than 0.02) whereas the low dose of naloxone failed to influence ACTH secretion. In six patients with ACTH dependent Cushing's disease or Nelson's syndrome both doses failed to alter plasma ACTH levels. These results support the concept of inhibitory delta- or kappa-opiate receptors in the regulation of ACTH secretion. In patients with Cushing's disease or Nelson's syndrome ACTH secretion is insensitive to naloxone, presumably because of an autonomous pituitary adenoma or hypothalamic derangement.

Adrenocorticotropin, calcitonin, and antidiuretic hormone as tumor markers in patients with bronchogenic carcinoma of various histological types.

We measured basal and dexamethasone-suppressed plasma ACTH in 246 patients with bronchogenic carcinoma (105 with small-cell carcinoma); in 138 of these patients (67 with small-cell carcinoma) basal and pentagastrin-stimulated serum calcitonin was also determined. In addition, in a subgroup of 120 patients (58 with small-cell carcinoma) plasma ADH with reference to plasma osmolality was also assayed. Non-suppressible plasma ACTH was found in 45% of patients with small-cell carcinoma but only in isolated cases of large-cell carcinoma, adenocarcinoma, and squamous-cell carcinoma. Serum calcitonin was increased in 28% of patients with small-cell carcinoma but only in few patients with other tumor types. Stimulation of calcitonin by pentagastrin was ineffective. Plasma ADH was inappropriately high in 47% of patients with small-cell carcinoma. Strikingly high also was the incidence of increased ADH concentrations in patients with large-cell (40%), adenocarcinoma (46%), and squamous-cell carcinoma (29%). By measuring plasma ACTH after dexamethasone suppression and ADH with reference to osmolality, the sensitivity of these tumor markers in detecting pathological hormone secretion is markedly increased. In small-cell carcinoma the simultaneous measurement of ACTH, ADH, and calcitonin gives a high yield of positive results (74%), indicating that this set of tumor markers is a promising aid in diagnosis and therapy control.

Effect of meclastine, a selective H1 receptor antagonist, upon ACTH release.

To elucidate further the role of histamine in the control of ACTH secretion we investigated the effect of the selective H1 receptor antagonist meclastine on the ACTH response to insulin hypoglycaemia and to metyrapone-induced hypocortisolaemia in normal subjects. Intravenous meclastine (4.8 mg/90 min) significantly inhibited the hypoglycaemia-induced ACTH and cortisol increase whereas serum GH and PRL concentrations were unaffected. Orally administered meclastine (3 X 2 mg) also reduced the ACTH feedback response to cortisol deficiency in a modified metyrapone test, compared to a placebo. Our findings support the concept of an excitatory influence of histamine upon ACTH secretion via H1 receptors, possibly by stimulation of CRF release.

[Stimulating action of Brucella melitensis lipopolysaccharide on hemopoiesis in mice]. / O stimuliruiushchem deistvii lipopolisakharida Brucella melitensis na gemopoéz u myshei.

The bacterial mass, brucellar protective antigen and lipopolysaccharide (LPS) obtained from B. melitensis stimulated the formation of endogenous colonies in the spleen of mice belonging to different strains, subjected to irradiation in sublethal doses. The maximum stimulating effect was observed when the antigens were introduced 24 hours prior to irradiation. LPS introduced in the optimal dose induced an increase in the number of hemopoietic stem cells (HSC) in the s-phase of the cell cycle, thus stimulating the postirradiation survival of mice irradiated in a lethal dose. 24 hours after the injection of LPS the total number of HSC in the spleen increased 1.5 times. These data indicate that LPS has a stimulating effect on hemopoiesis in mice. The effect rendered by LPS is seemingly linked with an increase in the proliferation of HSC and, to a lesser extent, depends on changes in the migration of HSC.

[Activation of DNA synthesis in lymphocytes of guinea pigs induced by Staphylococcus antigens]. / Aktivatsiia sinteza DNK v limfotsitakh morskikh svinok pod vliianiem antigenov stafilokokka.

The proliferative activity of lymphocytes in the spleen and the thymus of intact guinea pigs in response to protein A isolated from Staphylococcus aureus, strain Cowan-1, and the corpuscular antigens of Staphylococcus aureus, strains Cowan-1 and Wood-46, has been studied. All Staphylococcus aureus antigens have been shown to have mitogenic activity in respect of splenic cells and to exert no influence on the synthesis of DNA in thymic lymphocytes. The mitogenic effect of protein A on splenic lymphocytes depends on the content of immunoglobulins in the serum used as culture medium. The stimulating action of Staphylococcus aureus, strain Cowan-1, on splenic lymphocytes is more pronounced than that of strain Wood-46; this fact is mainly due to the presence of protein A in the cell wall of the former strain. The antigens used in this study are probably polyclonal mitogens for the splenic lymphocytes of intact guinea pigs. This fact is indirectly confirmed by the results of experiments on incorporation of 3H-thymidine into splenic lymphocytes during their cultivation together with some T and B-mitogens.

Effects of a met-enkephalin analog on adrenocorticotropin (ACTH), growth hormone, and prolactin in patients with ACTH hypersecretion.

The effect of D-Ala2, MePhe4, Met-(0)enkephalinol (Sandoz FK 33-824; 0.5 mg, im) on pituitary hormone secretion was studied in 11 patients with Addison's disease and 11 patients with ACTH-dependent Cushing's disease. In patients with Addison's disease, a pronounced fall of plasma ACTH levels was observed (P less than 0.005). The ACTH response to FK 33--824 was partially reversed by naloxone (4 mg, iv). In patients with Cushing's disease, no unequivocal decrease in either ACTH or cortisol was seen. Moreover, FK 33--824 failed to influence the vasopressin-induced ACTH increase in 5 patients with Cushing's disease. In patients with cortisol deficiency due to either Addison's disease or bilateral adrenalectomy for Cushing's disease, FK 33--824 led to increases in PRL and GH similar to those described in normal subjects. However, in the presence of longstanding hypercortisolism, the PRL increase was significantly diminished, and the GH response to FK 33--824 was completely abolished. Our results suggest that in Addison's disease ACTH release is influenced by inhibitory opiate receptors. In patients with Cushing's disease, ACTH secretion is insensitive to FK 33-284, presumably because of an autonomous pituitary adenoma or hypothalamic derangement. The impairment of the PRL and GH responses to FK 33--824 in Cushing's syndrome seems to reflect a direct action of the elevated cortisol level, for it is not seen after bilateral adrenalectomy.