Biomedical subjects
Publications and source records attributed to B Allolio.
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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.
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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)
The experience with bilateral simultaneous inferior petrosal sinus catheterization and determination of the ACTH-concentration in 21 patients is reported. Venous blood sampling in the right and left inferior petrosal sinus was obtained before and after stimulation with Corticotropin-Releasing-Hormone (CRH). In 13 patients with Cushing's Syndrome a ACTH gradient (central versus peripheral) was measured. In all patients who were operated (11/13) a microadenoma was confirmed. In all patients with a central/peripheral gradient of the ACTH-levels at the same time an ipsi versus contralateral gradient between the two sides could be established after administration of CRH, which allowed a correct localization of the microadenoma. In 11 of 13 patients the site of the microadenoma was confirmed intraoperatively.
Bilateral, selective and simultaneous catheterization of the inferior petrosal sinus with measurements of ACTH after stimulation with ovine corticotrophin-releasing factor (CRF) is now frequently used to establish the differential diagnosis in patients with Cushing's disease and to determine the side of the microadenoma in the pituitary. To investigate whether CRF has any effect on other pituitary hormones, we also determined prolactin (PRL) concentrations in the samples obtained during this procedure. Fourteen patients under evaluation for Cushing's syndrome and one patient with a hormonally inactive pituitary tumour were catheterized. Baseline PRL levels in the peripheral veins were within the normal range before and after CRF in all patients (3.7-16.0 ng/ml). In 10 patients ACTH- and PRL concentrations lateralized to one side of the pituitary and could both be stimulated by CRF. The gradient of PRL between inferior petrosal sinus and periphery ranged from 7 to 147 ng/ml after CRF. There was no correlation between ACTH and prolactin increase in response to CRF. In three patients with no ACTH-gradient but a positive response to CRF, no tumours could be found during transsphenoidal surgery; they had no PRL-gradient and showed no PRL response to CRF. One patient with the ectopic ACTH syndrome had no ACTH- and no PRL response to CRF. The patient with the inactive pituitary tumour showed a normal ACTH-, but no PRL response to CRF. These data demonstrate for the first time that in normo-prolactinaemic patients with Cushing's disease, in contrast to patients bearing no microadenoma, PRL is secreted in response to CRF.(ABSTRACT TRUNCATED AT 250 WORDS)
The imidazole derivative etomidate has been shown to block (reversibly) adrenocortical steroid synthesis. Long-term sedation with etomidate has been associated with adrenocortical insufficiency and increased mortality in severely ill patients. The significance of adrenocortical blockade after a single induction dose of etomidate remains a matter of debate. This study was designed to analyze the role of glucocorticoid deficiency after a single induction dose of etomidate for major surgery. In a prospective controlled double-blind study, 20 consecutive patients scheduled for colorectal surgery were randomly allocated to either hydrocortisone substitution or placebo (glucose 5%). Hydrocortisone was given as a continuous infusion in a dose of 100 mg dissolved in 5% glucose over 10 h. We combined general anesthesia and epidural anesthesia (L3-4) using bupivacaine (0.5%). Induction of anesthesia: etomidate (0.2-0.3 mg/kg), fentanyl (0.1-0.2 mg), pancuronium (2 mg), and succinyl-choline (1.0-1.5 mg/kg), with endotracheal intubation and mechanical ventilation. Anesthesia was maintained at N2O/O2 2:1 and fluothane (0.4-0.6 vol%). At the end of surgery patients were extubated after oxygenation. In all patients blood pressure, heart rate, central venous pressure, and ECG were monitored continuously, both intra- and postoperatively. During induction, patients received 1,000 ml 0.9% NaCl, followed by continuous administration of 0.9% NaCl, 6 ml/kg per hour intraoperatively and 40 ml/kg per 24 hours post-operatively.(ABSTRACT TRUNCATED AT 250 WORDS)
ACTH concentration was measured in simultaneously drawn blood samples from the left and right inferior petrosal sinuses before and after administration of corticotropin-releasing hormone (CRH). Such samples were successfully obtained in 20 of 21 patients with ACTH-dependent Cushing's syndrome on whom it was attempted. In 11 of the 20 patients there was no concentration difference between petrosal sinus and peripheral blood. But 13 of 19 patients had a unilateral central to peripheral concentration gradient greater than 1.4 after CRH administration. In the other six patients no ipsi- to contralateral gradient was demonstrable. Two of these patients had a proven ectopic ACTH-producing tumor; no adenoma was found at operation in three; on patient is awaiting operation. In 10 of 13 patients with unilateral gradient a microadenoma was found on the same side at operation. One patient had a hemi-hypophysectomy on the side of the higher gradient: hypocortisolemia developed in her postoperatively. Two other patients are awaiting operation. The results indicate that simultaneous bilateral catheterization of the inferior petrosal sinus with CRH stimulation is a highly informative examination with few side-effects and will contribute to better diagnosis and treatment of Cushing's syndrome.
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.
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.
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.
We investigated the chromatographic pattern of serum prolactin in 41 patients with prolactinoma and correlated the distribution of immunoreactive prolactin with the clinical variables sex, tumour size, age, and response to bromocriptine therapy. In addition, the effect of long-term storage and repeated freezing and thawing on the different molecular weight forms of prolactin was evaluated. Gel chromatography (column 100 cm X 1.5 cm) was performed in 0.1 mol/l phosphate buffer, pH 7.5, using Ultrogel ACA 54 (LKB). No correlation of age or the response to drug therapy to the elution pattern of prolactin was found. Females showed a higher percentage of big prolactin than males (10.4 +/- 1.2% vs 6.8 +/- 0.7%, mean +/- SEM, P less than 0.05) and patients with microprolactinomas too had a higher percentage of big prolactin than those with macroprolactinomas (11.3 +/- 1.8% vs 7.7 +/- 0.7%, P less than 0.05). Serum samples kept frozen for more than 2 years showed a higher percentage of bigbig prolactin (P less than 0.01) than samples stored for less than 12 months suggesting formation in vitro. However, examination of fresh samples prior to freezing also demonstrated bigbig prolactin, indicating that bigbig prolactin circulates in vivo. Repeated freezing and thawing of bigbig prolactin led to almost complete interconversion to little prolactin without any increase in immunoreactivity. This finding supports the concept that bigbig prolactin represents little prolactin loosely associated to a carrier molecule.
To further investigate the role of opioids in the regulation of the pituitary-adrenal axis we studied the effect of morphine and naloxone on human corticotropin-releasing hormone (hCRH)-induced ACTH, immunoreactive (ir) beta-endorphin, and cortisol release in normal subjects. Protocols: 1. 30 mg of a slow-release preparation of morphine or placebo was given orally 3 h prior to administration of hCRH (0.1 mg iv) (N = 7). 2. Naloxone (4 mg as bolus iv) or placebo was given 5 min prior to hCRH (N = 7). 3. Naloxone (4 mg iv as bolus followed by a continuous infusion of 6 mg over 75 min) or placebo was started 15 min prior to hCRH (N = 6). hCRH was injected at 11.00 h (protocol 1, 2) or at 17.00 h (protocol 3). Oral morphine not only suppressed basal hormone levels (P less than 0.02), but also the peak response to hCRH compared with placebo (cortisol: 270 +/- 50 vs 559 +/- 80 nmol/l; ACTH: 5.1 +/- 1.5 vs 13.1 +/- 2.7 pmol/l; ir beta-endorphin: 48.5 +/- 8.7 vs 88 +/- 14 pmol/l; mean +/- SEM, P less than 0.02). Similarly, the maximum incremental changes and the area under the curve were significantly reduced for all three hormones compared with placebo (P less than 0.05). After 4 mg of naloxone in the morning, no significant hormonal changes in response to hCRH were observed.(ABSTRACT TRUNCATED AT 250 WORDS)
To further elucidate the inhibitory action of cyproheptadine on ACTH release, we studied the influence of cyproheptadine (0.1 mg/kg body weight) on the corticotropin releasing hormone (CRH)--induced hormone release in normal subjects. On two occasions six healthy volunteers underwent a CRH-test (0.1 mg hCRH as bolus i.v.) combined with an infusion of either cyproheptadine or saline starting 30 min prior to the CRH injection. Cyproheptadine led to a significant suppression of the plasma ACTH (p less than 0.05) and serum cortisol (p less than 0.005) response to CRH compared to placebo suggesting a direct inhibitory action of cyproheptadine at the pituitary level.
The ACTH-producing microadenoma is by far the most common cause of hypercortisolism in patients with Cushing's syndrome. Selective transsphenoidal surgery is the treatment of choice for Cushing's disease, however, it is not uniformly successful. Aim of this study was to determine simultaneously the ACTH-concentration in the right and left sinus petrosus inferior in patients with Cushing's syndrome before and after stimulation with CRF. The procedure was attempted in 17, successfully carried out in 16 patients. In the 14 of whom Cushing's disease was diagnosed, 11 had a gradient greater than 1.4 (central versus peripheral ACTH) after administration of CRF, two patients had no gradient, yet responded to CRF. One patient had the ectopic ACTH-syndrome and showed no response to CRF and no gradient. One patient, found to have no Cushing's disease, had no gradient and responded normal to CRF. In 9 of the 11 patients with a gradient, the microadenoma was found on the side of the higher ACTH-level; one patient underwent hemihypophysectomy of the side where the gradient was directed towards and was cured. No complications occurred. We conclude, that selective, simultaneous and bilateral catheterization of the sinus petrosus inferior is a safe method to localize the side of the microadenoma preoperatively.
We studied the effect of low dosage (0.26 mg/kg as a single induction dose) and high dosage (30 mg/h for long term sedation) etomidate on serum testosterone and serum luteinizing hormone (LH) concentrations in males. During high dose etomidate we found inhibition of both 11 beta-hydroxylase and cholesterol-side-chain cleavage enzyme with unresponsiveness of progesterone, 17 alpha OH-progesterone and 11-deoxycortisol to stimulation with ACTH. However, neither high dosage nor low dosage etomidate had any influence on serum testosterone or LH concentrations. We conclude that, in contrast to other substituted imidazole derivatives, etomidate does not interfere with testicular testosterone synthesis. It therefore may be possible to find clinically useful imidazole derivatives with endocrine actions confined to either the adrenals or the testes.