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Biomedical subjects

B Allolio

Publications and source records attributed to B Allolio.

At least 19 recordsLinked to original sources

Preclinical Cushing's syndrome in adrenal "incidentalomas": comparison with adrenal Cushing's syndrome.

Adrenal tumors are usually diagnosed by clinical symptoms of hormone excess. The increasing use of ultrasound and computed tomography results in the detection of a substantial number of incidentally discovered adrenal tumors. Most of these tumors are nonfunctional adrenocortical adenomas, but a few cases of subclinical cortisol production in "incidentalomas" have been reported. We investigated prospectively the prevalence of autonomous cortisol production in 68 patients (44 females and 24 males, aged 25-90 yr) with adrenal incidentalomas at our institution. As a screening procedure all patients with incidentalomas underwent an overnight dexamethasone suppression test (1 mg). Patients who failed to suppress serum cortisol below 140 nmol/L (5 micrograms/dL) underwent more comprehensive studies (prolonged dexamethasone suppression test, determination of the diurnal rhythm of cortisol secretion in saliva, and CRH stimulation test). Eight patients (12% of all patients with incidentalomas; 5 females and 3 males, aged 25-71 yr) were finally identified as having cortisol-producing tumors, and the findings in these patients were compared with those of overt Cushing's syndrome in 8 patients (8 females, aged 26-50 yr) suffering from cortisol-producing adrenal adenomas. The tumor size of patients with cortisol-producing incidentalomas ranged from 2-5 cm. No specific signs and symptoms of hypercortisolism were present, but arterial hypertension (seven of eight subjects), diffuse obesity (four of eight subjects), and noninsulin-dependent diabetes mellitus (NIDDM; two of eight subjects) were frequently observed. Baseline cortisol levels were in the normal to upper normal range, whereas baseline ACTH levels were suppressed in five of the eight patients. In none of the patients was serum cortisol suppressible by low dose or high dose dexamethasone. The ACTH and cortisol responses to CRH were normal in two, blunted in one, and suppressed in four patients. Unilateral adrenalectomy was performed in seven patients and resulted in temporary adrenal insufficiency in four of them. After surgery, improvement of arterial hypertension, a permanent weight loss in obese subjects, and a better metabolic control of NIDDM were noted in the majority of patients. The following conclusions were reached. Incidentally diagnosed adrenal tumors with pathological cortisol secretion in otherwise clinically asymptomatic patients are more frequently observed than previously assumed. Adrenocortical insufficiency is a major risk in these patients after adrenalectomy. After surgery, hypertension, obesity, and NIDDM may improve. Patients with asymptomatic adrenal incidentalomas, therefore, should be screened for cortisol production by means of an overnight dexamethasone suppression test.

Adrenal Gland Neoplasms

[Reproducibility of bone density measurements of the distal radius using a high resolution special scanner for peripheral quantitative computed tomography (Single Energy PQCT)].

Reliable determination of bone loss in the skeletal system depends on the accuracy of bone mineral density (BMD) measurements. We investigated short-term and long-term accuracy in vitro and in vivo using a new, commercially available special-purpose computed tomography scanner (Single Energy Peripheral QCT: XCT 900, Stratec FRG) for BMD measurements. Using a phantom, the long-term accuracy (3 months) in vitro yielded a coefficient of variation (cv) of 0.18%. Repeated measurements in 37 patients showed excellent reproducibility, with a cv of 0.71%. The differentiation into groups of low, average and high trabecular bone density demonstrated values of 0.61%, 0.59% and 0.98%, respectively for cv. BMD determination with pQCT is a high-precision method. It seems to be suitable for detection of trabecular bone loss in the range of the annual decrease in bone mass, provided the forearm is positioned with maximum care.

Bone Density

Clonal composition of pituitary adenomas in patients with Cushing's disease: determination by X-chromosome inactivation analysis.

The synthesis and secretion of anterior pituitary hormones are subjected to a variety of positive and negative feedback mechanisms. Aberrancies of these highly regulated phenomena may lead to hyperplasia involving multiple cells of the anterior lobe. Alternatively, a rare genetic mutation in a single cell may precede its clonal expansion. Which of these mechanisms is operative in the development of corticotroph adenomas is not known. To examine this question, we studied the clonal composition of ACTH-producing pituitary adenomas from female patients with Cushing's disease by using X-chromosome inactivation analysis. Nine of 27 patients examined were heterozygous at 1 of the 2 X-chromosome-linked polymorphic loci, hypoxanthine-phosphoribosyl-transferase and phosphoglycerate-kinase. The methylation patterns of the hypoxanthine-phosphoribosyl-transferase and phosphoglycerate-kinase genes, distinguishing between the active and inactive alleles, were analyzed in DNA extracted from the central part of the tumor and compared with those of autologous lymphocyte DNA. Six tumors (4 microadenomas and 2 macroadenomas) showed a single active allele of the X-chromosome-linked genes and were monoclonal in nature. The other 3 pituitary adenomas (1 microadenoma and 2 macroadenomas, 1 from a patient with Nelson's syndrome) revealed a polyclonal pattern of X-chromosome inactivation. Our data demonstrate that corticotroph adenomas of the pituitary may arise from a single cell or from more than one cell. Whether fundamentally different endocrine mechanisms underlie the two processes remains to be seen.

Adenoma

[Vascular risk factors in patients with ophthalmoplegia].

The occurrence of high-risk factors for vascular disorders was analysed in a group of 43 patients suffering from diplopia of unknown aetiology. The subjects (25 men and 18 women) were aged between 17 and 78 years. Previously excluded were patients with intracranial or orbital tumors, ocular myositis or myasthenia, multiple sclerosis, endocrine orbitopathy, head trauma, cerebral hemorrhage or aneurysms, leucaemic infiltrates or metastasising tumors. Compared to the control groups of extensive epidemiological studies, the patients showed a higher prevalence of arterial hypertension and diabetes mellitus. Adipositas, lipometabolic disturbance and cigarette smoking were also more frequent. The findings support the hypothesis of a vascular origin of eye-muscle paresis.

Adolescent

[AIDS-related complex: a superfluous concept?].

The clinical value of different classification systems of HIV-infection has been examined in a cohort of 99 HIV-infected individuals. AIDS-related complex (ARC), Walter-Reed (WR) stage 5 and Centers for Disease Control (CDC) group IV without AIDS cases were equally capable of identifying patients with bad prognosis: Out of 12 patients progressing to AIDS, 9 WR 5, 7 CDC IV and 7 ARC. Prognostic parameters (Erythrocyte sedimentation rate, Haemoglobin, Leucocytes, CD4-lymphocytes and Beta 2-Microglobulin) did not differ in the three groups. However, there were great differences in the frequency of patients infected by homosexual contacts and of intravenous drug-abusers. Drug-abusers were more often seen in the ARC-group, whereas there was a slight dominance of homosexuals in the WR 5-group (and a marked preponderance in the AIDS-group). Using 3 different ARC-definitions we found an ARC-frequency of 10%, 24% and 41% in our cohort. Thus the great variability of the ARC-concept could be demonstrated. In conclusion we believe that for the purpose of clinical documentation and studies the ARC-concept is unnecessary. Further studies have to evaluate other classification systems (Walter-Reed, CDC) or to establish new ones.

AIDS-Related Complex

The corticotrophin releasing hormone test in late pregnancy: lack of adrenocorticotrophin and cortisol response.

Biologically active corticotrophin-releasing-hormone (CRH) is produced by the placenta in large amounts and can be measured in the maternal circulation during third trimester of pregnancy. Its physiological significance is unknown. To further investigate the action of CRH in pregnancy, we performed a standard CRH-test (1 micrograms/kg synthetic human CRH) in seven pregnant women 1 week prior to their calculated delivery data and 4-5 weeks post-partum. No response of plasma ACTH to CRH administration could be measured in any of the third trimester pregnant women. Post-partum, basal ACTH levels were significantly lower (1.6 +/- 0.3 vs 5.3 +/- 0.2 pmol/l) and reacted promptly to CRH administration (1.6 +/- 0.3-4.2 +/- 0.5 pmol/l; P less than 0.05). Concentration of cortisol in plasma and salivary cortisol paralleled the ACTH response to administration of CRH. However, one pregnant woman experienced physical and emotional stress during the CRH-test and reacted with a sharp rise in cortisol secretion. The lack of the ACTH and cortisol response in this study to exogenously administered CRH in third trimester pregnancy may be due to high circulating glucocorticoid concentrations, desensitization of the pituitary corticotroph and/or in part due to circulating specific CRH-carrier protein.

Adolescent

Diurnal salivary cortisol patterns during pregnancy and after delivery: relationship to plasma corticotrophin-releasing-hormone.

The circadian rhythm of salivary cortisol was studied in 10 healthy women every 4 weeks throughout pregnancy. In addition, in 12 women the diurnal patterns of salivary cortisol, serum cortisol, plasma ACTH, plasma CRH and serum progesterone were analysed in late third trimester pregnancy and again 3-5 days after delivery. Salivary cortisol profiles exhibited a clear circadian rhythm during pregnancy with an increase in mean salivary cortisol from the 25th to 28th week onwards reaching concentrations in late pregnancy more than twice as high as in non-pregnant controls, rapidly returning to normal concentrations after delivery. The coefficient of variation of salivary cortisol profiles decreased in third trimester pregnancy due to a parallel upward shift of cortisol concentrations (40.2 +/- 3.4% vs 77.6 +/- 6.6% after delivery, P less than 0.01). A diurnal pattern was also found for plasma ACTH and serum cortisol before and after delivery with lower concentrations post-partum (P less than 0.01). In late pregnancy, progesterone concentrations were significantly higher in the evening (930 +/- 85 nmol/l vs 813 +/- 74 nmol/l at 0900 h, P less than 0.01) but showed no diurnal variation post-partum. Plasma CRH was significantly elevated in late third trimester pregnancy (1.22 +/- 0.23 micrograms/l at 0900 h) but showed no diurnal change (1.30 +/- 0.28 micrograms/l at 1900 h). Moreover, no correlation between the free cortisol increase in late pregnancy and plasma CRH was noted despite a wide range of CRH levels (0.13-3.60 micrograms/l). In contrast, a significant correlation was observed between the serum progesterone increase and the salivary cortisol increase in late pregnancy (r = 0.70, P less than 0.05). These findings demonstrate that placental CRH is not the only regulator of maternal ACTH and cortisol release. Instead, our study suggests that placental CRH has little influence on baseline maternal adrenocortical function in pregnancy. The elevated salivary cortisol levels in pregnancy may be explained by glucocorticoid resistance owing to the antiglucocorticoid action of high progesterone concentrations.

Adult

Infusion of low dose etomidate: correction of hypercortisolemia in patients with Cushing's syndrome and dose-response relationship in normal subjects.

To investigate the adrenostatic potential of a nonhypnotic low dose etomidate infusion, we administered 0.03 mg/kg etomidate in a bolus injection, followed by constant infusion of 0.3 mg/kg.h for 24 h to 6 patients with severe Cushing's syndrome. The dose-response relationship also was determined in 15 normal subjects. Three groups of 5 received, respectively, doses of 0.03, 0.1, and 0.3 mg/kg.h etomidate for 5 h after an initial bolus dose of 0.03 mg/kg. The response to exogenously administered ACTH [0.25 mg ACTH-(1-24)], injected after the etomidate or control infusion, was determined in all normal subjects. In the six hypercortisolemic patients, serum cortisol concentrations decreased from 1374 +/- 436 nmol/L (mean +/- SEM) to 188 +/- 91 nmol/L after 11 h of etomidate infusion and remained low until the end of the infusion. Cortisol levels returned to pretreatment concentrations by 24 h. Excretion of urinary free cortisol decreased from 1180 +/- 196 to 185 +/- 66 nmol/day. In the normal subjects, administration of etomidate led to a dose-dependent decrease in serum cortisol from about 550 to 83 nmol/L, while 11-deoxycortisol rose from low or undetectable levels up to 346 nmol/L. In response to ACTH, cortisol levels rose in inverse proportion to the etomidate dose. It was, however, significantly reduced compared to normal saline infusion even after the lowest dose. Changes in aldosterone and corticosterone concentrations were similar to those in cortisol, and 11-deoxycorticosterone changed in a pattern similar to that of 11-deoxycortisol. Two of five normal subjects reported tiredness during the highest etomidate infusion. No other side-effects were noted. We conclude that iv administered etomidate in a low nonhypnotic dose reduces serum cortisol concentrations in a dose-dependent manner in both hyper- and eucortisolemic subjects. This study suggests that etomidate at a dose of 0.1 mg/kg.h or lower may be an effective strategy for the control of severe hypercortisolemia.

Adolescent

A multihormonal response to corticotropin-releasing hormone in inferior petrosal sinus blood of patients with Cushing's disease.

Bilateral, selective, and simultaneous catheterization of the inferior petrosal sinus is not only a valuable tool in the differential diagnosis of Cushing's syndrome, but may also provide new insights into paracrine interactions at the pituitary level. We have investigated whether CRH (1 microgram/kg BW) has any effect on the release of PRL, GH, TSH, or the alpha-subunit of hCG during this procedure. Sixteen patients under evaluation for Cushing's syndrome (Cushing's disease, n = 12; ectopic ACTH syndrome, n = 2; glucocorticoid resistance, n = 1; hormonally inactive adenoma, n = 1) were catheterized. Two of the patients with Cushing's disease received 4.0 mg naloxone iv 15 min before stimulation with CRH. Patients with Cushing's disease demonstrated a central/peripheral gradient and an intersinus gradient not only for ACTH, but also for PRL, alpha-subunit, GH, and TSH, provided that the latter two hormones were not completely suppressed by the glucocorticoid excess. Moreover, all hormones increased in response to CRH on the side with the highest ACTH concentration; PRL rose from 31.2 +/- 6.4 to 61.6 +/- 12.4 micrograms/L (P less than 0.01), and alpha-subunit from 2.6 +/- 0.6 to 6.4 +/- 1.7 micrograms/L, (P less than 0.01). Naloxone was unable to abolish the PRL or alpha-subunit increase in response to CRH. A multihormonal response to CRH in inferior petrosal sinus blood was also observed in the patient with glucocorticoid resistance and in the patient with the hormonally inactive tumor, but not in the patients with ectopic ACTH secretion. The multihormonal response to CRH could be explained by cosecretion of other hormones together with ACTH from corticotroph adenoma, by an effect of CRH on pituitary blood flow, or by a paracrine action of pituitary corticotrophs on adjacent normal pituitary cells. Our results do not support the concept that such a paracrine action is mediated by beta-endorphin. However, a higher dose of naloxone may be required to antagonize the action of pituitary beta-endorphin.

Adrenocorticotropic Hormone

Infusion of beta-endorphin has no suppressive effect on the releasing hormone-stimulated pituitary-adrenal-axis of normal human subjects.

The existence of a short-loop feedback inhibition of pituitary ACTH release by administration of beta-endorphin was postulated. However, data on the effect of peripherally administered beta-endorphin in humans are highly controversial. We infused human synthetic beta-endorphin at a constant rate of 1 microgram.kg-1.min-1 or normal saline to 7 normal volunteers for 90 min. Thirty min after starting the beta-endorphin or placebo infusion, releasing hormones were injected as a bolus iv (oCRH and GHRH 1 microgram/kg, GnRH 100 micrograms, TRH 200 micrograms) and blood was drawn for measurements of beta-endorphin immunoreactivity, all other pituitary hormones, and cortisol. Infusion of beta-endorphin resulted in high beta-endorphin plasma levels with a rapid decrease after the infusion was stopped. During the control infusion, beta-endorphin plasma levels rose in response to CRH. Plasma ACTH and serum cortisol levels in response to the releasing hormone were not different in subjects infused with beta-endorphin or placebo. The PRL response to TRH was significantly higher after beta-endorphin than after placebo (area under the stimulation curve 1209 +/- 183 vs 834 +/- 104 micrograms.l-1.h). There was no difference in the response of all other hormones measured. Our data on ACTH and cortisol secretion do not support the concept of a short-loop negative feedback of beta-endorphin acting at the site of the pituitary.

Adrenocorticotropic Hormone

Intracellular free amino acid patterns in duodenal and colonic mucosa.

We report for the first time the concentrations of free amino acids in human intestinal biopsies obtained by routinely performed endoscopy. We studied 15 medical patients with no changes of the mucosa and six HIV-infected persons with duodenitis. The mean (and SD) sum of all amino acids, taurine excepted, was 61.9 (5.4) mmol/kg dry weight in duodenal biopsies of HIV-negative subjects (n = 11) and 82.9 (0.6) mmol/kg in colonic specimens: 50% (44%) of the total (minus taurine) consisted of aspartate and glutamate and 14% (12%), of the essential amino acids. The relative amino acid pattern in duodenum and colon differed completely from that for muscle: aspartate was fourfold higher; glutamate, phenylalanine, glycine, valine, leucine, and isoleucine were about twofold higher. In contrast, glutamine amounted only to 4% (duodenum) to 14% (colon) of muscle glutamine. In duodenal biopsies of the HIV-infected persons, we found significantly (P less than 0.01, except glutamine: P less than 0.025) increased concentrations of glutamate (24.1 vs 17 mmol/kg dry weight), ornithine (1.4 vs 0.4), valine (2.2 vs 1.7), and glutamine.

Acquired Immunodeficiency Syndrome

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)

Acromegaly

[Principles of glucocorticoid therapy from the viewpoint of the internist].

40 years after the first clinical application of cortisone, glucocorticoids have become an indispensable part of the treatment of various internal disorders. The many side effects of glucocorticoids, however, clearly diminish their utility and stand in the way of their full acceptance by the patient. All principles of glucocorticoid therapy, therefore, aim at the improvement of the ratio between benefits and unwanted effects. There are 3 ways to achieve this goal: 1. Topical application (e.g. beclomethasone-17, 21-dipropionate for the local therapy of bronchial asthma); 2. special timing of glucocorticoid administration (e.g. alternating therapy); 3. active fight against unwanted effects by means of additional therapeutic measures (e.g. prophylactic therapy of osteoporosis induced by steroids). New perspectives may offer themselves as soon as macrocortin--a mediator of glucocorticoid action--will become available.

Administration, Topical