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Biomedical subjects

M Boscaro

Publications and source records attributed to M Boscaro.

At least 91 records · Page 5Linked to original sources
PubMed1992

Effect of digoxin on the in vitro secretion of renin and angiotensin II/III immunoreactivity by the human adrenal gland.

Cardiac glycosides in man inhibit renin secretion, probably through a direct effect at the renal level (i.e. inhibition of juxtaglomerular cell Na/K ATPase). Since there is evidence that the human adrenal possesses an intrinsic renin-angiotensin system, we investigated the effect of digoxin on the in vitro generation of renin and angiotensin II/III, as well as of aldosterone, by the human adrenal gland. Minced normal adrenal tissues were studied in a superfusion system, measuring in the 15-min superfusate fractions active renin by immunoradiometric assay and angiotensin II/III and aldosterone by radioimmunoassay, respectively. In a first set of four experiments using different concentrations of digoxin in sequence for 45 min periods, digoxin 10(-5), but not 10(-8) and 10(-6) mol/l, significantly reduced renin and angiotensin II/III output from adrenals, while no change in aldosterone was observed. In a second set of three experiments, the addition of digoxin 10(-5) mol/l for 120 min caused a sustained reduction of renin and angiotensin II/III, but not of aldosterone. In the final experiment, the decrease of renin and angiotensin II/III during superfusion with digoxin 10(-5) mol/l was significantly greater than that observed during superfusion with digoxin in the presence of antidigoxin antibodies. Our data indicate that digoxin at high doses reduces renin and angiotensin II/III but not aldosterone secretion by the human adrenal gland. This suggests two different effects of digoxin, probably both mediated by inhibition of the Na/K ATPase activity, on the adrenal renin-angiotensin- and aldosterone-secreting cells.

Adrenal Glands↗
PubMed1991

Effects of prolonged sodium restriction on the morphology and function of rat adrenocortical autotransplants.

Regenerated adrenocortical nodules were obtained by implanting fragments of the capsular tissue of excised adrenal glands into the musculus gracilis of rats (Belloni et al. 1990). Five months after the operation, operated rats showed a normal basal blood level of corticosterone, but a very low concentration of circulating aldosterone associated with a slightly increased plasma renin activity (PRA). Regenerated nodules were well encapsulated and some septa extended into the parenchyma from the connective-tissue capsule. The majority of parenchymal cells were similar to those of the zonae fasciculata and reticularis of the normal adrenal gland, while zona glomerulosa-like cells were exclusively located around septa (juxta-septal zone; JZ). In vitro studies demonstrated that nodules were functioning as far as glucocorticoid production was concerned, while mineralocorticoid yield was very low. Prolonged sodium restriction significantly increased PRA and plasma aldosterone concentration, and provoked a marked hypertrophy of JZ, which was due to increases in both the number and average volume of JZ cells. Accordingly, the in vitro basal production of aldosterone and other 18-hydroxylated steroids was notably enhanced. The plasma level of corticosterone, as well as zona fasciculata/reticularis-like cells and in vitro production of glucocorticoids by regenerated nodules were not affected. These findings, indicating that autotransplanted adrenocortical nodules respond to a prolonged sodium restriction similar to the normal adrenal glands, suggest that the relative deficit in mineralocorticoid production is not due to an intrinsic defect of the zona glomerulosa-like JZ, but is probably caused by the impairment of its adequate stimulation under basal conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

18-Hydroxydesoxycorticosterone↗
PubMed1991

Steroids and hypertension.

Primary aldosteronism is the principal disorder of zona glomerulosa and a number of subsets have been identified: unilateral adenoma; bilateral micro- or macro-nodular hyperplasia (idiopathic aldosteronism); primary hyperplasia and aldosterone-producing carcinoma either adrenal or ectopic. The diagnostic criteria for a correct differential diagnosis of these subsets are now quite reliable and our experience is presented in detail. Unfortunately the pathogenesis of most of these forms is still poorly recognized and requires further investigation. An extreme sensitivity to angiotensin II is present in patients with idiopathic aldosteronism, and a role for adrenal renin is now being advocated. A peculiar form of hyperaldosteronism is the glucocorticoid-remediable subtype. An unusual sensitivity of aldosterone to ACTH is present in this form. A qualitative biochemical abnormality in this disorder consists of marked over-production of products of the cortisol C18-oxidation pathway, 18-hydroxycortisol and 18-oxocortisol, which are more abundant than aldosterone and 18-hydroxycorticosterone. A family with three affected sibs has been studied by our group. In other clinical situations, classical zona fasciculata mineralocorticoids [deoxycorticosterone (DOC), corticosterone and their 18-hydroxy compounds] are secreted in excess. The hypertensive diseases of this zone are rare DOC-secreting tumors and two forms of congenital adrenal hyperplasia (CAH), the 11 beta-hydroxylase (11-OHDS) and the 17 alpha-hydroxylase deficiency syndromes (17-OHDS), which are identified by the presence of hypokalemia and suppressed renin activity. DOC is the only mineralocorticoid hormone (MCH) oversecreted in the 11-OHDS, while all ACTH-dependent MCH are very high in the 17-OHDS. The molecular basis of gene abnormalities of this disorder are currently under investigation, and preliminary data obtained in some of our patients are presented. Finally a syndrome of apparent mineralocorticoid excess, which is not a primary disorder of the adrenal cortex, describes the association of an unexplained hypermineralocorticoid state with a decreased rate of peripheral 11 beta-hydroxy dehydrogenation of cortisol to cortisone. Studies on this syndrome have led to the hypothesis that peripheral cortisol inactivation is the normal mechanism permitting specific mineralocorticoid recognition. The syndrome exists in two forms both characterized by a decreased turnover of a normal level of plasma cortisol, but in the type I variant an elevated cortisol/cortisone metabolite ratio is found, whereas in the type II variant this ratio is normal. Three patients of the latter form have recently been described by us and are shortly illustrated.(ABSTRACT TRUNCATED AT 400 WORDS)

Cushing Syndrome↗
PubMed1991

Venous thrombosis and tissue plasminogen activator release deficiency: a family study.

Thrombotic events are often due to fibrinolytic defects such as impaired tissue plasminogen activator (tPA) synthesis and/or release or increased plasminogen activator inhibitor (PAI) levels. In this report we describe four members of a family with a history of recurrent venous thrombosis, who demonstrated defective tPA release after dynamic tests. Two symptomatic patients and one asymptomatic individual showed absent or abnormally low tPA antigen (tPA:Ag) and activity (PA) increases after DDAVP infusion and/or 20 min of venous occlusion. In these patients PAI values were slightly higher than controls. A satisfactory tPA:Ag release was found in the fourth asymptomatic patient. All other coagulation tests were within the normal ranges. This familial defect of the fibrinolytic system seems to be inherited as an autosomal trait.

Adult↗
PubMed1991

Ketoconazole treatment in Cushing's syndrome: experience in 34 patients.

OBJECTIVE: Ketoconazole treatment of Cushing's syndrome has been reported in single cases and a few small groups of 5-8 patients. We report our experience in 34 patients. DESIGN: Clinical study, with pretreatment and post-treatment evaluations. PATIENTS: Out of 67 patients with Cushing's syndrome admitted during the last 6 years, 34 (28 females/six males; age range 14-67 years) received ketoconazole as a palliative treatment due to severe clinical conditions or management of the disease while awaiting results of definitive therapy. MEASUREMENTS: Urinary cortisol, plasma cortisol and ACTH, and routine chemistry were measured every week for 4 weeks, and then once a month. RESULTS: Comparing the last values (mean +/- SEM) during treatment with baseline, urinary cortisol decreased from 1296 +/- 176 to 270 +/- 69 nmol/d (n = 34; P less than 0.001); plasma cortisol decreased from 672 +/- 31 to 549 +/- 35 nmol/l (n = 34; P less than 0.001). For patients with pituitary-dependent Cushing's syndrome, urinary cortisol decreased from 1073 +/- 126 to 200 +/- 21 nmol/d (n = 28; P less than 0.001) while plasma ACTH changed from 12.5 +/- 1.3 to 11.3 +/- 0.8 pmol/l (n = 26; not significant). Twelve patients were treated for more than 6 months, and those with pituitary-dependent disease all received pituitary radiation therapy, except the two who eventually escaped pharmacological control. One additional patient with adrenal carcinoma and one with ectopic ACTH syndrome showed lack of control of urinary cortisol levels. Ketoconazole was withdrawn within the first week in two patients for allergic reaction and acute liver toxicity. Other side-effects included: asymptomatic liver function abnormalities in three patients; gastrointestinal symptoms in four; worsening of gynaecomastia in one. Rapid clinical improvement was observed together with the normalization of urinary cortisol levels, with regression of symptoms such as diabetes mellitus, hypertension, hypokalaemia, and restoration of well being. CONCLUSIONS: These data confirm that ketoconazole is valuable in the management of hypercortisolism, provided that patients are closely watched to exclude those who may develop liver toxicity and to prevent the occurrence of adrenal insufficiency.

Adolescent↗
PubMed1991

In vitro evidence for local generation of renin and angiotensin II/III immunoreactivity by the human adrenal gland.

The adrenal gland of various mammalian species has been shown to contain all the components of a functional renin-angiotensin system. We investigated the existence of this local system in human adrenal tissues surgically obtained. Eight normal adrenals (cortex and medulla) and 6 aldosterone-producing adenomas (aldosteronomas) were examined. Minced tissues were superfused over 270 min, and 15-min fractions were collected. In the perfusates, active renin was measured by immunoradiometric assay with human anti-renin monoclonal antibodies; immunoreactive angiotensin II/III and aldosterone were measured by radioimmunoassay. Adrenal tissues, either normal or pathological, were found concomitantly to release renin, angiotensin II/III and aldosterone. The pattern of this spontaneous release exhibited a pulsatile character. The total amount of renin and angiotensin II/III secreted during superfusion clearly exceeded the tissue content (determined by extraction). Addition of the angiotensin-converting enzyme inhibitor quinaprilat (4 x 10(-6) mol/l) in the superfusion caused a concomitant decrease of angiotensin II/III and aldosterone secretion by 3 normal tissues, and no change in 2 aldosteronomas. These data provide evidence that the human adrenal gland in vitro generates and releases both renin and angiotensin II/III, and support the hypothesis that locally formed angiotensin II/III may play a role as a paracrine regulator of physiological aldosterone secretion.

Adenoma↗
PubMed1990

Pro-gamma-MSH levels in various disorders of pituitary-adrenal axis.

N-Terminal (1-76) portion of proopiomelanocortin (hNT) was measured in normals, Addison's, Nelson's, Cushing's disease, and in dexamethasone suppressible hyperaldosteronism (DSH) by using a specific homologous RIA. Mean basal immunoreactive hNT level was 94.2 +/- 6 pg/ml (mean +/- SE) in normal subjects. In Cushing's disease hNT values were slightly but not significantly (121 +/- 26.5 pg/ml) higher. In patients with DSH the levels were within normal range while they were much higher in Addison's and Nelson's syndromes. A strong correlation was found between IR-hNT and ACTH in plasma of normal subjects and patients with different disorders of the pituitary-adrenal axis (r = 0.83, p less than 0.01). Corticotropin-Releasing-Hormone (CRH) test in Cushing's disease stimulated the release of both ACTH and IR-hNT, showing a slightly different pattern of secretion. Similar patterns of secretion were found for hNT and ACTH in various pituitary-adrenal abnormalities. Normal levels of hNT in DSH do not support a role of this peptide in the pathogenesis of the disorder. Measurement of hNT in plasma can provide an additional tool for the diagnosis of patients with various disorders of the hypothalamic-pituitary-adrenal axis.

Addison Disease↗
PubMed1990

Low-dose ketoconazole treatment in hirsute women.

Ketoconazole is an orally active antimycotic agent and a potent inhibitor of gonadal and adrenal steroidogenesis. As inhibitor of steroid production, it has been employed in Cushing's syndrome, prostatic cancer and precocious puberty due to autonomous Leydig-cell hyperfunction. By virtue of its selective action on androgen synthesis at low doses by inhibition of C17-20 lyase, this drug could be of potential therapeutic utility in hirsutism. We evaluated the hormonal and clinical effects of a low-dose regimen (400 mg/day) for 3 months in 16 women with a spectrum of disorders from idiopathic hirsutism to polycystic ovary syndrome. Four of them completed 6-month treatment. At 3 months, DHEA-S decreased from 9.9 +/- 1.0 (mean +/- SE) to 6.9 +/- 1.0 mumol/L (p less than 0.01), androstenedione from 13.3 +/- 1.5 to 8.3 +/- 1.3 nmol/L (p less than 0.005), and testosterone from 4.2 +/- 0.4 to 3.1 +/- 0.4 nmol/L (p less than 0.05). No significant changes were observed in LH, FSH, prolactin and estradiol levels. In patients treated for 6 months, androgens were within normal limits at the end of the study. Eleven out of 16 women (about 70%) reported some improvement in their hirsutism. There was a significant decrease in Ferriman-Gallwey's score (p less than 0.001) and mean hair-shaft diameter (p less than 0.001). The patients treated for 6 months showed a further improvement. Pelvic ultrasonography, when repeated (n = 8), was either unchanged or improved. Side effects (polymenorrhea, gastrointestinal reaction, somnolence) were generally mild and transient. Of 20 women who entered the study the dropout rate was 20% (n = 4).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Atrial natriuretic peptide in Cushing's disease.

Atrial Natriuretic Peptide (ANF), is secreted by atrial myocytes in response to atrial stretch. Its plasma levels have been found elevated in conditions leading to salt and fluid repletion and consequent atrial distention. Recently, it has been demonstrated that dexamethasone can enhance ANF secretion, by acting on ANF gene expression and mRNA synthesis. High plasma levels of ANF have been observed in normal man after administration of cortisol and ACTH. In the case of glucocorticoid excess, as in Cushing's disease, limited and conflicting data are available. Therefore, we measured ANF basal values and ANF response to postural changes and volume expansion in eight patients with Cushing's disease. In our patients ANF values were higher than normals. ANF responded to volume expansion, 47.8 +/- 5.1 pg/ml before sodium load and 69.9 +/- 7.0 pg/ml after sodium load, and changed minimally after postural manoeuvres, 47.3 +/- 3.2 pg/ml supine and 41.7 +/- 5.1 pg/ml upright. These data indicate that ANF secretion is enhanced in Cushing's disease, and its regulation is partially altered. Since in this condition hypervolemia has not been certainly demonstrated, a direct relationship between elevated ANF and glucocorticoid excess could be suggested.

Adult↗
PubMed1990

Inhibition of pituitary beta-endorphin by ACTH and glucocorticoids.

beta-Endorphin and ACTH are secreted concomitantly in baseline conditions and in response to physiological and pharmacological stimuli. However, few and contradictory data are available on their feedback inhibition mechanisms. To investigate this aspect, the effects of exogenous ACTH1-24 and glucocorticoids on endogenous ACTH1-39 and beta-endorphin were tested in 18 patients with Addison's disease. Two main experimental protocols were employed: (1) 7 patients were given ACTH1-24 50 micrograms as an intravenous bolus followed by a 50-micrograms infusion in 90 min. Blood samples for beta-endorphin, ACTH and cortisol were obtained at 0, 15, 30, 45, 60, 90, 120 min. Six other patients were given oCRH 100 micrograms i.v. plus ACTH1-24, as described above. (2) In 5 other patients, hydrocortisone 37.5 mg was administered i.v. in 90 min. Blood samples for beta-endorphin, ACTH and cortisol were drawn at 0, 15, 30, 45, 60, 90, 120 min. One week later, the same patients were given oCRH 100 micrograms i.v. and hydrocortisone 37.5 mg, as described above. ACTH1-24 administration caused a significant (p less than 0.01) decrease in endogenous ACTH but not in beta-endorphin. oCRH injection significantly stimulated both ACTH and beta-endorphin. The response of both ACTH and beta-endorphin was inhibited by exogenous ACTH1-24. There was a potent inhibition by hydrocortisone on both basal and stimulated beta-endorphin, confirming that the feedback mechanism of glucocorticoids concomitantly inhibits ACTH and beta-endorphin. On the other hand, only CRH-stimulated but not basal secretion of beta-endorphin seems affected by ACTH ultrashort feedback, suggesting an intrapituitary regulation.

Addison Disease↗
PubMed1990

New aspects of mineralocorticoid hypertension.

Primary aldosteronism is the principal disorder of the zona glomerulosa, and a number of subsets have been identified: unilateral adenoma, bilateral micro- or macronodular hyperplasia (idiopathic aldosteronism), primary hyperplasia, and aldosterone-producing carcinoma, either adrenal or ectopic. The diagnostic criteria for a correct differential diagnosis of these subsets are now quite reliable, and our experience is presented in detail. Unfortunately, the pathogenesis of most of these forms is still poorly recognized and requires further investigation. An extreme sensitivity to angiotensin II is present in patients with idiopathic aldosteronism, and a role of adrenal renin is now being advocated. A peculiar form of hyperaldosteronism is the glucocorticoid-remediable subtype. An unusual sensitivity of aldosterone to ACTH is present in this form. The qualitative biochemical abnormality in this disorder consists of a marked overproduction of products of the cortisol C-18-oxidation pathway, 18-hydroxycortisol and 18-oxocortisol, which are more abundant than aldosterone and 18-hydroxycorticosterone. A family with 3 affected sibs has been studied by our group. In other clinical situations, classical zona fasciculata mineralocorticoids (deoxycorticosterone [DOC], corticosterone, and their 18-hydroxy compounds) are secreted in excess. The hypertensive diseases of this zone are rare DOC-secreting tumors and two forms of congenital adrenal hyperplasia, the 11 beta-hydroxylase and 17 alpha-hydroxylase deficiency syndromes, which are identified by the presence of hypokalemia and suppressed renin activity. DOC is the only mineralocorticoid hormone (MCH) oversecreted in the 11-hydroxylase deficiency syndromes, while all ACTH-dependent MCH levels are very high in the 17-hydroxylase deficiency syndromes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗
PubMed1990

Psychological distress and quality of life in endocrine disease.

Despite an upsurge of research in psychoneuroendocrinology, there has been very little interest in the psychological aspects of clinical care in endocrine disease. The clinical and research implications of quality of life in endocrinology (life events preceding disease onset, psychological distress associated with acute illness and convalescence, abnormal illness behavior) are discussed.

Adaptation, Psychological↗
PubMed1990

Investigations on the morphology and function of adrenocortical tissue regenerated from gland capsular fragments autotransplanted in the musculus gracilis of the rat.

This paper describes the function and morphology of regenerated adrenocortical nodules obtained by implanting, in the musculus gracilis of rats, several (n = 6-7) fragments of the capsular tissue of their excised adrenal glands. Four months after the operation, each bilaterally adrenalectomized rat developed six or seven well encapsulated adrenocortical nodules about 2-3 mm in diameter and always lacking chromaffin cells, and displayed almost complete normalization of basal and stimulated blood levels of corticosterone, but not of aldosterone. In vitro study showed that regenerated nodules were well functioning as far as glucocorticoid production was concerned. Accordingly, electron microscopy and stereology indicated that the majority of the parenchymal cells (independently of their location in the outer subcapsular, middle, or inner portions) closely resembled those of the zonae fasciculata/reticularis of the adrenal gland of age-matched sham-operated rats. By contrast, regenerated nodules evidenced a relative impairment in aldosterone secretion, and this was coupled with the presence of only a few zona glomerulosa-like cells. Such cells were grouped in small islets located near the few connective trabeculae detaching from the capsule, and autoradiography showed that they were the only parenchymal elements of the nodule able to bind [125I]angiotensin-II. The possibility is suggested that the paucity of zona glomerulosa-like cells in regenerated nodules could be ascribed to the absence of zona medullaris, which is currently thought to exert a paracrine control on the growth and secretion of zona glomerulosa in the rat adrenal glands.

18-Hydroxycorticosterone↗
PubMed1988

Effects of naloxone on adrenal cortex regulation in patients with primary aldosteronism.

Excess production of proopiomelanocortin (POMC)-derived peptides with aldosterone-stimulating activity has been suggested to play a pathogenetic role in idiopathic hyperaldosteronism (IHA). To further investigate this issue, the opiate receptor antagonist naloxone was administered to 14 patients with primary aldosteronism, 6 with an aldosterone-producing adenoma (APA) and 8 with IHA. Clinical and hormonal effects of iv administration of naloxone (10 mg as a bolus) were compared with those obtained in 8 normal subjects. In normals as well as in APA and IHA patients, naloxone caused a significant increase in plasma cortisol, and no change in ACTH, plasma renin activity (PRA) and aldosterone levels. All subjects were retested after 2 mg dexamethasone. ACTH and cortisol were reduced and PRA was unchanged in all groups, without modifications after naloxone. Baseline aldosterone showed no significant changes in all groups. While normal subjects and APA failed to show any aldosterone response to naloxone after dexamethasone, IHA patients demonstrated a significant decrease. beta-endorphin concentrations were in the normal range before and after dexamethasone. In conclusion, naloxone may have a direct action upon adrenal zona fasciculata increasing the cortisol responsiveness to physiological levels of ACTH in either normals or APA and IHA patients. The decrease of aldosterone induced by naloxone in IHA may be due to an intraadrenal opioid control of zona glomerulosa in this disorder.

Adenoma↗
PubMed1988

Effect of naloxone on the adrenal cortex in primary aldosteronism.

Endogenous opioids have been suggested to play a pathogenetic role in idiopathic hyperaldosteronism (IHA). To investigate this issue, the opiate antagonist naloxone was administered to 8 normals and 14 patients with primary aldosteronism, 6 with an aldosterone-producing adenoma (APA) and 8 with IHA. In normals, APA, and IHA, naloxone caused a significant increase in plasma cortisol and no change in ACTH, renin activity (PRA), and aldosterone levels. All subjects were retested after dexamethasone 2 mg. ACTH and cortisol were reduced and PRA was unchanged without modifications after naloxone. Baseline aldosterone was unaltered in all. While normals and APA failed to show any aldosterone response to naloxone under dexamethasone, IHA patients demonstrated a significant decrease. beta-Endorphin concentrations were in the normal range before and after dexamethasone. In normals as well as in APA and IHA, naloxone may act directly on the adrenal cortex increasing zona fasciculata responsiveness to physiological levels of ACTH. The decrease of aldosterone induced by naloxone in IHA under dexamethasone may be due to an intra-adrenal opioid control of zona glomerulosa in this disorder.

Adenoma↗
PubMed1988

Stressful life events in the pathogenesis of Cushing's syndrome.

Some clinical observations suggested that stressful life events may play an aetiological role in Cushing's syndrome. However, there are no controlled investigations using standardized methods of life events assessment to substantiate this hypothesis. Events in the year before the first signs of disease onset were investigated in 30 consecutive patients with Cushing's syndrome (26 with a pituitary-dependent form, three with an adrenal adenoma, and one with an adrenal carcinoma) and 30 control subjects matched for sociodemographic variables by means of Paykel's Interview for Recent Life Events. Patients with Cushing's syndrome reported significantly more stressful life events than a normal control group (P less than 0.001) and had significantly more of the following: exits (P less than 0.05), undesirable (P less than 0.01) and uncontrolled (P less than 0.01) events. More events that had an objective negative impact (P less than 0.001) and more independent events (unlikely to be a consequence of the illness; P less than 0.001) were also reported. Such ratings were carried out by an independent rater unaware whether the event had occurred in patients or controls. The results are suggestive of a causal relationship between stressful life events and Cushing's syndrome. Such relationship largely pertains to the hypothalamic-pituitary forms of the illness. This is in agreement with a multifactorial model of pathogenesis in Cushing's disease and with current understanding of the complex interdependence of neurophysiological, biochemical and behavioural factors.

Adrenal Gland Neoplasms↗