Ketoconazole therapy in Cushing's disease.
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Biomedical subjects
Publications and source records attributed to A Angeli.
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Ten chronic male alcoholics presenting with hypogonadism but without overt liver failure were examined under basal conditions and after stimulation of the testicular steroidogenesis with a single dose of human chorionic gonadotropin (hCG, 2,000 IU im). Plasma concentrations of testosterone (T), 17 beta-estradiol (E2), progesterone (P) and 17-OH progesterone (17-OHP) were measured between 08:00-09:00 prior to injection and then every 24 h at the same time in the morning until the 96th hour following the injection. Controls were 10 male adult volunteers, examined under the same conditions. Four alcoholics underwent a second hCG stimulation after 10 day controlled abstinence from alcohol. Basal plasma T and P were significantly decreased and increased respectively in the alcoholics (p less than 0.001) whereas E2 and 17-OHP were much the same in both groups. The magnitude of the T response to hCG injection was significantly lower in the alcoholics at any considered time (p less than 0.001). The E2 response, too, was lower, whereas the ratio E2 change/T change after hCG was higher. The response peak occurred earlier for E2 than for T both in controls and alcoholics. The mean percent change at 24 h and the mean maximum increase of 17-OHP were higher in the alcoholics (p less than 0.01 and p less than 0.05 respectively). An increase in P after hCG was observed in only 5 alcoholics (responders), while some subjects displayed paradoxical decreases. Abstinence was always followed by an increased T response and a decreased 17-OHP response. The E2 response was unchanged and two P responders displayed an increased response.(ABSTRACT TRUNCATED AT 250 WORDS)
Plasma PRL, TSH, total and free T4, total and free T3, and 17 beta-estradiol were evaluated in 29 premenopausal women with well-documented fibrocystic disease of the breast and in 29 healthy matched controls. Plasma PRL and TSH dynamics after acute TRH injection (200 micrograms i.v.) were also determined. All hormonal measurements were performed in the follicular phase of the menstrual cycle. Neither patients nor controls showed any thyroid function impairment. Basal plasma levels of the examined hormones were in the normal range in both groups. When considering data pertinent to PRL and TSH secretory patterns after TRH stimulation, no difference was recorded between patients and controls for TSH secretion, evaluated in terms of maximum peak, net (delta) and percent (delta %) increase above the baseline level and integrated area of response. On the contrary, the response of PRL was significantly higher in patients than controls (maximum peak at 20 min, mean +/- SE, 119.9 +/- 14.1 vs. 60.8 +/- 5.5 ng/ml, p less than 0.001; integrated area of response, 5,725 +/- 908 vs. 3,243 +/- 266 ng/ml/120 min, p less than 0.01). The results are compatible with the view that, in most patients with fibrocystic disease of the breast, there are abnormalities in the control of PRL secretion, which lead to enhanced release of the hormone after stimulation. In such cases the control of TSH appears to be operating normally.
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Radioimmunoassayable levels of total and free 3,5,3'-triodothyronine (T3) and thyroxine (T4), thyroid stimulating hormone (TSH), thyroxine binding globulin (TBG) and prolactin (Prl) were measured in a series of samples of breast cyst fluid (BCF) aspirated from 73 pre-menopausal women with gross cystic disease of the breast and in coincidental blood samples. In BCF free T3 and free T4 were consistently higher than in plasma (P less than 0.001) as was also total T3 in the majority of cases (P less than 0.05). Total T4, TBG and Prl were much lower than in plasma (P less than 0.001). TSH was roughly as in plasma. No correlation was found between plasma and BCF values. The results indicate that thyroid hormones may be accumulated in their effective form in the cyst fluid. A highly significant inverse correlation was found between intracystic free T3 and log (Prl). Our data, considered in relation to previous experimental evidence, suggest the possibility that thyroid hormones act at the breast level in concert with Prl. Accumulation of thyroid hormones in BCF could play a role in the development or maintenance of gross cystic disease of the breast or be a mere consequence of the cystic changes.
Circulating Angiotensin Converting Enzyme (ACE) level, chest X-rays and respiratory function tests were determined in 76 male patients with silicosis. Mean serum ACE in the patients was significantly higher than in 30 healthy controls (129.8 +/- 4 U/ml and 92.4 +/- 22.7 respectively), although individual values were in the normal range in about half of the patients. Enzyme levels were independent of silica dust exposure, X-ray changes, functional lung impairment, age, smoking habits, and presence of chronic obstructive pulmonary disease. However, patients with more severe radiological changes tended to have lower ACE values. Our data confirm that serum ACE level is frequently raised in silicosis, but does not give further information in the evaluation of the disease.
The occurrence of a specific glucocorticoid binding activity was investigated in breast cyst fluid (BCF) samples aspirated from 481 women under treatment for breast cystic disease. [3H]cortisol was incubated with BCF at 4 degrees C with and without 100-fold molar excess of non-radioactive steroid in order to account for non-specific binding. Corticosterone, progesterone and dexamethasone-binding activities were also investigated in about 50% of the specimens. Consistent amounts of a specific cortisol-, corticosterone- and progesterone-binding component were observed in about 30% of samples. Apparent binding values ranged from 4.31 to 80.78 nmol/l for cortisol, from 3.94 to 75.72 nmol/l for corticosterone, and from 1.18 to 16.45 nmol/l for progesterone. No specific binding for dexamethasone was detected. Scatchard analyses for [3H]cortisol and [3H]progesterone were made in pools of 'positive' BCF, human serum and whey of human milk, respectively. The mean values of the apparent equilibrium association constant (Ka) were compatible with the existence of high affinity protein-hormone interactions in each considered medium. Data obtained in ligand competition experiments for different steroid molecules suggest the similarity of the glucocorticoid- and progesterone-binding component found in 30% of BCF samples examined with the plasma corticosteroid-binding globulin (CBG, transcortin) and especially with the transcortin-like component detected in the whey of the human milk. It is suggested that the transcortin-like component may play an important role in controlling kinetics of transport and in regulating the effective levels of cortisol and progesterone in numerous breast cyst fluids.
Nine chronic male alcoholics presenting with hypogonadism but without overt liver failure were examined under baseline conditions and after acute injection of gonadotropin releasing hormone (GnRH, 100 micrograms iv) and thyrotropin releasing hormone (TRH, 200 micrograms iv), performed at 60 min of a 3-h infusion of saline and 0.4 g/kg ethanol, respectively. Controls were 10 male adult volunteers examined under the same conditions. Six alcoholics and six controls underwent a third test with the infusion of 0.8 g/kg ethanol. Subjects were hospitalized and the infusion was started after a 48-h period of abstinence from alcohol. Tests were performed in random order at intervals of at least three weeks, always at 15:00 following a standard meal in the morning. Plasma levels of FSH, LH, prolactin (PRL) and testosterone (T) were measured by radioimmunoassay. Significantly higher levels of FSH, LH and PRL, and significantly lower levels of T were recorded in alcoholics vs. controls on plasma samples drawn at about 08:00 for three consecutive days. Ethanol infusion at the dose of 0.4 g/kg did not change the pattern of response to GnRH and TRH of controls and alcoholics. Doubling the alcohol dosage yielded a significant reduction of LH response in normal subjects whereas did not result in a similar effect in alcoholics. The mean LH increment of alcoholics was significantly less than that of normals at all times during saline and infusion of 0.4 g/kg ethanol; significance was not attained when the dose of ethanol was 0.8 g/kg.(ABSTRACT TRUNCATED AT 250 WORDS)
Measurement of adenohypophyseal hormones in the cerebrospinal fluid (CSF) was recently proposed as an useful procedure to differentiate pituitary intra and extrasellar tumors. So far, data reported are conflicting. We measured the concentrations of GH, TSH, LH and PRL in CSF and plasma in 30 controls and in 37 patients with various pituitary diseases (18 intrasellar adenomas, 14 extrasellar adenomas and 5 empty sella syndromes). The concentrations of examined hormones in CSF were very low or undetectable in all control subjects. In most patients with pituitary tumors, adenohypophyseal hormones were found to be present in CSF, in great amounts. No significant differences were found between intra and extrasellar tumors. In agreement with recently reported data, no significant correlation was found between GH, TSH, FSH and LH levels in CSF and plasma, while a significant correlation (p less than 0.01) was obtained between CSF and plasma levels of PRL, either in all patients or in those with extrasellar tumors only. All patients bearing an empty sella had PRL detectable in CSF: in 2 cases PRL levels were very high. In conclusion our data do not confirm that measurement of adenohypophyseal hormones in CSF represents an useful screening to differentiate tumors with extrasellar extension. PRL data deserve interest in order to gain understanding of the hormone dynamics between CSF and vascular compartments.
The circadian rhythm of glucocorticoid secretion represents an important endogenous synchronizer, a signal to place other bioperiodicities along an appropriate time scale. The results obtained both in experimental animals and in man by properly-timed administration of corticoids as well as personal observations in patients with Addison's disease given replacement therapy suggest that glucocorticoid action may not need continuous supply of hormone molecules to target cells but appropriate waves complying with the peripheral susceptibility. Furthermore, circadian changes in the susceptibility to glucocorticoid action may be phase-shifted among different targets. Evidence is presented that in human beings ACTH secretion is exquisitely sensitive to the negative feed-back effect by cortisol in the nocturnal hours following midnight, i.e. in a circadian stage preceding the acrophase of plasma glucocorticoid levels. In the circadian domain multiple rhythmic events, including chrono-feed-back and chrono-feed-forward mechanisms as well as the organization of steroid binding to plasma corticosteroid-binding globulin, provide stability, plasticity and economy to the activity of the entire hypothalamo-pituitary-adrenal system by conveying genetic and environmental control into a well-defined temporal program.
Concentration of dehydroepiandrosterone sulphate (DHAS), cortisol (F), aldosterone (A) and prolactin (PRL) were measured in 70 samples of breast cyst fluid (BCF) obtained by needle aspiration from patients having gross cystic disease of the breast. DHAS concentrations in our series of BCF were scattered over a broad range, up to values 200-fold higher than in plasma, with ample interindividual variability; cortisol was present in BCF in very small amounts. Aldosterone and PRL values were in the same order of plasma levels; moreover, a significant correlation was found between DHAS and PRL concentrations in BCF.
Twelve alcoholic men (28-55 yr) presenting hypogonadal features but without overt liver failure were hospitalized and examined still consuming alcohol regularly. Sleep was approximately from 2200 to 0600; three equicaloric meals were served at 0700, 1200, and 1800. Blood samples were drawn at 4-hr intervals throughout a 24-hr span starting from 0800. Measured levels of cortisol and testosterone were then analyzed by rhythmometric procedures in order to estimate parameters of the circadian oscillation such as mesor, amplitude, and acrophase, and the relevant confidence limits. Data were compared to those obtained in a matched group of 20 healthy controls. With regard to cortisol, the rhythmometric analyses allowed the demonstration of a normally synchronized circadian rhythm substantially superimposable in alcoholics and controls. With regard to testosterone, the results were compatible with a significant circadian oscillation only in the control group. Alcoholics did show ample interindividual variability of plasma testosterone levels, but the apparent lack of the circadian rhythm was independent of the steroid concentration. These data extend previous observations and are consistent with the occurrence of important abnormalities in the circadian pattern of plasma testosterone in chronic male alcoholics prior to liver failure.
Immunoglobulin levels of the major classes of IgG, IgA and IgM have been measured by radial immunodiffusion in 74 samples of breast cyst fluid (BCF) aspirated by women with "Gross Cystic Disease". Appreciable levels of Ig were found in all samples. No significant correlation was observed between intra-cystic Ig levels and the corresponding levels measured on coincidental blood specimens. A significant linear correlation was found between intra-cystic Ig levels and the apparent specific binding activity for cortisol attributable to a transcortin like component (n = 30; p less than 0.05 for IgA, p less than 0.0025 for IgG; p less than 0.05 for IgM).
To study effects on pituitary-adrenocortical activity of a sustained block of angiotensin II formation, six 'drug-resistant' patients with essential hypertension were studied before and during treatment with an inhibitor of the angiotensin-converting enzyme (Captopril, SQ 14,225). The drug was given in increasing doses (100-400 mg/day) for 2 weeks whilst patients received a moderately restricted sodium intake (60-80 mmol/day). Immunoreactive ACTH, cortisol, aldosterone, plasma renin activity (PRA) and the activity of the angiotensin-converting enzyme (ACE) were measured in blood samples drawn at 0800-0900 h. Urinary excretion of cortisol and aldosterone were measured in 24-h urine collections. Further information on pituitary-adreno-cortical function was obtained by measuring serial plasma corticosteroid levels after submaximal stimulation with a synthetic ACTH preparation. ACTH and cortisol did not change an observation which does not support the hypothesis that glucocorticoid activity is influenced by a decrease in plasma angiotensin II concentrations.
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Serum corticosteroid-binding globulin (CBG, transcortin) binding capacity for prednisolone and for cortisol, and levels of the circulating cortisol were evaluated in healthy adult subjects and in patients under long-term treatment with prednisone. Blood samples were drawn at 4-hr intervals throughout at least 24 hr; the prednisone administration was discontinued 24 hr before starting examination. Circadian fluctuations in the CBG-binding capacity for prednisolone occurred in healthy subjects: maximum binding was at 12 midnight and minimum binding at 8 a.m. The diurnal pattern of prednisolone-binding capacity was characterized by phase shifts of approximately 12 hr and 8 hr compared with those of serum cortisol and cortisol-binding capacity, respectively. There were no diurnal variations of prednisolone- and cortisol-binding capacity in the prednisone-treated patients. Moreover, the levels of both capacities, expressed as micrograms bound steroid/100 ml, were significantly reduced with respect to normal control subjects. Cyclic variations in serum CBG-binding capacity may represent an additional factor accounting for temporal differences in the action of synthetic corticoids which are bound by the transport protein. Synthetic derivatives when chronically administered may interfere not only with the adrenal secretion but also with the serum transport of glucocorticoids.
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