Bone turnover in patients with endogenous Cushing's syndrome before and after successful treatment.

UNLABELLED: We investigated bone turnover and its restoration in a large number of patients in the active phase and after cure of endogenous Cushing's syndrome. Furthermore, the usefulness of serum osteocalcin and collagen breakdown products as potential markers of active Cushing's syndrome was also evaluated. INTRODUCTION: Suppressed bone formation is one of the most characteristic features of Cushing's syndrome (CS). Despite numerous previous reports, many aspects of the disturbed bone metabolism of these patients are unexplored. In this study, we investigated the time course of bone marker changes after the cure of CS as well as correlations between bone markers and serum cortisol concentrations. METHODS: Eighty-seven patients with CS were studied. Patients were followed up to 48 months after surgical cure. Serum osteocalcin (OC) and collagen breakdown products (CTX) were measured with immunochemiluminescence method and compared to the results of 161 healthy controls. RESULTS: OC showed a negative, while CTX displayed a positive correlation with serum cortisol. Patients with diabetes mellitus and myopathy had significantly lower serum OC levels compared to those without these complications. The area under the curve of OC obtained by receiver-operating characteristics analysis for the discrimination of patients with CS from healthy controls was 0.9227. Postoperative OC increased rapidly from the first few days or weeks reaching its maximum at the sixth month and remained stable after the 24th postoperative month. CONCLUSIONS: Our study demonstrated significant correlations between serum cortisol and both bone formation and resorption markers in the active phase of CS. We propose that OC may serve as a sensitive biologic marker of glucocorticoid activity in endogenous CS during its active phase and it may reflect the clinical cure of the disease.

Plasma dehydroepiandrosterone sulfate levels in patients with hyperfunctioning and non-hyperfunctioning adrenal tumors before and after adrenal surgery.

To investigate the clinical significance of plasma dehydroepiandrosterone sulfate (DHEAS) measurements, 175 patients with histologically confirmed adrenal tumors, 10 cortisol-producing adenomas, 59 aldosterone-producing adenomas, 56 non-hyperfunctioning adenomas, 13 adrenocortical carcinomas, 13 adrenal cysts, and 24 adrenomedullary tumors were studied. Plasma DHEAS levels were expressed as percentage of the mean of sex- and age-matched groups of healthy, normal subjects (DHEAS %). We found that before adrenal surgery, DHEAS % values were significantly reduced in patients with cortisol-producing (mean, 15.2% of control; 95% confidence interval (CI), 9.4-24.7%), non-hyperfunctioning (28.4%; 22.4-36.0%) as well as aldosterone-producing adrenocortical adenomas (55.4%; 47.1-65.1%) compared with controls, while values were normal in patients with adrenal cysts and in those with adrenomedullary tumors. Plasma DHEAS % values exhibited a great variability in adrenocortical carcinomas (mean, 84.0%; 95% CI, 33.2-212.5%). Death from adrenocortical carcinoma was more frequent in patients with high plasma DHEAS % values compared with those with low DHEAS %. During long-term postoperative monitoring, we found that plasma DHEAS levels of patients with aldosterone-producing and non-hyperfunctioning adenomas returned to normal in the second and fourth postoperative year respectively. In patients with cortisol-producing adenomas, plasma DHEAS remained suppressed for as long as 8 years after the operation. These findings show that except in adrenocortical carcinomas and cysts, plasma DHEAS levels are significantly decreased in all groups of adrenocortical tumors, including non-hyperfunctioning and aldosterone-producing tumors. The extent of this decrease and the postoperative persistence of suppressed plasma DHEAS levels may be related to the glucocorticoid production of adrenocortical tumors.

Mineralocorticoid production of adrenal cortical adenomas.

We studied in vitro and in vivo corticosteroid production as well as the presence of symptoms of an increased mineralocorticoid effect in patients with 'silent' adrenal cortical adenomas, and compared these results to those found in patients with classical mineralocorticoid excess syndromes. We found that under in vitro conditions, cells from 'silent' adrenal cortical adenomas (n = 19) produced substantial amounts of both zona glomerulosa and fasciculata steroids, although the production of steroids in these cells was lower compared to that in mineralocorticoid-producing adenoma cells (n = 26). Patients with aldosterone-producing and 'silent' adenomas had significantly increased plasma atrial natriuretic peptide levels, which remained non-suppressible after upright posture and furosemide administration. Of the 25 patients with 'silent' adenomas, 11 had low and non-stimulable plasma renin activity (PRA) before but, in most cases, not after adrenal surgery. When compared to those with normal PRA (n = 14), patients with low PRA 'silent' adenomas (n = 11) had higher blood pressure which was significantly reduced after surgery, and a mild hypokalemia before but not after surgery. Although basal plasma concentrations of aldosterone, 18-hydroxy-corticosterone, corticosterone, deoxycorticosterone, 18-hydroxy-DOC, cortisol,11-deoxycortisol and 17-hydroxy-progesterone (17-OH-P) were not increased in either groups of 'silent' adenomas, ACTH stimulation produced a hyperreactive response for all measured steroids, of which an extremely high 17-OH-P seemed to be one of the most intriguing findings. We consider that these observations in 'silent' adrenal cortical adenomas may justify surgical intervention, irrespective of the size and potential malignancy of these adenomas.

Direct inhibitory effect of etomidate on corticosteroid secretion in human pathologic adrenocortical cells.

Etomidate has been shown to inhibit corticosteroid secretion in the normal adrenal gland, but its direct effect in human pathologic adrenals has not been clearly established. In the present study the effect of varying doses of etomidate (10(-11)-10(-5) M) was investigated on basal and adrenocorticotrophic hormone (ACTH)-stimulated corticosteroid secretions in isolated adrenocortical cells obtained from two patients with primary aldosteronism (adenoma and micronodular hyperplasia) and in those from a patient with Cushing's syndrome (adenoma). In cells from primary aldosteronism, increasing concentrations of etomidate (10(-11)-10(-5) M) produced a dose-dependent decrease of basal and ACTH-stimulated cortisol, aldosterone, 18-hydroxycorticosterone, and corticosterone secretions (ED50: 10(-9)-10(-8) M for each of these corticosteroids). In the same cells, the secretions of 11-deoxycortisol and deoxycorticosterone were increased in the presence of low (10(-9)-10(-7) M) but not high doses of etomidate (10(-6)-10(-5) M). In cells from Cushing's syndrome the changes in corticosteroid secretion were similar to those found in primary aldosteronism except that aldosterone and 18-hydroxycorticosterone could not be determined due to their low levels. Thus the potent inhibition of corticosteroids in human pathologic adrenocortical cells in the presence of low concentrations of etomidate may be predominantly due to inhibition of the 11 beta-hydroxylase enzyme, whereas higher doses of the drug may inhibit earlier steps of the corticosteroid biosynthetic pathway.

[Laparoscopic adrenalectomy]. / Laparoszkópos adrenalectomia.

The authors performed three left and one right sided laparoscopic adrenalectomies between 3rd April and 8th August 1997. The indication of surgery was hormonally active cortical adenoma of about 2 cm size in three cases, a 6 cm large hormonally inactive tumour in one case respectively. For the operation on the left side three, on the right side four trocars with 11 mm diameter was used. The duration of the operations was between 115 and 220 min. The patients left one the second or third postoperative day, no complication was observed. The authors' opinion based on both literature data and their own experience is that laparoscopic approach to adrenalectomies is the method of choice today.

[Thyroid-stimulating hormone-secreting pituitary adenoma]. / Thyreoidea stimuláló hormont termelö hypophysis adenoma.

A 40-year-old male patient with a 2 years history of recurring hyperthyroidism is presented with clinical hyperthyroidism and diffuse goiter. Despite thyreostatic treatment and surgical thyroid ablation the hyperthyroidism recurred. The patient had laboratory evidence of hyperthyroidism and his serum TSH was persistently and enormously elevated (T4:214 nmol/l, T3:6.9 nmol/l, TSH:218 mIU/l)> Computed tomography and magnetic resonance imaging confirmed a pituitary mass of 7 cm in a-p diameter, with supra-, parasellar and sphenoidal extension. The pituitary adenoma was partially resected by transsphenoidal surgery, which failed to result in a substantial decrease in the serum thyrotropin level. Pituitary irradiation and a long-term somatostatin analog octreotide treatment (300-600 micrograms/die) combined with bromocriptine therapy resulted in a significant, but still incomplete suppression of thyrotropin secretion (TSH level about 15 mIU/l) and persisting mild hyperthyroidism. The size of the adenoma was unchanged during the two years of highdose octreotide treatment period. According to our best knowledge this is the first reported case of a thyrotropin-secreting pituitary adenoma in Hungary.

[Flow-cytometric study of the DNA content in adrenal cortex tumors]. / Mellékvesekéreg-daganatok dezoxiribonukleinsav-tartalmának átáramoltatásos citometriás vizsgálata.

Flow cytometric deoxyribonucleic acid measurements were performed on 26 adrenocortical tumours and 9 non-tumours adrenals. All but one tumours were classified both histologically and clinically as benign, however, two thirds of them had abnormal deoxyribonucleic acid stemlines. Proliferative indices of adenomatous tissues were significantly higher than those of non-tumorous adrenals (p < 0.01). When compared to tumors smaller than 5 cm in size, tumours larger than 5 cm displayed significantly higher proliferative indices (p < 0.01). Thus, flow cytometry appears to have only a limited value in distinguishing between benign and malignant adrenocortical tumours, but it may provide additional information about the prognosis of these tumours.

Skeletal differences in bone mineral area and content before and after cure of endogenous Cushing's syndrome.

UNLABELLED: We examined bone densitometric data in a four-year follow-up period before and after the cure of CS. Plasma cortisol concentrations were similar, but the duration of estimated glucocorticoid excess was longer in patients with prevalent bone fractures compared to those without fractures. After therapy of CS, bone area, BMC and BMD increased significantly at the LS and femur during follow-up, but they decreased at the forearm, suggesting redistribution of bone minerals from the peripheral to the axial skeleton. INTRODUCTION: Only a few studies report the changes in bone mineral density (BMD) after the cure of Cushing's syndrome (CS). METHODS: Forty-one patients with Cushing's disease, 21 patients with adrenal CS and 6 patients with ectopic CS were prospectively enrolled. BMD, bone mineral content (BMC) and bone area were measured by DXA. RESULTS: No significant correlations were found between serum cortisol concentrations and baseline bone densitometric data. After successful therapy of CS, bone area and BMD increased significantly at the lumbar spine (LS) and femur during follow-up, but they decreased at the forearm. The progressive increase in BMC at the LS had a significant negative correlation with the change of the BMC of radius in the first and second follow-up years. The change in the body mass index was an independent predictor for changes in BMC both at the LS and at the forearm at the second year of remission. CONCLUSIONS: The regional differences and the time-dependent changes of BMC suggest that the source of marked increase in axial BMC after the cure of CS is, at least partly, due to the redistribution of bone minerals from the peripheral to the axial skeleton.

Thyrotropin-releasing hormone increases plasma atrial natriuretic peptide levels in human.

The effect of thyrotropin-releasing hormone (TRH) on plasma atrial natriuretic peptide (ANP), TSH, prolactin, cortisol and aldosterone levels in 26 patients with normal pituitary and thyroid gland function was examined. Bolus iv injection of 200 micrograms TRH produced, between 0 and 60 min, a significant gradual rise of plasma ANP concentrations from 30.4 +/- 2.3 to 54.8 +/- 6.4 pg/ml (mean +/- SE). Plasma prolactin and TSH concentrations increased four- and six-fold of basal values with peak responses at 15 and 30 min, respectively, whereas plasma cortisol and aldosterone concentrations remained unchanged after the drug treatment. The patients had no significant changes in blood pressure or pulse rate. We conclude that there may be indirect mechanism(s) which result in increased ANP levels after TRH administration.

Dissociation of plasma atrial natriuretic peptide responses to upright posture and furosemide administration in patients with normal-, low renin essential hypertension and primary aldosteronism.

Plasma levels of atrial natriuretic peptide (ANP) were measured in patients with normal renin essential hypertension (n = 12), low renin essential hypertension (n = 11) and primary aldosteronism due to aldosterone producing adenoma (APA, n = 8) and idiopathic hyperaldosteronism (IHA, n = 3) after overnight rest in the supine position and after 4 h upright posture and furosemide administration. Plasma renin activity (PRA) and aldosterone (Aldo) levels were also determined. Compared to normal renin essential hypertension (33.6 +/- 2.2 pg/ml), basal plasma ANP was significantly higher in low renin essential hypertension (66.8 +/- 6 pg/ml), IHA (54.1 +/- 6.3 pg/ml) and APA before (62.4 +/- 4.9 pg/ml) but not after adrenal surgery (22 +/- 3 pg/ml). After upright posture and furosemide administration plasma ANP was decreased (p less than 0.01) in patients with low renin and, less markedly, with normal renin essential hypertension, however not in IHA and APA. In about half of the patients with low renin essential hypertension, unchanged PRA after upright posture and furosemide administration was associated with increased plasma Aldo and decreased ANP levels. We conclude that (i) the relatively high basal plasma ANP levels in low renin essential hypertension, IHA and APA may reflect the presence of volume expansion in these patients; (ii) the hormonal responses to upright posture and furosemide administration in patients with normal and low renin essential hypertension may indicate a counterregulatory role of ANP during activation of the renin-angiotensin-aldosterone system; (iii) the high plasma ANP, which is unresponsive to upright posture and furosemide administration, in patients with APA and IHA may be a potentially interesting new finding whose pathophysiological significance remains to be established.

Atrial natriuretic peptide directly inhibits corticosteroid biosynthesis in human aldosterone-producing adenoma.

The effect of human atrial natriuretic peptide (hANP) on aldosterone, 18-OH-cortisterone, corticosterone, deoxycorticosterone, and cortisol secretion was examined in isolated human aldosteronoma cells from five patients with primary aldosteronism. hANP exerted a nearly identical inhibitory action on basal secretion of each of these steroids and antagonized also the stimulating effects of ACTH, serotonin, metoclopramide and vasoactive intestinal polypeptide. The results suggest that in human aldosteronoma cells hANP may be a non-selective inhibitor of corticosteroid biosynthesis and that the site of inhibition of steroidogenesis may be localized to the early pathway of steroid biosynthesis.

Comparative analysis of plasma 17-hydroxyprogesterone and cortisol responses to ACTH in patients with various adrenal tumors before and after unilateral adrenalectomy.

Patients with non-hyperfunctioning adrenal adenomas often have an increased plasma 17-hydroxyprogesterone response to ACTH stimulation. The effects of adrenal surgery on this abnormality have rarely been investigated. One hundred and sixty-one patients with unilateral adrenal tumors (non-hyperfunctioning adenomas, 78; cortisol-producing adenomas, 8; aldosterone-producing adenomas, 37; adrenal cysts, 12; pheochromocytomas, 26) were studied. Patients before and after adrenal surgery as well as 60 healthy subjects underwent an ACTH stimulation test using 2 mg synthetic ACTH(1-24) (Cortrosyn Depot, Organon). Basal and ACTH-stimulated plasma 17-hydroxyprogesterone and cortisol concentrations are reported. Before adrenal surgery, the basal plasma 17-hydroxyprogesterone concentrations were normal in patients with all types of tumors. However, the ACTH-stimulated plasma 17-hydroxyprogesterone levels were abnormally increased in 53% and 31% of patients with non-hyperfunctioning adenomas and aldosterone-producing adenomas, respectively. In addition, a few patients with adrenal cysts and pheochromocytomas also showed an increased ACTH-stimulated 17-hydroxyprogesterone response. After unilateral adrenalectomy, this hormonal abnormality disappeared in most, although not all patients with adrenal tumors. In patients with non-hyperfunctioning adrenal tumors, ACTH-stimulated plasma 17-hydroxyprogesterone and cortisol concentrations significantly correlated with the size of the tumors. These results firmly indicate that the tumoral mass itself may be responsible for the increased plasma 17-hydroxyprogesterone and cortisol responses after ACTH stimulation in patients with non-hyperfunctioning and hyperfunctioning adrenal adenomas.