Corticotrophic macroadenoma of the pituitary associated with hypoadrenalism

A 60-year-old man underwent transfrontal surgery for a macroadenoma of the pituitary which presented with chiasmal compression, and immunohistochemical examination of the resected specimen revealed a corticotrophic tumour. Despite subsequent external irradiation, he was left with a large tumour remnant, which continued to grow. There were no clinical signs of Cushing's syndrome either before or after surgery and 24 h urine excretion of cortisol was not elevated. Plasma ACTH concentrations were marginally raised. However, there was loss of circadian variation in serum cortisol concentrations and administration of high-dose oral dexamethasone was followed by a marked and reproducible rise in both ACTH and cortisol. Two years later he developed symptoms and signs of hypoadrenalism and urine cortisol excretion was low, even though the paradoxical response to dexamethasone was preserved. Treatment with 0.5 mg dexamethasone each day was associated with partial resolution of his symptoms and urine cortisol concentration rose into the normal range. This treatment was maintained until his death in hospital in April 1988. The possible mechanism underlying the association between a corticotrophic tumour and hypoadrenalism are discussed.     

Adrenocorticotrophin-independent macronodular adrenal hyperplasia in a patient with lysine vasopressin responsiveness but insensitivity to gastric inhibitory polypeptide

The aetiology of ACTH-independent macronodular adrenal hyperplasia (AIMAH) is uncertain. We examined a 55 year old man with Cushing's syndrome due to AIMAH, whose cortisol levels increased after stimulation with lysine-8-vasopressin (LVP) in vitro as well as in vivo. Abdominal MRI revealed nodular enlargement of both adrenal glands. No adenoma was evident on pituitary MRI. 131I-adosterol scintigraphy exhibited marked uptake into both adrenal glands. Although baseline plasma cortisol levels were within normal limits, urinary free cortisol excretion was 3-fold higher than the upper limit of the normal range. Plasma ACTH levels were undetectable. Oral dexamethasone failed to suppress plasma cortisol levels irrespective of dose, and administration of corticotrophin releasing hormone failed to increase plasma ACTH and cortisol levels. LVP injection failed to increase plasma ACTH levels, but elicited an increase in plasma cortisol levels. The direct stimulatory effect of LVP on cortisol secretion was confirmed in vitro in cultured adrenocortical cells from macronodules obtained at surgery. Food intake, gastric inhibitory polypeptide (GIP), or octreotide administration, which were reported to regulate cortisol release in patients with AIMAH, failed to affect plasma cortisol levels. In conclusion, plasma cortisol responsiveness to LVP, GIP, and octreotide is heterogeneous in patients with AIMAH.     

Serum bilirubin distribution and its relation to cardiovascular risk in children and young adults

The discovery of an asymptomatic adrenal mass (incidentaloma) during the investigation of an unrelated condition is relatively common. In this study, we report the clinical, radiologic, and endocrine evaluation of 38 patients (22 women and 16 men aged 24 to 84 years) with adrenal incidentaloma (size, 1 to 12 cm). The patients underwent basal and dynamic evaluation of the hypothalamic-pituitary-adrenal (HPA) axis, renin-angiotensin-aldosterone system, and adrenomedullary function. Moreover, computed tomograpy (CT) scan and 131I-6beta-iodomethyl-19-norcholest-5(10)-en-3beta-ol(NP-59) and/or 131I-metaiodobenzylguanidine (MIBG) scintigraphy were performed. The endocrine evaluation indicated two cases of pheochromocytoma and four cases of preclinical Cushing's syndrome, three of which underwent surgery with histologic diagnosis of two adrenocortical adenomas and one carcinoma. Low levels of serum dehydroepiandrosterone sulfate (DHEA-S), associated with a markedly increased 17-hydroxyprogesterone (17-OHP) response to a corticotropin (ACTH) test, were found in patients with incidentaloma. On the basis of endocrine and morphologic data, 13 patients underwent surgical treatment: five adrenocortical adenomas (two functioning), two pheochromocytomas, two ganglioneuromas, one cortisol-secreting adrenal carcinoma, one lymphangiomatous cyst, one myelolipoma, and one hemorrhage were found. Careful diagnostic assessment of incidentally discovered adrenal masses must be performed to exclude the presence of malignant and/or functioning lesions and to verify the possibility that patients with incidentaloma have a genetic or acquired deficit of adrenal steroidogenic activity.     

Pre-toxic adrenocortical adenoma ("pre-Cushing syndrome"): role of 17-hydroxyprogesterone dosage under ACTH analog stimulation. Apropos of a case

We report on a case of a 63-year-old male patient who presented with an adrenal incidentaloma corresponding to a pre-toxic adrenocortical adenoma ("pre-Cushing's syndrome"). Nycthemeral cortisol cycle and free urinary cortisol were within the normal range. Basal ACTH and dehydroepiandrosterone sulfate levels were decreased and the 17-hydroxyprogesterone (17OHP) response under ACTH stimulation (tetracosactide) was increased. The ACTh test appears mandatory in the incidentaloma work-up to order to identify the pre-toxic adenomas. Its elevation reflects likely intra-tumoral enzymatic defects. Pre-Cushing's syndrome therapeutic management is still debated. No surgery was performed in our patient. A 3-year follow-up did not show overt Cushing's syndrome features.     

Clinical characteristics of patients with the initial diagnosis of NIDDM with positivity for antibodies to glutamic acid decarboxylase

Bronchial carcinoid tumor is the most frequent occult source of ectopic ACTH-dependent Cushing's syndrome, but its initial localization may be very difficult, as well as its postoperative follow-up. We here present the case of a 21-year-old man with Cushing's syndrome and biochemical findings suggesting an ectopic source of ACTH (lack of inhibition of cortisol after overnight 8-mg dexamethasone suppression test, and lack of response to h-CRH challenge). Chest CT-scan showed a node adjacent to the left lung hilium whose nature was confirmed by uptake of 111Indium-DTPA labelled octreotide scintigraphy. Surgical resection of the tumor consisted in an upper lobectomy of the left lung. Microscopic examination identified a typical carcinoid tumor. After surgery pituitary-adrenal function normalized and a second scintigraphy offered additional data on the absence of tumor remnants.     

Klippel-Trenaunay-Weber syndrome with adrenal pseudocyst: characterization by blood pool and adrenocortical iodocholesterol scintigraphy

A 44-year-old woman with Klippel-Trenaunay-Weber syndrome (KTWS) was evaluated for an adrenal mass incidentally discovered on CT. An NP-59 scintigraph showed normal symmetric adrenal tracer uptake, and a Tc-99m labeled RBC scan showed no evidence for an adrenal hemangioma but did show characteristic dilated and tortuous vasculature at multiple other sites. The mass was removed and found to be an adrenal pseudocyst. The pseudocyst was believed to have arisen from a pre-existing, thrombosed and organized adrenal hemangioma. This case demonstrates the previously reported utility of RBC scintigraphy in the depiction of the vascular abnormalities in the diagnosis and treatment of patients with Klippel-Trenaunay-Weber syndrome, as well as the utility of NP-59 scintigraphy in evaluating patients with adrenal masses.     

The influence of dose and dose rate on the incidence of neoplastic disease in RFM mice after neutron irradiation

The effect of circadian rhythm and alterations in posture on plasma aldosterone concentration was studied in 13 patients with primary aldosteronism (six adenoma, five idiopathic hyperplasia, two carcinoma) to define the regulatory mechanism in each of these pathologic subtypes. Blood samples for aldosterone, cortisol, renin, and potassium concentrations were obtained every 4 h during prolonged recumbency (32 h) and upright posture (16 h). During recumbency, aldosterone and cortisol followed a normal circadian pattern in patients with adenoma and hyperplasia, with peak values at 0400-0800 h and the nadir at 1600-2400 h. Normalized aldosterone and cortisol values correlated significantly in both groups (adenoma r=+0.66, P less than 0.001; hyperplasia r=+0.42, P less than 0.01). With upright posture, aldosterone levels declined parallel to the normal circadian fall in cortisol in patients with adenoma (r=+0.68, P less than 0.001); whereas aldosterone levels increased in patients with hyperplasia parallel to small increments in renin (r=+0.65, P less than 0.001) and potassium (r=+0.64, P less than 0.001). During the administration of dexamethasone, aldosterone no longer correlated with cortisol in patients with adenoma but continued to correlate with renin during upright studies in patients with hyperplasia (r=+0.77, P less than 0.01). Aldosterone circadian rhythm was abnormal in patients with carcinoma and no effect of posture was noted. Unilateral adrenalectomy restored the normal postural relationship in four patients with adenoma. These studies suggest that aldosterone secretion is under continuous ACTH control regardless of posture in patients with adenoma, whereas persistent adrenal responsiveness to small increments in renin and/or potassium mediate the postural increase in plasma aldosterone in patients with hyperplasia. True adrenal autonomy occurs only in patients with adrenal carcinoma and when ACTH is suppressed in those with adenoma.     

Hormonal responses during various phases of autoimmune adrenal failure: no evidence for 21-hydroxylase enzyme activity inhibition in vivo

Adrenal autoantibodies (ACA) are markers of adrenal cortex involvement in idiopathic Addison's disease. Recently the 21-hydroxylase (21-OH) enzyme has been discovered to be the major autoantigen of the ACA. A potential role of these antibodies in determining adrenal failure by inhibition of the 21-OH has been recently postulated. To test this hypothesis, cortisol and aldosterone (final products of adrenal steroid synthesis) and 17-hydroxyprogesterone (17-OH-progesterone) (as a marker of 21-OH impairment) have been investigated in baseline conditions and after ACTH (1-24) stimulation test in a group of 42 patients positive for both ACA and 21-OH autoantibodies. Patients were divided into five groups according to the stages (0-4) of adrenal failure. With progression toward overt Addison's disease, baseline 17-OH-progesterone, cortisol, and aldosterone remained almost unchanged but with impairment of their responses to ACTH (1-24) stimulation. The 17-OH-progesterone/cortisol ration remained normal both in basal conditions and after stimulation at stages 0-3. At stage 4 (overt Addison's disease), this ratio increased in baseline condition with no changes after ACTH (1-24), probably because of persistent 17-OH-progesterone gonadal production. In conclusion, there was a progressive and concomitant impairment of the synthesis of all steroids tested over various phases of adrenal failure. The pattern of response of the 17-OH-progesterone/cortisol ratio to ACTH stimulation in patients with 21-OH autoantibodies was not consistent with the autoantibodies inhibiting the 21-OH activity. This suggests that the inhibiting effect of 21-OH autoantibodies on 21-OH activity is not usually evident in vivo.     

Homicide in the United States, 1951-1990: synchronous age-specific rate changes in adult men

We report a man with pre-Cushing's syndrome due to ACTH-independent bilateral macronodular adrenocortical hyperplasia. Plasma ACTH was low and urinary 17-OHCS was not suppressed by a high dose of dexamethasone (8 mg), but plasma cortisol was responsive to exogenous ACTH. The adrenal glands were enlarged and contained multiple nodules composed of large clear cells and small compact cells. The steroid levels in the adrenal glands were lower than those in overt Cushing's syndrome due to the adrenocortical adenoma. This suggests that the tumor produces insufficient amounts of active hormones to have a clinical effect.     

Pulmonary stenosis: defect-specific diagnostic accuracy of heart murmurs in children

The role of the adrenals in the polycystic ovary syndrome (PCOS) is debated. Both single steroid-converting enzyme abnormalities and increased adrenal activity have received support. The conventional Synacthen test using pharmacological doses of ACTH results in unphysiological levels of ACTH. Therefore, we used insulin-induced hypoglycemia (0.15 IU/kg BW) to asses the responses of ACTH, cortisol, pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, progesterone, 17-hydroxyprogesterone, and androstenedione in 18 women with PCOS and in 17 normal women of similar age and body mass index. The blood glucose concentration at 30 min was 2 mmol/L or less in all women, i.e. well below the threshold of the hormonal counterregulatory response. The women with PCOS showed a lower ACTH response, expressed as the maximum increment above basal [mean (95% confidence interval): PCOS, 11.1 (6.9-15.3); controls, 19.9 (13.8-26) pmol/L; P < 0.05], but a quantitatively comparable [PCOS, 207.2 (148.5-266.5); controls, 167.1 (100.6-233.2) nmol/L; P = NS] and more prompt cortisol response than the controls (by chi2 test, P < 0.05), resulting in a higher molar ratio between the maximum increments of cortisol and ACTH [PCOS, 13.9 (8.7-19); controls, 8.8 (5.7-12); P < 0.05]. The women with PCOS did, however, show a more rapid decline in cortisol levels than the controls (P < 0.05 at 120 and 180 min). The responses of the androgens and intermediate adrenal steroids were similar in women with PCOS and controls. The findings suggest an adaptation to increased adrenal reactivity to endogenous ACTH in women with PCOS. Exposure to hypoglycemia as a model of stress was not followed by hypersecretion of adrenal androgens and revealed no signs of steroid enzyme disturbances in women with PCOS.     

The frequency of late-onset 21-hydroxylase and 11 beta-hydroxylase deficiency in women with polycystic ovary syndrome

OBJECTIVE: To determine the frequency of late-onset adrenal hyperplasia (LOCAH) due to 21-hydroxylase (21-OH) and 11 beta-hydroxylase (11 beta-OH) deficiency in women with clinical and biochemical features of polycystic ovary syndrome (PCOS). DESIGN: Eighty-three consecutively selected women with PCOS and eighteen normal women were included in the study. METHODS: Ultrasound, clinical and hormonal parameters were used to define PCOS. Basal FSH, LH, testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S), sex hormone-binding globulin (SHBG) and cortisol levels were measured. Serum 17-hydroxyprogesterone (17-OHP) and 11-deoxycortisol (11-DOC) levels were also measured before, 30 and 60 min after a single bolus injection of 0.25 mg ACTH (1-24) at 0900 h during the mid-follicular phase of the cycle. ACTH-stimulated 17-OHP levels > 30 nmol/l were considered as the criteria of 21-OH deficiency. The diagnosis 11 beta-OH deficiency was made if the adrenal 11-DOC response to ACTH stimulation exceeded threefold the 95th percentile of controls. RESULTS: Basal serum testosterone, free testosterone, androstenedione, DHEA-S, cortisol and 11-DOC levels were significantly higher in PCOS than in control subjects. ACTH-stimulated 17-OHP (P < 0.05) and 11-DOC (P < 0.0005) levels were found to be significantly higher in patients with PCOS than in controls. Seven (8.4%) patients had an 11-DOC response to ACTH higher than threefold the 95th percentile of controls, while no patients showed evidence of 21-OH deficiency. CONCLUSIONS: We have found that 8.4% of the women with clinical and biochemical features of PCOS could be presumed to have 11 beta-OH deficiency. No patients among the women with PCOS showed evidence of 21-OH deficiency. 11 beta-OH deficiency is unexpectedly more common than 21-OH deficiency in women with PCOS.     

Initial sign and clinical course of the most severe form of acute proliferative retrolental fibroplasia (type II) (author''s transl)

Hypothalamic-pituitary-adrenocortical function was investigated in 14 patients with anorexia nervosa. Impaired suppression of plasma cortisol by dexamethasone was revealed. In 14 patients with anorexia nervosa, circadian rhythm of plasma cortisol, insulin tolerance test, rapid ACTH test and overnight dexamethasone suppression test were examined. Levels of plasma cortisol were higher than those in control subjects throughout the day, and normal circadian rhythm of plasma cortisol was not observed. Basal levels of plasma ACTH were within normal range. tthe response of plasma cortisol to insulin-induced hypoglycemia was lower than that in control subjects, while the response of plasma cortisol in rapid Acth test was normal. In overnight suppression tests, in which one mg dexamethasone was administered orally, 11 of 14 patients showed no suppression of plasma cortisol and 3 other patients showed incomplete suppression. Elevated levels of plasma cortisol and the absence of normal circadian rhythm in patients with anorexia nervosa and malnutrition have already been reported by other investigators, and these abnormalities were ascribed to the delayed half life of plasma cortisol due to impaired cortisol metabolism. However, according to our investigation, it is difficult to explain the failure of dexamethasone to suppress cortisol only by the delayed half life of plasma cortisol, and it is supposed that some kind of abnormal hypothalamic control is also involved.     

Suppressibility of plasma adrenocorticotropin by hydrocortisone: potential usefulness in the diagnosis of Cushing's disease

Repeatedly normal cortisol suppressibility by dexamethasone in 2 patients with Cushing's disease led to the present study of the prevalence of this phenomenon in 58 patients with otherwise incontrovertible evidence of Cushing's disease. Because as many as 23% of these patients manifested this phenomenon, we investigated the suppressibility of plasma ACTH: 1) during i.v. infusion of hydrocortisone, after a priming dose (7 mg), at 3 mg/h in 8 patients and 8 normal controls; and 2) for 2 h, after oral hydrocortisone, 0.25 mg/kg, in 13 patients and 16 controls. The data showed invariable suppression of plasma ACTH to < or = 10 pg/mL (< or = 2.2 pmol/L) after 120 min of the infusion or at 90 min after oral hydrocortisone in 16 fasting normal subjects given oral hydrocortisone between 0800 and 0830 h. Plasma ACTH exceeded 10 pg/mL (2.2 pmol/L) at the same times in 14/14 patients with active Cushing's disease, including 3 patients whose cortisol suppressibility by dexamethasone had been misleadingly normal and in 4/7 patients with intermittent hypercortisolism. Occasional variations in plasma cortisol elevations after the oral dose require that plasma cortisol concentration be monitored at 60 min after the oral hydrocortisone dose, because the present evidence supports the validity of the conclusion that a plasma ACTH concentration below 10 pg/mL excludes Cushing's disease only when plasma cortisol concentration at 60 min lies between 16 and 38 microg/dL. Further evaluation of ACTH suppressibility by cortisol would be worthwhile, to confirm its potential value in facilitating positive diagnosis of Cushing's disease when dexamethasone suppressibility seems misleading.     

I. Adrenal cortex and steroid 21-hydroxylase autoantibodies in adult patients with organ-specific autoimmune diseases: markers of low progression to clinical Addison's disease

Adrenal cortex antibodies (ACA) were measured by immunofluorescence in 8840 adult patients with organ-specific autoimmune diseases without overt hypoadrenalism. Sixty-seven (0.8%) patients were ACA-positive, with the highest prevalence in those with premature ovarian failure (8.9%). Forty-eight ACA-positive and 20 ACA-negative individuals were enrolled into a prospective study. Antibodies to steroid 21-hydroxylases (21-OH), steroid 17 alpha-hydroxylase (17 alpha-OH) and cytochrome P450 side chain cleavage enzyme (P450scc) were measured by immunoprecipitation assay. Human leucocyte antigens D-related (HLA-DR) genotyping was also carried out and adrenal function assessed by ACTH test. On enrollment, 75% of ACA-positive patients had a normal adrenal function, while 25% revealed a subclinical hypoadrenalism. 21-OH antibodies were positive in 91% of ACA-positive sera. Eleven patients were positive for steroid-cell antibodies by immunofluorescence, and 9 revealed a positivity for antibodies to 17 alpha-OH and/or P450scc. During the prospective study, overt Addison's disease developed in 21% and subclinical hypoadrenalism in 29% of ACA-positive patients, while 50% maintained normal adrenal function. Progression to Addison's disease was more frequent in patients with subclinical hypoadrenalism, high titers of ACA and higher levels of 21-OH antibodies, complement-fixing ACA and HLA-DR3 status. All 20 persistently ACA-negative patients were also negative for antibodies to 21-OH, 17 alpha-OH, and P450scc, and all maintained normal adrenal function during follow-up. In conclusion, the detection of ACA/21-OH antibodies in adults is a marker of low progression toward clinical Addison's disease.     

From venous ligation to vena cava filter. Objectives and hazards of vena cava interruption

Adrenocortical adenomas (ACA) are frequently discovered at autopsy. Nowadays, modern radiologic techniques incidentally uncover the usually silent ACA during lifetime. On the basis of various reports and the results of endocrine tests, i.e. dexamethasone suppression (DST) and CRH response, we characterize 3 major types of functioning ACA. Type I ACA (cortisol < 100 nmol/l after 1 mg dexamethasone (DXM)) comprises the majority of the so-called 'nonfunctioning' adrenocortical adenomas. However, these adenomas may not be 'truly nonfunctioning' ACA, as their mean FMAX/ACTHMAX-ratio after CRH is significantly higher than in controls without ACA. Also, 19-iodocholesterol adrenal scan has shown persistent adrenal uptake despite DXM administration in some patients with normal DST. Type II ACA ('pre-Cushing's') is comparable to the euthyroid autonomous adenoma. The results of function tests suggest the existence of an ACTH-hyperresponsive subtype. Finally, type III ACA are associated with overt hypercortisolism. An ACTH-responsive and an ACTH-unresponsive form can be characterized. A continuous functional spectrum and the transition between the different types of adenomas is discussed.     

Single-dose four hour dexamethasone suppression test in normal men and its application for the diagnosis of Cushing's syndrome

As a four hour morning test, plasma cortisol levels were radioimmunoassayed before and at two and four hours after dexamethasone (0, 0.5 mg, 1.0 mg or 2.0 mg) was administered at 8-9 a.m. in 20 normal subjects. The 1.0 mg four hour test was most effective in suppression of cortisol and it showed the same suppressibility as the widely used single-dose overnight test. With the 1.0 mg four hour test, 2 patients with Cushing's syndrome due to adrenal hyperplasia could be differentiated from normal and obese subjects. The four hour morning test would be more useful than the widely used overnight test from the reasons; i) it shows the same suppressibility as the overnight test, ii) it obviates the need for bothersome midnight administration of dexamethasone, iii) because it takes only one morning to perform, it can save a day, iv) and it might be applicable for the differential diagnosis of Cushing's syndrome because 4.0 mg morning test resulted in complete suppression of plasma cortisol in a tested Cushing's syndrome, whereas with even 8.0 mg, plasma cortisol was not suppressed in the overnight test in 2 such patients examined.     

The pituitary corticotroph is not the rate limiting step in the postoperative recovery of the hypothalamic-pituitary-adrenal axis in patients with Cushing syndrome

Patients cured from endogenous Cushing syndrome usually develop postoperative adrenal suppression in the year ensuing surgery. To define whether the pituitary corticotroph is the rate limiting step in the postoperative recovery of this secondary/tertiary form of adrenal insufficiency, we examined surgically cured patients with Cushing syndrome 10 days, 3 months, and 6-12 months after surgery, by administering ovine CRH (oCRH) iv at the dose of 1 microgram/kg.h over 24 h. The pituitary corticotroph of these patients responded vigorously to oCRH, with ACTH concentrations reaching above the normal range at all three times of testing. Parallel measurements of cortisol in nonadrenalectomized patients demonstrated subnormal adrenal responsiveness at 10 days and 3 months and normalization at 6-12 months after surgery. The circadian rhythm of ACTH was maintained postoperatively at 10 days and 6-12 months, and the circadian rhythm of cortisol was also present at 6-12 months after surgery, in spite of the constant infusions of pharmacological doses of oCRH, suggesting that factors other than CRH secretion regulate this rhythm. We conclude that the corticotroph is not the rate limiting step in the recovery of the hypothalamic-pituitary-adrenal axis from glucocorticoid-induced adrenal suppression, and that the locus of the defect resides in the hypothalamic CRH neuron and/or its higher regulatory inputs.     

Tuft-to-capsule adhesions and their precursors: differences between the vascular and tubular poles of the human glomerulus

The hypothalamo-pituitary-adrenal (HPA) axis is modulated by sex hormones. Few data exist on the relation between acute estrogen deficit and HPA axis response to corticotropin-releasing hormone (CRH). The effects of a sudden drop in estradiol levels on basal and CRH-stimulated levels of ACTH, cortisol, testosterone, androstenedione and 17-hydroxyprogesterone (17-OHP) were assessed in nine premenopausal women (44-48 years of age), before and after ovariectomy. The CRH test was performed before and 8 days after ovariectomy. A significant reduction in ACTH and adrenal steroids but not in cortisol response to CRH was observed after ovariectomy. The ratio of deltamax androstenedione/17-OHP after CRH stimulation was substantially the same before and after ovariectomy, whereas deltamax 17-OHP/cortisol was significantly lower in ovariectomized women showing increased 21- and 11beta-hydroxylase activity. The results show that the acute estrogen deficit induces changes in the HPA axis characterized by reduced stimulated secretion of ACTH and steroids but normal stimulated cortisol production.     

Ambulatory treatment of erectile dysfunction

To evaluate whether low DHEA-S levels are predictors of cortical origin, benignity and hormonal activity in incidentally detected adrenal masses, thirty-five patients with adrenal incidentalomas were studied. All patients were operated on and the diagnosis was histologically confirmed. Basal endocrine workup included plasma determination of cortisol before and after dexamethasone (1 mg overnight), plasma ACTH (08:00 h), 17-OH-progesterone, testosterone and potassium, standing plasma renin activity and aldosterone, supine and standing plasma noradrenaline and adrenaline. If necessary, we performed dexamethasone suppression tests at low (2 mg) and high (8 mg) doses, or the loperamide test (16 mg os) for evaluation of glucocorticoid activity and the glucagon test (1 mg i.v.) for exploring adrenal medulla function. Plasma DHEA-S was measured in all patients and the results were compared to those obtained in controls matched for age, sex and menopausal status. Suppression of DHEA-S was found in 11 out of 35 patients (31.5%). However, this hormonal finding occurred in 50% of the extracortical adrenal lesions, while in proven cortical adenomas (no. = 19) it was detected in only 5 patients (26.3%). Sensitivity, specificity, diagnostic accuracy and positive predictive value of low DHEA-S in indicating a cortical origin of the mass were 0.27, 0.0, 0.25, and 0.80. In malignancies (no. = 6) low DHEA-S levels were found in 1 out of 2 metastases and never in cortical carcinomas. Sensitivity, specificity, diagnostic accuracy and positive predictive value of low DHEA-S in indicating a benign form were 0.34, 0.83, 0.42, and 0.91. Six out of 19 patients with cortical adenomas showed signs of hypothalamic-pituitary adrenal (HPA)-axis dysfunction. Low DHEA-S levels were found in 50% of adenomas with HPA-axis abnormality and in 15.3% of adenomas without hormonal activity. Sensitivity, specificity, diagnostic accuracy, and positive predictive value of low DHEA-S levels in indicating hormonal activity of the mass were 0.50, 0.84, 0.73, and 0.60. Our data indicate that the association between low DHEA-S levels and adrenal incidentalomas is frequent. Low DHEA-S appears to be a poor predictor of hormonal activity with low sensitivity and specificity in respect of cortical origin and benignity of the mass. In conclusion, our results show that DHEA-S measurement does not offer relevant clinical information in the management of adrenal incidentalomas.     

Regulation of 18-oxocortisol and 18-hydroxycortisol by the renin-angiotensin system and ACTH in man

Based on urinary excretion studies the secretion of the cortisol derivatives, 18-oxocortisol and 18-hydroxycortisol are believed to be regulated by ACTH and to a lesser degree by the renin-angiotensin system. Plasma concentrations of 18-oxocortisol and 18-hydroxycortisol were measured during the simultaneous activation of the renin-angiotensin system and inhibition of ACTH secretion. Five healthy male subjects consuming a sodium diet ad libitum were studied. Blood was drawn at 0800 h after 1 h in the supine position. In the first set of experiments, the subjects remained in the supine position from 0800 to 1000 h with or without the oral administration of 2 mg dexamethasone at 0800 h. In the second set of experiments the subjects were placed in the upright position after drawing the 0800 h sample. The subjects were studied with and without dexamethasone administered at 0800 h. Blood was drawn again at 1000 h. Plasma levels of 18-oxocortisol, 18-hydroxycortisol, ACTH, plasma renin activity (PRA), cortisol, aldosterone and 18-hydroxycorticosterone were measured by radioimmunoassay. None of these parameters changed during the 2 h in the supine position. 18-Oxocortisol, 18-hydroxycortisol, aldosterone, 18-hydroxycorticosterone and PRA increased, but ACTH and cortisol did not change when the subjects were placed in the upright position. After dexamethasone administration, 18-oxocortisol, 18-hydroxycortisol, cortisol, aldosterone and 18-hydroxycorticosterone decreased in the supine position and no increase occurred in 18-oxocortisol, 18-hydroxycortisol and 18-hydroxycorticosterone in the upright position. PRA and aldosterone increased and ACTH and cortisol decreased in these subjects. 18-Oxocortisol and 18-hydroxycortisol were more dependent on ACTH regulation and less on the renin-angiotensin system than aldosterone.