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

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

Sensitivity of cortisol and adrenal androgens to dexamethasone suppression in hirsute women

To test the hypothesis that adrenal androgen secretion is more easily suppressed than is cortisol secretion by glucocorticoids, we examined the dose-response relationship for suppression of serum dehydroepiandrosterone (DHA), DHA sulfate (DHAS), testosterone, and cortisol by dexamethasone. Nine hirsute women received daily doses of dexamethasone, starting with 0.1 mg and increasing by 0.1-mg increments every 4 weeks, until the cortisol response to ACTH was reduced to 20% or less of the response before treatment. Serum hormone levels were measured at each dexamethasone dose before and after iv administration of 25 U synthetic ACTH. Although low doses of dexamethasone caused a similar suppression of basal cortisol, DHA, and DHAS levels, ACTH-stimulated DHA levels were suppressed to a greater extent than ACTH-stimulated cortisol levels. Higher dexamethasone doses did not result in a significant difference between the degree of cortisol and adrenal androgen suppression, as near-maximal suppression occurred for all three hormones. Maximal suppression of basal testosterone levels occurred at or below the dexamethasone dose of 0.3 mg. We conclude that the adrenal androgen secretory capacity is more sensitive to suppression by dexamethasone than is the adrenal cortisol secretory capacity. Furthermore, glucocorticoid therapy for hirsutism need not achieve complete cortisol suppression to effect a major reduction in adrenal androgen levels.     

Pheochromocytoma combined with pre-clinical Cushing's syndrome in the same adrenal gland

Pheochromocytoma (PHEO) occasionally associates with pathological lesions of the adrenal cortex. In most of them, ectopic adrenocorticotropic hormone (ACTH) produced by PHEO resulted in bilateral adrenocortical hyperplasia. The coexistence of PHEO and pre-clinical Cushing's syndrome (PCS) of the same adrenal gland has rarely been reported. We report on a patient and discuss the peculiar diagnostic aspects of this entity. A 52-yr-old Turkish woman was hospitalized at Farabi Hospital for further examinations of a right adrenal mass that was incidentally discovered by abdominal ultrasonography during examinations for abdominal bloating and "gas" in other hospital. The patient had a history of palpitations, nervousness, sweating and heat intolerance. On admission, her blood pressure was 140/90 mmHg. A physical examination revealed no signs of an excessive production of adrenocortical steroids such as in CS. Tension Holter monitoring revealed paroximal hypertension attacks (183/105 mmHg). Urinary catecholamines were markedly increased. Her serum cortisol concentrations ranged from 5 to 17 microg/dl, whereas ACTH levels were undetectable. Cortisol was not suppressed on the overnight 1 mg oral dexamethasone suppression test (DST), 2-day low-dose dexamethasone suppression test (DST). Abdominal computed tomography and magnetic resonance imaging studies revealed a solid round tumor approximately 4 cm in diameter, located in the right adrenal gland. A 131 lodine-metaiodobenzylguanidine (131 I-MIBG) scan revealed uptake within tumor in the right adrenal gland. Right adrenalectomy was performed; the surgical specimen revealed PHEO and adrenocortical hyperplasia. To our knowledge, the present report is a rare case of PHEO combined with PCS in the same adrenal gland.     

Bilateral adrenocortical adenomas causing ACTH-independent Cushing's syndrome at different periods: a case report and discussion of corticosteroid replacement therapy following bilateral adrenalectomy

We report a rare case of bilateral adrenocortical adenomas causing ACTH-independent Cushing's syndrome at different periods 9 yr apart. The subject, a 24-yr-old woman, in June 1989 had a typical Cushingoid appearance. Her baseline plasma cortisol levels did not show a diurnal rhythm and she had a very low baseline plasma ACTH level. Plasma cortisol levels could not be suppressed by overnight low-dose or two-day high-dose dexamethasone suppression test. Marked uptake of 131I-6beta-iodomethyl-19-norcholesterol (NP-59) was observed in the right adrenal gland. Abdominal computed tomography (CT) showed a right adrenal tumor. The right adrenal gland with adenoma was removed. The non-tumorous part of the adrenal cortex was atrophic. By April 1998, she had experienced a weight gain of more than 20 kg over a two-yr period. The baseline plasma cortisol levels were at the lower limit of the normal range with loss of diurnal rhythmicity. The baseline plasma ACTH levels were very low. Neither a two-day low-dose nor a two-day high-dose dexamethasone suppression test could suppress serum cortisol or urinary free cortisol levels. NP-59 adrenal scan revealed increased uptake of the left adrenal gland at 72 h after intravenous injection of the tracer. Abdominal CT and magnetic resonance imaging (MRI) all demonstrated a left adrenal mass. Left adrenalectomy was performed in June 1998; histological features showed a cortical adenoma and atrophic change in the non-tumorous part of the adrenal cortex. Elevated plasma ACTH levels after bilateral adrenalectomy could be suppressed with conventional corticosteroid replacement therapy and overnight low-dose dexamethasone suppression test.     

KCNJ5 mutations in aldosterone- and cortisol-co-secreting adrenal adenomas

Adrenal aldosterone-producing adenomas (APA) are rarely associated with the clear co-secretion of cortisol. Somatic mutations of the potassium channel KCNJ5 gene, with the hotspots G151R and L168R, have been recently identified in patients with APA. However, whether APAs that secrete cortisol have these mutations remains unclear. We examined three patients with APAs showing clear autonomous secretion of cortisol who possessed a 1 mg dexamethasone suppression test (DST) with a failure of the serum cortisol level to drop below 3.0 μg/dL, a morning plasma ACTH level of less than 10 pg/mL, and suppressed accumulation in the intact adrenal on (131)I- adosterol scintigraphy, or postoperative adrenal insufficiency. Laparoscopic adrenectomy revealed all tumors to be golden yellow, and histological examination confirmed them to be adrenocortical adenomas. All these patients required replacement therapy with hydrocortisone after surgery. Sequencing demonstrated that 2 of three cases showed a mutation of the KCNJ5 gene, one with c.451G>A, p.G151R and one with c.503T>G, p.L168R. Furthermore, the mRNA levels of steroidogenic enzymes including CYP11B1, CYP11B2, HSD3B2, CYP17A1, CYP11A1 and KCNJ5 in the 3 cases did not differ from those in 8 pure APAs not showing any of the above conditions for autonomous cortisol secretion. In addition, all 8 pure APAs harbored mutations of the KCNJ5 gene. These findings suggested that at least some aldosterone- and cortisol-co-secreting adrenal tumors have mutations of the KCNJ5 gene, suggesting the origin to be APA, and pure APAs may show a high incidence of KCNJ5 mutations.     

Unilateral adrenalectomy improves insulin resistance and polycystic ovaries in a middle-aged woman with virilizing adrenocortical adenoma complicated with Cushing's syndrome

A benign virilizing adrenal adenoma is rare among adrenal neoplasms in middle-aged women. A 39-yr-old Japanese woman who presented with hirsutism, obesity, diabetes mellitus and hypertension was admitted. Plasma concentrations of testosterone and DHEAS were high. While the basal level of plasma ACTH was suppressed, serum cortisol level was high and its circadian rhythm was absent. Serum cortisol level was not suppressed with the low- and high-dose overnight dexamethasone suppression test. Abdominal computed tomography showed a left adrenal tumor, and an adrenocortical scintigraphy revealed uptake of the tracer on the left side. Polycystic ovaries were also found and bone mineral density revealed osteoporosis. Histopathological features of resected adrenal tumor were consistent with those of adrenocortical adenoma. Immunoreactivity of all the steroidogenic enzymes was apparent in the tumor cells and particularly dehydroepiandrosterone sulfotransferase (DHEA-ST) immunoreactivity was markedly expressed. Cortical atrophy and reduced expression of DHEA-ST were detected in the cortex of the adjacent non-neoplastic adrenal gland. Plasma testosterone, DHEAS and cortisol levels returned to normal after surgery, concomitantly with the disappearance of polycystic ovaries. This is a very rare case of virilizing adrenocortical adenoma complicated with Cushing's syndrome (CS).     

A case of preclinical Cushing's disease,accompanied with thyroid papillary carcinoma and adrenal incidentaloma

A 75-year-old woman had tumors in her pituitary, thyroid and left adrenal gland. Plasma ACTH and cortisol levels were both mildly elevated. Both plasma ACTH and cortisol concentrations were partially suppressed by 1 mg of overnight dexamethasone suppression test, while both were inhibited with a dosage of 8 mg dexamethasone. Plasma ACTH and cortisol levels were increased in response to human CRH and desmopressin. Together with the observation of pituitary microadenoma, the patient had a pituitary ACTH-producing tumor. The patient, however, had no typical Cushingoid features, hypertension, or impaired glucose tolerance, suggesting that the tumor had an autonomic ACTH secretion that was insufficient for expressing clinical symptoms, the so-called preclinical Cushing's disease. A case of preclinical Cushing's disease is extremely rare. Further, the patient had thyroid papillary carcinoma and non-functioning adrenal tumor. Molecular genetic analysis demonstrated a polymorphism of the menin gene in the patient. Even without Cushingoid features in pituitary incidentaloma, we concluded that the elevated ACTH and cortisol levels should be followed up by CRH, desmopressin and dexamethasone suppression tests. This patient with preclinical Cushing's disease would be observed whether the physical conditions in the patient develop to overt Cushing's disease.     

Suppressed Levels of Serum Cortisol Following High-Dose Oral Dexamethasone Administration Differ between Healthy Postmenopausal Females and Patients with Established Primary Vertebral Osteoporosis

Hypercortisolism and glucocorticoid treatment, even in a low dose or administered topically, may influence bone metabolism. It was the aim of this study to investigate whether there might be differences in the regulation of endogenous cortisol secretion between patients with established primary vertebral osteoporosis and healthy controls. Suppressed morning serum cortisol concentrations in a 3 mg dexamethasone overnight suppression test were compared in well-defined healthy postmenopausal women (n = 149) and osteoporotic patients classified as having established primary vertebral osteoporosis with no clinical features of hypercortisolism (n = 78). Suppressed cortisol in the healthy controls was 1.08 +/- 0.44 microg/dl and in the primary osteoporotics 1.58 +/- 1.42 microg/dl (p < 0.0001). Of the investigated primary osteoporotics 15.4% (n = 12) had suppressed cortisol levels above the 97.5th percentile (1.96 microg/dl) of the healthy controls. Subgroup analysis regarding the influence of gonadal steroid hormone replacement in both groups and gender in the osteoporotic group did not change the results. Four of the 12 patients with incomplete suppressive cortisol underwent adrenal endosonography, unilateral adrenal nodular hyperplasia being detected in three cases. In two patients the diagnosis was confirmed by histology and normalisation of a dexamethasone suppression test following endoscopic adrenalectomy. These data yield evidence for a difference in the regulation of cortisol secretion following high-dose dexamethasone administration between healthy subjects and a subgroup of patients with primary osteoporosis. This might be due to a relevant amount of autonomous cortisol secretion in some of these patients; however, even cortisol resistance has to be taken into account.     

Biochemical screening for subclinical cortisol-secreting adenomas amongst adrenal incidentalomas

OBJECTIVE: Biochemistry and I-6beta-iodomethyl norcholesterol scintigraphy (IMS) have both been used to assess cortisol secretion by adrenocortical incidentalomas. However, which biochemical abnormalities indicate subclinical corticoid excess is still debatable whilst IMS is expensive and cumbersome. The aim of the study was to evaluate prospectively patients with adrenal incidentalomas using both IMS and biochemical methods to examine whether the IMS pattern is associated with biochemical abnormalities and, if this is so, to find a biochemical parameter that could be used as a screening test to identify a subset of patients on whom IMS could subsequently be performed. METHODS: Thirty-one patients with benign cortical adenomas were recruited from 43 consecutive patients with adrenal incidentalomas. All 31 patients underwent IMS and measurement of (i) 0800 h serum cortisol, ACTH, dehydroepiandrosterone and 17-hydroxyprogesterone; (ii) midnight serum cortisol; (iii) 2400 h excretion of urinary free cortisol; (iv) cortisol after the overnight 1 mg dexamethasone (DEX) suppression test; (v) cortisol after an i.v. 4 mg DEX test; (vi) determination of the diurnal variation in serum cortisol. RESULTS: Sixty-one per cent of patients displayed unilateral uptake during IMS and 39% showed bilateral uptake. Patients with unilateral uptake exhibited significantly lower ACTH concentrations (P=0.0005), higher midnight cortisol concentrations (P=0.02), disrupted diurnal variation of serum cortisol (P=0.02) and higher cortisol concentrations after DEX suppression tests (P=0.01). Cortisol concentrations following the two DEX suppression tests correlated closely (r=0.80, P=0.0001). The i.v. 4 mg DEX test was clearly more sensitive for the diagnosis of unilateral uptake than the overnight 1 mg DEX test (76 vs 52%). Using various thresholds of cortisol concentration following the overnight 1 mg DEX test, it was found that the sensitivity of the test could be improved to 100% if the threshold was set at 60 nmol/l rather than the classical value of 138 nmol/l. All patients but one with post-test serum cortisol concentrations above 60 nmol/l as against none of patients with cortisol below 60 nmol/l exhibited at least one associated biochemical abnormality indicating subclinical glucocorticoid excess. CONCLUSION: In adrenocortical incidentalomas, unilateral uptake during IMS suggests subclinically excessive and/or autonomous cortisol secretion. A cortisol concentration above 60 nmol/l following the overnight 1 mg DEX test is highly correlated with unilateral uptake and is associated with biochemical abnormalities indicating subclinical glucocorticoid excess. Our results favour the use of the 1 mg overnight DEX test with revised criteria of interpretation as a screening test for subclinical hypercortisolism among patients with adrenocortical incidentalomas.     

Primary aldosteronism caused by a unilateral adrenal adenoma accompanied by autonomous cortisol secretion.

A 35-year-old Japanese woman was referred for further examination of persistent hypertension with hypokalemia. Her serum aldosterone levels were high and her plasma renin activity markedly suppressed. Radiological examinations revealed the presence of a 3-cm diameter left adrenal tumor. (131)I-adosterol was specifically accumulated in the left adrenal tumor, whereas the accumulation in the right adrenal was completely suppressed. Low-dose dexamethasone failed to suppress cortisol secretion although the serum cortisol levels were within the normal range. Urinary excretion of 17-hydroxycorticosteroids but not 17-ketosteroids was increased. Levels of plasma adrenocorticotropin (ACTH) and serum dehydroepiandrosterone sulfate (DHEAS) were decreased. Upon diagnosis of left aldosteronoma with autonomous secretion of cortisol, left adrenalectomy was performed by laparoscopy. In the resected adenoma tissues, clear cells expressed P450c17 protein and the ratio of CYP17/CYP11B2 mRNA evaluated by quantitative real-time polymerase chain reaction (PCR) was apparently higher than that of typical aldosteronomas. Based on the corticotropin-releasing hormone (CRH) loading tests, the contra-lateral adrenal functions were restored 3 months after surgery. These results indicate that evaluation for autonomy of cortisol secretion and contra-lateral adrenal function is clinically important to avoid the risk of adrenal failure after surgery for primary aldosteronism.     

Endogenous subclinical hypercortisolism: Diagnostic uncertainties and clinical implications

Subclinical hypercortisolism (SH) is a newly characterized hormonal disorder that is almost exclusively detected in the context of incidentally discovered adrenal masses. The diagnostic criteria used for the definition of this condition are at present controversial. Amongst the various tests used for the detection of this abnormality (dexamethasone suppression, urinary free cortisol, ACTH levels, midnight serum or salivary cortisol concentrations, ACTH responses to CRH stimulation), the dexamethasone suppression tests (DST) seem to better accomplish the task of unmasking subtle abnormalities of cortisol secretion. Several versions of DST have been used: the 1-mg overnight, the 3-mg overnight and the classical 2-day low-dose DST. This latter test has the theoretical advantage that, by more efficiently suppressing pituitary ACTH secretion, it may provide a measure of the residual (ie non- ACTH-dependent) cortisol secretion from the adrenal mass. In this way, post-dexamethasone cortisol concentrations may quantify the degree of autonomous cortisol hypersecretion. In fact, post-dexamethasone cortisol concentrations have a negative correlation with basal ACTH levels and a positive correlation with midnight cortisol concentrations as well as the size of the incidentally discovered adrenal mass. Most of the existing data indicate that SH detected in the context of adrenal incidentalomas may have some clinically significant implications. In fact, patients with higher post-dexamethasone cortisol concentrations demonstrate higher lipid levels and lower bone mass densities. It has also been suggested that SH may be responsible for biochemical and phenotypic changes reminiscent of the metabolic syndrome. In summary, SH does exist and is associated with a negative impact in patients' health; however, hormonal cut-off criteria for decision-making remain to be defined.     

A case of preclinical Cushing's syndrome associated with diurnal rhythms of ACTH and cortisol in blood: correlation with histological findings

We describe a case of adrenocortical adenoma with preclinical Cushing's syndrome demonstrating diurnal rhythms of ACTH and cortisol in blood. A 50-year-old man was admitted to the hospital for the evaluation of incidental right adrenal mass with hyperglycemia and hypertension. On admission, there were no signs of clinical manifestation of hypercortisolism. The basal levels of cortisol (9.3 microg/dl) and ACTH (9.4 pg/ml) at 0800 h were not elevated and these diurnal rhythms were maintained. One or 8 mg of dexamethasone given orally overnight suppressed the plasma ACTH but not serum cortisol. Ultrasonogram, CT and scintiscan of (131)I adosterol all demonstrated an enlarged adrenal mass in the right adrenal gland. The right adrenal gland was subsequently resected by laparoscopic surgery. Histopathological findings of resected adrenal tumor were consistent with adrenocortical adenoma. Adjacent non-neoplastic adrenal tissue demonstrated adrenocortical atrophy but DHEA-sulfotransferase immunoreactivity in the zona reticularis was detected.     

Subclinical Cushing's syndrome.

Classic Cushing's syndrome is a rare disease with an estimated incidence of 1 case per 100,000 persons. With routine use of imaging techniques such as ultrasound and CT, adrenal masses are being detected with increased frequency. A substantial percentage of these incidentalomas are hormonally active, with 5% to 20% of the tumors producing glucocorticoids. Autonomous glucocorticoid production without specific signs and symptoms of Cushing's syndrome is termed subclinical Cushing's syndrome. With an estimated prevalence of 79 cases per 100,000 persons, subclinical Cushing's syndrome is much more common than classic Cushing's syndrome. Depending on the amounts of glucocorticoids secreted by the tumor, the clinical spectrum ranges from slightly attenuated diurnal cortisol rhythm to complete atrophy of the contralateral adrenal gland with lasting adrenal insufficiency after unilateral adrenalectomy. Patients with subclinical Cushing's syndrome lack the classical stigmata of hypercortisolism but have a high prevalence of obesity, hypertension, and type 2 diabetes. All patients with incidentally detected adrenal masses scheduled for surgery must undergo testing for subclinical Cushing's syndrome to avoid postoperative adrenal crisis. The best screening test to uncover autonomous cortisol secretion is the short dexamethasone suppression test. Because the adrenal origin of a pathologic cortisol secretion is anticipated, the author prefers a higher dexamethasone dose (3 mg instead of 1 mg) to reduce false-positive results. A suppressed serum cortisol level of less than 3 micrograms/dL (80 nmol/L) after dexamethasone excludes significant cortisol secretion by the tumor. A serum cortisol level greater than 3 micrograms/dL requires further investigation, including confirmation by high-dose dexamethasone (8 mg) suppression testing, a CRH test, and analysis of diurnal rhythm. Determination of urinary free cortisol is less useful because increased values are a late finding usually associated with emerging clinical signs of Cushing's syndrome. Patients with suppressed plasma ACTH in response to CRH generally have adrenal insufficiency after surgery and require adequate perioperative and postoperative substitution therapy. Whether patients with subclinical Cushing's syndrome should undergo adrenalectomy is a matter of debate. The author performs surgery in young patients (< 50 years), in patients with suppressed plasma ACTH, and in patients with a recent history of weight gain, substantial obesity, arterial hypertension, diabetes mellitus, and osteopenia. In completely asymptomatic patients with normal plasma ACTH concentrations and in patients older than 75 years, the author recommends a nonsurgical approach. A large prospective randomized study is necessary to evaluate the benefits of surgery versus conservative treatment in patients with subclinical Cushing's syndrome.     

The low-dose dexamethasone suppression test: a reevaluation in patients with Cushing's syndrome

Low-dose dexamethasone suppression testing has been recommended for biochemical screening when Cushing's syndrome is suspected. The criterion for normal suppression of cortisol after dexamethasone is controversial. To assess diagnostic utility (sensitivity), we report the results of low-dose dexamethasone suppression testing in 103 patients with spontaneous Cushing's syndrome. There were 80 patients with Cushing's disease (78%), 13 with the ectopic ACTH syndrome (13%), and 10 with cortisol-producing adrenocortical adenomas (10%). Fourteen (18%) of 80 patients with Cushing's disease suppressed serum cortisol to less than 5 micro g/dl (<135 nmol/liter) after the overnight 1-mg test, whereas six patients (8%) actually showed suppression of serum cortisol to less than 2 micro g/dl (<54 nmol/liter). In addition, the 2-d, low-dose dexamethasone suppression test yielded false-negative results in 38% of patients when urine cortisol was used and 28% when urinary 17-hydroxycorticosteroids were used. Serum cortisol after the 1-mg test correlated with baseline urinary free cortisol (r = 0.705, P < 0.001), plasma ACTH level (r = 0.322, P = 0.001), and urinary free cortisol after the 2-d test (r = 0.709, P = 0.001). This study provides evidence that low-dose dexamethasone may suppress either plasma cortisol or urinary steroids to levels previously thought to exclude Cushing's syndrome and that these tests should not be used as the sole criterion to exclude the diagnosis of endogenous hypercortisolism.     

Pathophysiology of deoxycorticosterone-secreting adrenal tumors

Two patients with hypermineralocorticoidism due to deoxycorticosterone (DOC) excess are described. The plasma 17-deoxysteroids of the zona fasciculata (ZF), namely DOC, corticosterone, 18-hydroxydeoxycorticosterone, and 18-hydroxycorticosterone, were elevated. Plasma androgen concentrations were normal, and plasma aldosterone and renin levels were low. One patient, who had benign adrenocortical adenoma, had normal plasma cortisol levels. The other patient, who had metastatic adrenocortical carcinoma, had low plasma cortisol, presumably due to elevated plasma corticosterone levels. While tumors producing only 17-deoxysteroids are rare, they have provided new insights into the regulation of 17-deoxysteroid secretion by the ZF. Presumptive suppression of a non-ACTH factor by adenoma-produced DOC transiently impaired the early postoperative responses to ACTH of the ZF 17-deoxysteroids of the contralateral adrenal. The dissociation of 17-deoxysteroids from cortisol in normal subjects given either dexamethasone or DOC acetate provides additional evidence for such a factor.     

Vasopressin responsiveness of subclinical Cushing's syndrome due to ACTH-independent macronodular adrenocortical hyperplasia

OBJECTIVE: Vasopressin (AVP) is reported to be an important factor for regulating cortisol secretion in patients with Cushing's syndrome due to ACTH-independent macronodular adrenocortical hyperplasia (AIMAH). Recently, there have been several case reports of subclinical Cushing's syndrome due to AIMAH, in which the pathophysiological role of AVP has been unknown. The aim was to conduct an extensive investigation of AVP in the autonomous secretion of cortisol in subclinical Cushing's syndrome due to AIMAH. PATIENTS AND MEASUREMENTS: Five cases of AIMAH with subclinical Cushing's syndrome underwent prospective study including physical examination, imaging (MRI, CT and 131I-adosterol scintigraphy) and endocrinological evaluation that comprised basal plasma cortisol levels and urinary excretions of steroid metabolites, a dexamethasone suppression test and an AVP stimulation test. In case 1, left adrenalectomy was performed and the pathological diagnosis of AIMAH was established. An in vitro experiment using the cultured AIMAH adrenal cells was conducted to investigate cortisol secretion and expression of the V1-AVP receptor, mRNA by RT-PCR. RESULTS: All five cases were discovered incidentally to have bilateral adrenal nodules. Imaging by MRI and CT revealed large multinodular lesions in both adrenal glands, which showed positive uptake on 131I-adosterol scintigraphy. Although the basal values of plasma cortisol and urinary excretions of steroid metabolites were within normal limits, autonomous secretion of cortisol was assumed to occur because of lack of suppression during dexamethasone suppression. The five patients had no overt signs of Cushing's syndrome, and they were therefore diagnosed with subclinical Cushing's syndrome due to AIMAH. In all five patients, AVP stimulated cortisol secretion in vivo, whereas desmopressin acetate failed to affect cortisol secretion. In case 1, AVP stimulated cortisol secretion from cultured AIMAH adrenal cells, but this secretion had no relationship with cAMP production. In addition, over-expression of V1-AVP receptor mRNA in AIMAH tissue was determined by RT-PCR. CONCLUSION: Patients with subclinical Cushing's syndrome due to AIMAH commonly exhibit cortisol responsiveness to AVP, and this is probably mediated through activation of overexpressed V1-AVP receptors.     

Primary adrenocortical micronodular adenomatosis causing Cushing's syndrome. Effects of ketoconazole on steroid production and in vitro performance of adrenal cells

Mild Cushing's syndrome was diagnosed in a 35 year old woman. Elevated plasma and urinary cortisol levels were unsuppressible with up to 32 mg dexamethasone per day. Aldosterone, 18-OH-corticosterone and testosterone in plasma were normal and dehydro-epiandrosterone-sulphate was low. No adrenal tumour was found by CT or adrenal venography, and bilateral cortisol secretion was demonstrated by steroid measurements in adrenal venous blood. A circadian rhythm of plasma cortisol was absent. Plasma ACTH was suppressed, even after injection of CRH, during insulin-induced hypoglycaemia and after metyrapone administration, which led to a large fall in plasma cortisol but to a subnormal rise of plasma 11-deoxy-cortisol. The clinical diagnosis of primary micronodular adenomatosis of the adrenal gland was histologically confirmed, when the patient finally underwent bilateral adrenalectomy. In vitro, the adrenal cells did not produce more cortisol and aldosterone than adrenal cells from cadaver kidney donors. In vivo and in vitro, cortisol was slightly less than normally responsive to ACTH. Intermittent treatment of the patient with 800 mg/day of ketoconazole led to a rapid fall of cortisol secretion and clinical signs of adrenocortical insufficiency. Treatment for 7 weeks with 200-400 mg ketoconazole per day reduced plasma and urinary cortisol less dramatically into the normal range. This case unequivocally documents autonomous dysfunction of the adrenal cortex in this rare form of Cushing's syndrome and the efficacy of ketoconazole in the treatment of ACTH-independent hypercortisolism.     

A case of Cushing's disease associated with a non-functioning adrenal tumor]

A 52-year-old woman was admitted to our hospital for further examination of central obesity, hypertension and hirsutism suggesting Cushing's syndrome. Hirsutism had been remarkable for two years, and muscle weakness of the lower extremities gradually developed during the past year. CT scan revealed a tumor in the left adrenal gland which was 1 cm in diameter, round, well-circumscribed, homogeneous and not enhanced. Endocrine data disclosed increased urinary 17-OHCS (11.5-16.4 mg/day) and elevated plasma ACTH (125 pg/ml) and cortisol (19 micrograms/dl) with a lack of diurnal rhythm. Administration of the single-dose dexamethasone (1mg) did not suppress plasma cortisol. However, consecutive administration of either 2mg or 8mg of dexamethasone for 2 days suppressed both plasma cortisol and urinary 17-OHCS. Administration of metyrapone raised both urinary 17-OHCS and plasma ACTH levels. Rapid ACTH test resulted in a hyperresponse of plasma cortisol. CRF injection raised plasma ACTH and cortisol. Bilateral adrenal glands were well demonstrated by 19-iodocholesterol (I-131) scintigraphy during the administration of dexamethasone. MRI with Gd-contrast revealed a microadenoma in the sella turcica. With the diagnosis of Cushing's disease, the microadenoma was removed by the transsphenoidal approach and adrenal function was normalized. However, the left adrenal tumor remained on CT scan but was not demonstrated by scintigraphy. These findings indicate that this is a very rare case of Cushing's disease which was associated with an unilateral non-functioning adrenal tumor.     

Enhancement of adrenal cortisol secretion after intravenous high dose dexamethasone

To assess the possible existence of a short loop feedback mechanism of direct glucocorticoid suppression on the adrenal glands, we performed a series of tests employing insulin hypoglycemia or ACTH infusions to obtain adrenal stimulation by ACTH levels that remained within the physiological range. Although the rapidity of glucocorticoid suppression of the pituitary thwarted efforts to use endogenous ACTH as a stimulus, we were able to mimic the stressed state by very low dose ACTH infusions (0.05 microgram/kg BW). No inhibition of cortisol secretion in response to ACTH infusions was detected in tests done after administration of dexamethasone compared to placebo [mean integrated response, 29.37 +/- 1.91 (+/- SE) vs. 29.12 +/- 1.12 microgram . h/dl, respectively]. Furthermore, when high doses of dexamethasone were administered iv, a small paradoxical increase in cortisol secretion was found (33.82 +/- 1.44 microgram . h/dl) without a difference in ACTH levels. These data do not support the concept of significant direct glucocorticoid inhibition of adrenal secretion. Non-ACTH factors that may enhance cortisol secretion in the presence of ACTH may exist.