Subclinical Cushing's syndrome due to adrenal myelolipoma

We describe a patient with an incidental adrenal myelolipoma associated with biochemical evidence of Cushing's syndrome who lacked the physical stigmata of cortisol excess (subclinical Cushing's syndrome). Pathologic examination revealed the presence of adrenocortical cells mixed with myelolipomatous tissue. Although cases of clinically evident Cushing's syndrome due to adrenal myelolipomas have been reported previously, to our knowledge this is the first report associating adrenal myelolipoma and subclinical Cushing's syndrome.     

Hormone receptor abnormalities in adrenal Cushing's syndrome

Cortisol secretion in ACTH-independent primary adrenal Cushing's syndromes was previously believed to be autonomous. In most cases, the pathophysiology of the disease was largely unknown. However, recent work by our group and others have shown that these cortisol-producing adrenocortical tumors may be under the control of inappropriate, illicit or ectopic hormone receptors. This review provides a rapid overview of the physiology of the normal adrenal cortex and outlines recent findings supporting the hypothesis that cortisol production may be regulated by a diversity of abnormal or ectopic hormone receptors in primary adrenal Cushing's syndrome.     

Bilateral massive macronodular adrenal gland hyperplasia. A rare cause of Cushing's syndrome

A 46-year-old man with known arterial hypertension for 10 years had, over the last two years, developed increasing obesity, particularly of the trunk, with other symptoms typical of Cushing's syndrome. Hormone analysis demonstrated hypercortisolism and decreased plasma ACTH concentration. The dexamethasone inhibition test failed to show any significant suppression of serum cortisol. Plasma ACTH was not increased in the corticotrophin-releasing hormone and the metyrapone tests. In the short ACTH test there was an excessive cortisol increase. Abdominal computed tomography revealed both adrenals to be enlarged (6 x 4 cm) and coarsely nodular. Adrenolytic treatment with ketoconazole (400 mg daily) caused symptoms of adrenal insufficiency, but a reduced dosage of 200 mg daily lowered the cortisol level to between 5 and 11 micrograms/dl and normalized the blood pressure and clinical signs of Cushing's syndrome disappeared. Subsequent bilateral adrenalectomy confirmed the diagnosis of massive macronodular adrenal hyperplasia. Substitution treatment with twice daily 25 mg cortisone acetate and 0.05 mg fludrocortisone was started postoperatively.     

Recurrent Cushing's syndrome due to recurrent adrenocortical tumor--fragmentation or tumor in ectopic adrenal tissue?

A 33-yr-old woman was found to have Cushing's syndrome due to a left adrenal cortical tumor. The tumor and the surrounding adrenal gland were removed intact and in toto. Four years later, she noticed recurrent symptoms of Cushing's syndrome, and 6 yr postoperatively, an adrenal tumor was demonstrable on computed tomography. Fourteen years after the initial procedure, a left adrenal tumor, presumably arising in ectopic adrenal tissue, was removed with relief of her symptoms of Cushing's syndrome. The site and functional capacity of ectopic adrenal tissues are reviewed.     

Exophthalmos and iatrogenic Cushing's syndrome

A 38-year-old physician presented with a 9-month history of progressive self-administration of oral prednisone < or = 160 mg per day for Addison's disease. Examination demonstrated typical Cushingoid features and bilateral proptosis with elevated intraocular pressure. Computed tomography disclosed increased intraorbital adipose tissue. We hypothesize that the increased intraorbital adipose deposition was due to the differential binding of glucocorticoids to adipose tissue receptors and an enhancement of lipoprotein lipase activity. We conclude that the findings in this case may be related to glucocorticoid-induced changes in the ocular and periorbital structures. Cushing's syndrome should be considered in the differential diagnosis of acquired exophthalmos and elevated intraocular pressure and findings of increased orbital fat on orbital imaging.     

Relative lymphopenia in Cushing's syndrome

The differential white blood cell (WBC) count often reveals relative lymphopenia in Cushing's syndrome and may be a clue to the discovery of the ailment. However, the incidence of this finding has rarely been reported in the literature. We conducted a study on 40 patients with Cushing's syndrome due to adrenocortical adenoma to evaluate the diagnostic implications of relative lymphopenia. Total WBC count, differential WBC count, basal level of plasma cortisol, urinary excretion of free cortisol and thyroid function were evaluated preoperatively. We also investigated the differential WBC count in 40 patients with thyroid tumors matched for age and sex with the Cushing's syndrome patients. The proportion of lymphocytes among WBCs was also compared between the two groups. The proportion of lymphocytes among WBCs was significantly lower in the patients with Cushing's syndrome (19.4 +/- 10.8%) than in those with thyroid tumors (42.3 +/- 9.5%, mean +/- SD, p < 0.05). The incidence of relative lymphopenia was high (82.5%) as well as that of increased urinary excretion of free cortisol (85.3%) in Cushing's syndrome patients. The low T3 syndrome was frequently seen (73.9%), whereas the incidences of leukocytosis and an increased level of basal plasma cortisol were relatively low (42.5% and 47.5%, respectively). Relative lymphopenia provides useful information for diagnosing Cushing's syndrome since it has high sensitivity although it should be kept in mind that its specificity is low.     

Chronic bronchopulmonary aspergillosis in a horse with Cushing's syndrome

An atypical case of chronic equine bronchopulmonary aspergillosis with an unusual hyphal morphology was diagnosed in a horse with Cushing's syndrome. Because of the hyphal localization in chronic ectatic bronchi and bronchioles, and juxtabronchiolar processes, the observed type of aspergillosis is similar to 'saprophytic bronchopulmonary aspergillosis' or 'semi-invasive pulmonary aspergillosis' in humans. The aetiological diagnosis of aspergillosis was accomplished by the application of a panel of monospecific polyclonal and monoclonal antibodies in immunohistochemical techniques.     

Cushing's syndrome from the patient's perspective

Forty-one patients with Cushing's syndrome described the physical, mental, and emotional effects of the disease, and the effects that the disease has on their families and performance at work or school. The majority of patients reported that Cushing's syndrome greatly affected everyday life. Areas in which physicians and nurses can provide critical assistance and support are described.     

Aminoglutethimide in the treatment of Cushing's syndrome

The efficacy and tolerability of aminoglutethimide for the treatment of Cushing's syndrome was assessed in 66 cases three of which are described in the present paper. Aminoglutethimide provided palliation from the signs and symptoms of hypercorticism in 13 of 21 patients with metastatic adrenocortical carcinoma and four of six patients with ectopic ACTH production due to metastatic carcinomas. All six of the patients with adrenal adenomas showed clinical and biochemical improvement, while 14 of the 33 patients with bilateral adrenal hyperplasia of pituitary origin improved. Adverse reactions attributed to aminoglutethimide such as drowsiness, rash, and nausea occurred in 58 per cent of cases. These data suggest that aminoglutethimide has a place in controlling the signs and symptoms of adrenocorticoid excess in patients with Cushing's syndrome due to malignancy and is effective preoperative therapy for patients with adrenal adenomas and bilateral hyperplasia.     

Variation in response to dexamethasone of a patient with Cushing's syndrome

A patient with Cushing's syndrome due to a nonresectable chromophobe adenoma underwent external irradiation of the hypothalamic-pituitary area. The signs of Cushing's syndrome ameliorated subsequently but recurred eventually, necessitating bilateral adrenalectomy 30 months after initial presentation. Response to dexamethasone suppression testing on four occasions varied greatly. These results may reflect alterations in sensitivity of the tumour or the hypothalamic-pituitary axis to feedback inhibition by glucocorticoids.     

Cushing's syndrome due to bilateral adrenocortical adenomas with different pathological features

A 48-year-old woman with Cushing's syndrome due to bilateral adrenocortical adenomas is reported. The patient presented with a typical Cushingoid appearance. The serum cortisol level was elevated with loss of the diurnal rhythm and the plasma adrenocorticotropic hormone (ACTH) level was undetectable. Dynamic testing showed no suppression of urinary 17-OHCS by high-dose dexamethasone and no stimulation by metyrapone. An abdominal computed tomography (CT) scan showed bilateral adrenal tumors. Bilateral adrenalectomy was performed. The right adrenal gland contained a tumor that was encapsulated and consisted mainly of compact cells. The surrounding cortex was atrophic. The left adrenal gland contained an encapsulated tumor composed predominantly of clear cells. There were numerous small adrenocortical nodules in the surrounding cortex. Immunohistochemical analysis of steroidogenic enzymes (P450scc, 3beta-HSD, P450c21, P450c17 and P450c11) was performed. Immunoreactivity of all the enzymes was intense in the compact cells of the right adrenocortical adenoma, while the adjacent non-neoplastic cortex was negative for the enzymes. In the left adrenal tumor, the immunoreactivity of 3beta-HSD was intense, while that of P450c17 was weak. In the adrenocortical nodules, 3beta-HSD activity was sporadically observed. G protein genes encoding Gs alpha and Gi2 were examined for activating mutations at codons 201 and 227 (Gs alpha) and codons 179 and 205 (Gi2 alpha) in the bilateral adrenal tumors, but no mutations were found. The bilateral adenomas of this patient showed marked differences in microscopic and immunohistochemical studies, suggesting that the capacity of steroidogenesis differs between the right and left tumors.     

Biochemical and radiologic diagnosis of Cushing's syndrome

In summary, the technological advances in the past decade have greatly improved the biochemical and radiological diagnosis of Cushing's syndrome. Figure 13 illustrates an algorithm for the differential diagnosis of Cushing's syndrome that focuses on the importance of ACTH-IRMA and provides two potential diagnostic approaches for the evaluation of ACTH-dependent hypercortisolism. The first approach directly proceeds to IPSS as the most rapid and possibly most cost effective method to establish an accurate diagnosis. A more traditional approach employs high dose dexamethasone suppression testing followed by MR studies of the pituitary. If the biochemical or radiological studies are the least bit equivocal, IPSS should be performed before definitive therapy is recommended.     

Influence of left ventricular function on survival and mode of death after implantable defibrillator therapy (Cleveland Clinic Foundation and Montefiore Medical Center experience)

To determine the influence of left ventricular (LV) function on survival and mode of death in patients with an implantable cardioverter-defibrillator (ICD), sudden death, surgical mortality, total arrhythmia-related death, total cardiac death and total death were retrospectively evaluated in 377 consecutive patients. The outcomes were also compared between patients with an LV ejection fraction > or = 30% (214 patients, group 1) and < 30% (148 patients, group 2). Surgical mortality was 3.9% (1.8% in group 1, 7% in group 2). During the follow-up of 25 +/- 20 months, actuarial survival rates of all patients at 3 years were 96% for sudden deaths, 81% for total cardiac deaths and 74% for total mortality. When the 2 groups were compared, survival rates of groups 1 and 2 at 3 years, respectively, were 99 and 90% for sudden death (p < 0.05), 97 and 84% for sudden death and surgical mortality (p < 0.01), 94 and 80% for the total arrhythmia-related death (p < 0.001), 88 and 68% for total cardiac death (p < 0.0001), and 81 and 62% for total mortality (p < 0.002). In group 2, 73% of total cardiac deaths within 1 year were causally related to the arrhythmia. Thus, in patients with an ICD, sudden death rates were very low. However, total cardiac death and total death rates were relatively higher. The outcomes of patients with an ICD were strongly influenced by the degree of LV dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Determinants of serum leptin levels in Cushing's syndrome

Corticosteroids and insulin increase leptin expression in vivo and in vitro. To investigate whether increased serum cortisol influences serum leptin concentrations in humans, we analyzed fasting serum leptin and insulin levels in 50 patients with Cushing's syndrome [34 female patients: 27 with the pituitary form and 7 with the adrenal form; age, 41.6 +/- 2.7 yr; body mass index (BMI), 29.6 +/- 1.2 kg/m2; 16 male patients all with the pituitary form; age, 39.2 +/- 3.1 yr; BMI, 26.3 +/- 2.3 kg/m2] and in controls matched for BMI, age, and gender. Serum leptin levels were higher in female than in male patients in both the Cushing (P < 0.01) and control (P < 0.001) groups. Disease-specific differences in serum leptin levels were only detected in male (106 vs. 67 pmol/L; Cushing's syndrome vs. control, P < 0.05), not female, patients. Multiple stepwise regression analysis of both patient groups revealed insulin as the best predictor of serum leptin concentrations, accounting for 37% of the variance in serum leptin levels, in contrast to BMI or mean serum cortisol (as measured by sampling in 10-min intervals over 24 h). In the subgroup of patients (n = 9) with pituitary adenoma, serum leptin levels were reduced after tumor resection, with concurrent decreases in serum cortisol, insulin, and BMI. In conclusion, chronic hypercortisolemia in Cushing's syndrome appears not to directly affect serum leptin concentrations, but to have an indirect effect via the associated hyperinsulinemia and/or impaired insulin sensitivity.     

Vasopressin receptors modulate the pharmacological phenotypes of Cushing's syndrome

We have examined the expression profiles of the different vasopressin receptors (V1, V2, V3) that can be expressed in the three different types of tumors associated with Cushing's syndrome. V3 (V1b) receptor cDNA was cloned from a pituitary tumor responsible for Cushing's disease. We show that it is overexpressed in these tumors and can respond to DD-AVP. High expression of the V3 receptor on highly differentiated, ACTH-secreting, bronchial carcinoid tumors explain why these non-pituitary tumors occasionally respond to vasopressin, mimicking a "pituitary-like" behavior. A retrospective analysis showed that vasopressin induced an ACTH-independent cortisol rise in 27% of the adrenocortical tumors responsible for Cushing's syndrome. V1 mRNA was detected in normal adrenal cortex and in all tumors. Adenomas had significantly higher levels than carcinomas. V1 mRNA levels were higher in responders than in non-responders. One adenoma which had a brisk cortisol response in vivo, also had in vitro cortisol responses that were inhibited by a specific V1 antagonist. In situ hybridization showed the presence of V1 mRNA in the normal human adrenal cortex where the signal predominated in the compact cells of the zona reticularis. A positive signal was also present in the tumors with high V1 mRNA levels determined by RT-PCR; its distribution pattern was heterogeneous and showed preferential association with compact cells. High-and not ectopic-expression of the V1 receptor occurs in a minority of adrenal cortical tumors which become directly responsive to vasopressin stimulation.