Primary Adrenal Cushing's Syndrome Research Articles

The Incidence of Long-Term Adrenal Insufficiency Following Unilateral Adrenalectomy is Low: Case Series and Review of Literature

Introduction: Acquired adrenal insufficiency is a known risk of unilateral adrenalectomy. However, the rates of early and prolonged adrenal insufficiency following unilateral adrenalectomy are not well defined in the literature. Patients and Methods: We reviewed a case series of 184 consecutive patients to determine the likelihood of steroid supplementation at 30 days and 1 year following adrenalectomy. 109 lesions were non-functional and 75 (41%) demonstrated functionality, including 33 pheochromocytomas, 20 cortisol-producing adenomas, 19 aldosteronomas, and 3 cases of cortisol-secreting hyperplasia. No patients with a nonfunctional lesion, pheochromocytoma, or aldosteronoma required steroid supplementation following surgery. Eleven of 23 patients (48%) with primary adrenal Cushing syndrome required cortisol supplementation at 30 days, and only 1 patient (4%) necessitated supplementation one year following surgery. Discussion: Approximately 50% of patients with cortisol-producing lesions in the adrenal gland will require supplementation 30-days following surgery. Only 4% will require persistent exogenous steroids at 1-year. Conversely, less than 1% of patients with different types of functional or non-functional tumors required supplementation after surgery. Conclusion: The incidence of adrenal insufficiency following unilateral adrenalectomy is low. A large majority of patients requiring steroid supplementation 30 days following surgery are able to wean off this requirement by 1 year. With this information, we can better counsel our patients and set clearer expectations for the potential need of cortisol supplementation following adrenalectomy

Circadian Plasma Cortisol Measurements Reflect Severity of Hypercortisolemia in Children with Different Etiologies of Endogenous Cushing Syndrome

Background: The utility of circadian cortisol variation in estimating the degree of hypercortisolemia in different forms of endogenous Cushing syndrome (CS) has not been evaluated in children yet. Methods: A retrospective cohort study, including children who underwent surgery due to CS (n = 115), was divided into children with a pituitary adenoma (Cushing disease) (n = 88), primary adrenal CS (n = 21), or ectopic adrenocorticotropin- or corticotropin-releasing hormone (ACTH-/CRH)-secreting tumors (n = 6). Circadian plasma cortisol measurements were obtained at 11: 30 p.m. and at midnight, and at 7: 30 and 8: 00 a.m. The ratios between the morning and late-night concentrations were calculated. Results: Plasma cortisol early-morning and midnight (AM/PM) ratios negatively correlated with 24-h urinary free cortisol (UFC) collections among the full study population and in each of the individual etiologies. Plasma ACTH concentrations positively correlated with plasma cortisol AM/PM ratios among patients with ACTH-independent CS. Finally, patients with primary pigmented nodular adrenocortical disease showed no correlation between UFC collections and the plasma cortisol AM/PM ratio, in contrast with other etiologies for primary adrenal CS, which showed a strong negative correlation between them. Conclusion: Our study shows the association between the plasma cortisol AM/PM ratio and the degree of hypercortisolemia in children with CS.

Coagulation Profile in Patients with Different Etiologies for Cushing Syndrome: A Prospective Observational Study.

Previous studies reported a higher prevalence of venous-thromboembolic events among patients with Cushing disease (CD) compared to those with ACTH-independent Cushing syndrome (CS) from adrenal sources. The objective of the current study was to evaluate the coagulation profile of patients with CS from different etiologies. A prospective observational study was conducted at a clinical research center. The study included adult patients admitted for evaluation of suspected CS (n=85), that were divided into 3 groups: CD (n=22), ACTH-independent CS from an adrenal tumor/hyperplasia (adrenal CS, n=21), and a control group consisting of subjects with negative screening for CS (rule-out CS, n=42). Coagulation profiles were drawn before and 8.5±4.3 months after surgery (trans-sphenoidal or adrenalectomy, n=18), and included fibrinogen, Factor VIII (FVIII), von Willebrand factor antigen (vWF:Ag), plasminogen activator inhibitor-1 (PAI-1), antithrombin III (ATIII), Protein C (PC), Protein S (PS), α2-antiplasmin (α2AP), and aPTT measurements. Patients with CD had higher baseline mean cortisol levels, ATIII activity and vWF:Ag levels compared with adrenal CS. Differences in ATIII activity and vWF:Ag levels remained even after controlling for BMI, and ATIII after also controlling for 24-h urinary free cortisol collections. Our study showed for the first time the differences in coagulation profiles between various etiologies of CS. We assume that the higher cortisol burden among CD patients may explain the differences found in the coagulation profile as well as the higher risk for VTE compared with primary adrenal CS patients.

Newly Diagnosed Carney Complex in 3 Young Adults with Primary Adrenal Cushing Syndrome – A Case Series and Review of the Literature

ABSTRACT Objective: Carney complex (CNC) is a very rare cause of adrenocorticotropic hormone (ACTH)-independent Cushing syndrome (CS). We describe 3 cases of CNC diagnosed through the evaluation of CS, with no other major manifestations of CNC. Methods: We present the relevant history, laboratory, and pathologic data of the current cases, and review relevant documentation from the literature. Results: Among all 3 patients, CS symptomatology was the main clinical characteristic, which was also supported by a diminished diurnal rhythmicity of plasma cortisol and ACTH levels. The paradoxical increase in cortisol after both low and high dose dexamethasone suppression tests (Liddle's test) proved to be the most useful biochemical clue for the diagnosis of primary pigmented nodular adrenocortical disease (PPNAD) in these patients. The absence of bilateral macronodular or unilateral adrenal lesion led to the possible diagnosis of PPNAD/CNC. None of the 3 patients demonstrated any of the other described major man...

Factors predicting the duration of adrenal insufficiency in patients successfully treated for Cushing disease and nonmalignant primary adrenal Cushing syndrome

Successful treatment of Cushing syndrome causes transient or permanent adrenal insufficiency deriving from endogenous hypercortisolism-induced hypothalamus-pituitary-adrenal-axis suppression. We analyzed pre-treatment factors potentially affecting the duration of adrenal insufficiency. We conducted a retrospective analysis on patients successfully treated for Cushing disease (15 patients) who underwent transsphenoidal surgery, and nonmalignant primary adrenal Cushing syndrome (31 patients) who underwent unilateral adrenalectomy, divided into patients with overt primary adrenal Cushing syndrome (14 patients) and subclinical primary adrenal Cushing syndrome (17 patients). Epidemiological data, medical history, and hormonal parameters depending on the etiology of hypercortisolism were collected and compared to the duration of adrenal insufficiency. The median duration of follow-up after surgery for Cushing disease and primary adrenal Cushing syndrome was 70 and 48 months, respectively. In the Cushing disease group, the median duration of adrenal insufficiency after transsphenoidal surgery was 15 months: younger age at diagnosis and longer duration of signs and symptoms of hypercortisolism before diagnosis and surgery were associated with longer duration of adrenal insufficiency. The median duration of adrenal insufficiency was 6 months for subclinical primary adrenal Cushing syndrome and 18.5 months for overt primary adrenal Cushing syndrome. The biochemical severity of hypercortisolism, the grade of hypothalamus-pituitary-adrenal-axis suppression, and treatment with ketoconazole before surgery accounted for longer duration of adrenal insufficiency. In patients with Cushing disease, younger age and delayed diagnosis and treatment predict longer need for glucocorticoid replacement therapy after successful transsphenoidal surgery. In patients with primary adrenal Cushing syndrome, the severity of hypercortisolism plays a primary role in influencing the duration of adrenal insufficiency after unilateral adrenalectomy.

A genetic and molecular update on adrenocortical causes of Cushing syndrome.

Primary adrenal Cushing syndrome is the result of cortisol hypersecretion mainly by adenomas and, rarely, by bilateral micronodular or macronodular adrenocortical hyperplasia. cAMP-dependent protein kinase A (PKA) signalling is the major activator of cortisol secretion in the adrenal cortex. Many adenomas and hyperplasias associated with primary hypercortisolism carry somatic or germline mutations in genes that encode constituents of the cAMP-PKA pathway. In this Review, we discuss Cushing syndrome and its linkage to dysregulated cAMP-PKA signalling, with a focus on genetic findings in the past few years. In addition, we discuss the presence of germline inactivating mutations in ARMC5 in patients with primary bilateral macronodular adrenocortical hyperplasia. This finding has implications for genetic counselling of affected patients; hitherto, most patients with this form of adrenal hyperplasia and Cushing syndrome were thought to have a sporadic and not a familial disorder.

Cell-to-cell communication in bilateral macronodular adrenal hyperplasia causing hypercortisolism.

It has been well established that, in the human adrenal gland, cortisol secretion is not only controlled by circulating corticotropin but is also influenced by a wide variety of bioactive signals, including conventional neurotransmitters and neuropeptides, released within the cortex by various cell types such as chromaffin cells, neurons, cells of the immune system, adipocytes, and endothelial cells. These different types of cells are present in bilateral macronodular adrenal hyperplasia (BMAH), a rare etiology of primary adrenal Cushing’s syndrome, where they appear intermingled with adrenocortical cells in the hyperplastic cortex. In addition, the genetic events, which cause the disease, favor abnormal adrenal differentiation that results in illicit expression of paracrine regulatory factors and their receptors in adrenocortical cells. All these defects constitute the molecular basis for aberrant autocrine/paracrine regulatory mechanisms, which are likely to play a role in the pathophysiology of BMAH-associated hypercortisolism. The present review summarizes the current knowledge on this topic as well as the therapeutic perspectives offered by this new pathophysiological concept.

ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of primary adrenal Cushing's syndrome (CS). ARMC5 germline mutations have been identified recently in PBMAH. To determine the prevalence of ARMC5 mutations and analyze genotype-phenotype correlation in a large cohort of unrelated PBMAH patients with subclinical or clinical CS. ARMC5 was sequenced in 98 unrelated PBMAH index cases. PBMAH was identified by bilateral adrenal nodular enlargement on computed tomography scan. The effect on apoptosis of ARMC5 missense mutants was tested in H295R and HeLa cells. Clinical and hormonal data were collected including midnight and urinary free cortisol levels, ACTH, androgens, renin/aldosterone ratio, cortisol after overnight dexamethasone suppression test, cortisol and 17-hydroxyprogesterone after ACTH 1-24 stimulation and illegitimate receptor responses. Computed tomography and histological reports were analyzed. ARMC5-damaging mutations were identified in 24 patients (26%). The missense mutants and the p.F700del deletion were unable to induce apoptosis in both H295R and HeLa cell lines, unlike the wild-type gene. ARMC5-mutated patients showed an overt CS more frequently, compared to wild-type patients: lower ACTH, higher midnight plasma cortisol, urinary free cortisol, and cortisol after dexamethasone suppression test (P = .003, .019, .006, and <.001, respectively). Adrenals of patients with mutations were bigger and had a higher number of nodules (P = .001 and <.001, respectively). ARMC5 germline mutations are common in PBMAH. Index cases of mutation carriers show a more severe hypercortisolism and larger adrenals. ARMC5 genotyping may help to identify clinical forms of PBMAH better and may also allow earlier diagnosis of this disease.

Cushing syndrome.

Cushing syndrome.

Abnormal Sensitivity to Glucagon and Related Peptides in Primary Adrenal Cushing's Syndrome.

Illegitimate G-protein coupled receptors are known to control cortisol secretion in adrenal adenomas and bilateral macronodular adrenal hyperplasias (BMAHs) causing Cushing's syndrome. In the present study, we have evaluated the role of glucagon in the regulation of cortisol secretion in 13 patients with BMAH or adrenocortical adenoma causing subclinical or overt Cushing's syndrome. Injection of glucagon provoked an increase in plasma cortisol in 2 patients. After surgery, immunohistochemical studies showed the presence of glucagon receptor-like immunoreactivity in clusters of spongiocytic cells in adrenal tissues from patients who were sensitive in vivo to glucagon. We also observed an in vitro cortisol response to vasoactive intestinal peptide from an adenoma, which was insensitive to glucagon and pituitary adenylate cyclase-activating peptide. Altogether, our data show that ectopic glucagon receptors are expressed in some adrenal cortisol-producing benign lesions. Our results also indicate that circulating glucagon may influence cortisol release under fasting conditions.

Intraadrenal Corticotropin in Bilateral Macronodular Adrenal Hyperplasia

BackgroundBilateral macronodular adrenal hyperplasia is a rare cause of primary adrenal Cushing's syndrome. In this form of hyperplasia, hypersecretion of cortisol suppresses the release of corticotropin by pituitary corticotrophs, which results in low plasma corticotropin levels. Thus, the disease has been termed corticotropin-independent macronodular adrenal hyperplasia. We examined the abnormal production of corticotropin in these hyperplastic adrenal glands.MethodsWe obtained specimens of hyperplastic macronodular adrenal tissue from 30 patients with primary adrenal disease. The corticotropin precursor proopiomelanocortin and corticotropin expression were assessed by means of a polymerase-chain-reaction assay and immunohistochemical analysis. The production of corticotropin and cortisol was assessed in 11 specimens with the use of incubated explants and cell cultures coupled with hormone assays. Corticotropin levels were measured in adrenal and peripheral venous blood samples from 2 patients.ResultsThe expression of proopiomelanocortin messenger RNA (mRNA) was detected in all samples of hyperplastic adrenal tissue. Corticotropin was detected in steroidogenic cells arranged in clusters that were disseminated throughout the adrenal specimens. Adrenal corticotropin levels were higher in adrenal venous blood samples than in peripheral venous samples, a finding that was consistent with local production of the peptide within the hyperplastic adrenals. The release of adrenal corticotropin was stimulated by ligands of aberrant membrane receptors but not by corticotropin-releasing hormone or dexamethasone. A semiquantitative score for corticotropin immunostaining in the samples correlated with basal plasma cortisol levels. Corticotropin-receptor antagonists significantly inhibited in vitro cortisol secretion.ConclusionsCortisol secretion by the adrenals in patients with macronodular hyperplasia and Cushing's syndrome appears to be regulated by corticotropin, which is produced by a subpopulation of steroidogenic cells in the hyperplastic adrenals. Thus, the hypercortisolism associated with bilateral macronodular adrenal hyperplasia appears to be corticotropin-dependent. (Funded by the Agence Nationale de la Recherche and others.)

Transumbilical Single Port Laparoscopic Adrenalectomy: A Technical Report on Right and Left Adrenalectomy Using the Glove Port

Recently, single port laparoscopic surgery has been the focus of attention due to the advanced laparoscopic skills accumulated from experience and developments in laparoscopic instruments. Herein, we present two cases of initial single port laparoscopic adrenalectomies. Case 1 was a 38-year-old female patient diagnosed with primary hyperaldosteronism because of a the right adrenal 2.5-cm sized adenoma, and case 2 was a 31-year-old female patient diagnosed with primary adrenal Cushing's syndrome because of a left adrenal 2.9-cm sized adenoma. Both patients successfully underwent single port laparoscopic adrenalectomies via a transumbilical transperitoneal approach. There was no estimated blood loss and the total operating times were 60 and 70 minutes, respectively. Both patients recovered uneventfully. We believe that this technique presented could provide potential benefits (lesser wound pain, better cosmetic satisfaction, and shorter convalescence) if the indications are carefully selected.

Irregular and frequent cortisol secretory episodes with preserved diurnal rhythmicity in primary adrenal Cushing's syndrome.

To evaluate the pathophysiology of altered cortisol secretion in patients with primary adrenal hypercortisolism, cortisol secretion was investigated in 12 patients, seven with a unilateral adenoma and five with ACTH-independent macronodular adrenal hyperplasia compared with age- and gender-matched controls and with patients with pituitary-dependent hypercortisolism. Pulsatile secretion was increased 2-fold (P = 0.04), attributable to increased event frequency (P = 0.002). All patients showed a significant diurnal rhythm with a delay in phase shift of 3 h (P = 0.01). Approximate entropy ratio, a feedback-sensitive measure, was increased compared with controls (P = 0.00003) but similar to that of pituitary-dependent hypercortisolism (P = 0.77), denoting loss of autoregulation. Cortisol burst-mass tended to be smaller in patients with ACTH-independent macronodular adrenal hyperplasia than in unilateral adenoma (P = 0.06). In conclusion, increased cortisol secretion in patients with primary adrenal Cushing's syndrome is caused by amplified pulsatile secretion via event frequency modulation. We speculate that partial preservation of secretory regularity and diurnal rhythmicity point to incomplete autonomy of these tumors.

Growth hormone secretion in primary adrenal Cushing's syndrome is disorderly and inversely correlated with body mass index.

To evaluate the impact on the somatotropic axis of endogenous cortisol excess in the absence of primary pituitary disease, we investigated spontaneous 24-h growth hormone (GH) secretion in 12 adult patients with ACTH-independent hypercortisolism. Plasma GH concentration profiles (10-min samples) were analyzed by deconvolution to reconstruct secretion and approximate entropy to quantitate orderliness of the release process. Comparisons were made with a body mass index (BMI)-, age-, and gender-matched control group and an age- and gender-matched lean control group. GH secretion rates did not differ from BMI-matched controls but were twofold lower compared with lean subjects, mainly due to a 2.5-fold attenuation of the mean secretory burst mass (P = 0.001). In hypercortisolemic patients, GH secretion was negatively correlated with BMI (R = -0.55, P = 0.005) but not cortisol secretion. Total serum IGF-I concentrations were similar in the three groups. Approximate entropy (ApEn) was increased in patients with Cushing's syndrome compared with both control groups (vs. BMI-matched, P = 0.04; vs. lean, P = 0.001), denoting more irregular GH secretion patterns. ApEn in patients correlated directly with cortisol secretion (R = 0.77, P = 0.003). Synchrony between cortisol and GH concentration series was analyzed by cross-correlation, cross-ApEn, and copulsatility analyses. Patients showed loss of pattern synchrony compared with BMI-matched controls, but copulsatility was unchanged. We conclude that hyposomatotropism in primary adrenal hypercortisolism is only partly explained (approximately 30%) by increased body weight and that increased GH secretory irregularity and loss of synchrony suggest altered coordinate regulation of GH release.

CT and MR imaging of the adrenal glands in ACTH-independent cushing syndrome.

Adrenocorticotropic hormone (ACTH)-independent hypercortisolism accounts for 15%-20% of cases of Cushing syndrome and always arises from primary adrenal disease. Computed tomographic (CT) and magnetic resonance (MR) imaging findings in 37 patients with primary adrenal Cushing syndrome were analyzed and correlated with pathologic findings. Hyperfunctioning adenomas (n = 24), together with functioning carcinomas (n = 10), accounted for 92% of cases. Adenomas had a significantly smaller mean size (3.5 vs 14.5 cm) and lower mean unenhanced CT attenuation value (11 vs 28 HU) than did carcinomas. The presence of necrosis, hemorrhage, and calcification favored a diagnosis of carcinoma. Six of 10 carcinoma patients had metastases at presentation. Two adenomas were seen within a myelolipoma, which was recognized at both CT and MR imaging due to its fat content, and two adenomas were of uncertain malignant potential. Bilateral disease--primary pigmented nodular adrenal dysplasia (PPNAD) (n = 2) and ACTH-independent macronodular adrenal hyperplasia (AIMAH) (n = 1)--had characteristic imaging features. In PPNAD, multiple tiny (2-5-mm) nodules were visible bilaterally, with no overall glandular enlargement and normal intervening adrenal tissue. In AIMAH, both glands were grossly enlarged and contained nodules up to 3 cm in diameter. Familiarity with the range of imaging appearances of the adrenal glands in primary adrenal Cushing syndrome may help establish the underlying diagnosis.

Adrenocortical tumours

Adrenocortical tumours have to be differentiated from cortical hyperplasias, medullary tumours and extra-adrenal tumours or metastases. These diagnoses are mostly possible using routine paraffin sections. In some cases, immunostaining for differing cortical and medullary tumours and metastases are necessary. Adrenal hyperplasias can be congenital or acquired. They are diffuse, micronodular or macronodular and may be inactive or induce a cortical hyperfunction. Very rarely, macronodular hyperplasias may transform into autonomous adenomas. Primary, pigmented adrenocortical disease is a rare, special type of primary adrenal Cushing's syndrome, showing many small tumours with pleomorphic cells and an atrophic surrounding cortical tissue. Adrenal adenomas are mostly unilateral and solitary tumours weighing less than 50 g. Adrenal cortical carcinomas are mostly larger. Like the adenomas, they may be inactive and may induce a hypercortisolism, a hyperandrogenism or (very rarely in carcinomas) a hyperaldosteronism. Differentiating cortical adenomas and carcinomas is difficult in some cases but is possible using a diagnostic algorithm. Myelolipomas are benign, inactive tumours composed of mature fat cells and bone marrow cells. They have to be differentiated from adenomas with myelolipomatous metaplasia. Further, rare primary cortical tumours are mentioned.

Assessment of cortisol and ACTH responses to the desmopressin test in patients with Cushing's syndrome and simple obesity.

The desmopressin test has recently been introduced in clinical practice as an adjunctive tool in the differential diagnosis of ACTH-dependent Cushing's syndrome (CS). It has been reported that the majority of patients with pituitary-dependent CS (Cushing's disease, CD) respond to desmopressin, while no such response is usually observed in other forms of this syndrome. In the present study, the responsiveness of the HPA axis to desmopressin was studied in a group of obese subjects. In addition, the ability of desmopressin administration to differentiate between patients with obesity and the various forms of Cushing's syndrome was investigated. Cortisol and ACTH responses to the administration of desmopressin (10 microg bolus i.v.) were examined in 20 consecutive patients with obesity (14 women and six men; BMI range: 34.5-66.7 kg/m2). Obese subjects had no clinical stigmata of CS. In all obese patients, either an overnight (dex 1 mg at 2300 h) (n = 8) or a formal low-dose (dex 0.5 mg 6-hourly for 2 days) (n = 12) dexamethasone suppression test was performed for the exclusion of Cushing's syndrome. Three of eight subjects showed failure of cortisol suppression (i.e. F > 28 nmol/l) to the overnight dexamethasone suppression test, but they had undetectable cortisol levels (< 28 nmol/l) on further testing with the formal 2-day test. All but two of the remaining subjects had undetectable cortisol levels (< 28 nmol/l) following the formal 2-day, low-dose, dexamethasone suppression test. For comparison, desmopressin responses were also tested in 33 patients with CS of varied aetiologies (25 patients with pituitary-dependent CS, three patients with occult ectopic ACTH secretion and five patients with primary adrenal CS). A positive response was considered to be an increment greater than 20% and 50% from baseline levels of cortisol and ACTH, respectively. Mean cortisol (F) and ACTH levels did not differ from the baseline at any time point following desmopressin administration in the obese group (basal F: 417 +/- 41, peak F: 389 +/- 32 nmol/l, P > 0.05; basal ACTH: 33.5 +/- 4.3, peak ACTH: 50.6 +/- 16.6 ng/l, P > 0.05), or in patients with occult ectopic or primary adrenal CS. In contrast, in the group of patients with CD, there was a significant rise in the mean ACTH and F levels from baseline (basal F: 725 +/- 50, peak F: 1010 +/- 64 nmol/l, P < 0.01; basal ACTH: 88.6 +/- 11.8, peak ACTH: 351 +/- 64 ng/l, P < 0.01). Cortisol responses greater than 20% from baseline were observed in 21/25 (84%) patients with CD, but in only 3/20 (15%) of the obese patients. With regard to ACTH, increments greater than 50% over baseline were observed in 23/25 (92%) of patients with CD, and in only 3/20 (15%) of the obese patients. As previously reported, none of the patients with occult ectopic ACTH secretion or primary adrenal CS had a positive response. The prevalence of subjects who met the criteria adopted to define positive cortisol and ACTH responses to the desmopressin test was significantly higher in the group of patients with Cushing's disease than in the group of patients with obesity. It is therefore suggested that this test may be occasionally useful in the differentiation between simple obesity and the pituitary-dependent form (but not other forms) of Cushing's syndrome.

Clinical Evaluation of the Presence of Abnormal Hormone Receptors in Adrenal Cushingʼs Syndrome

ACTH-independent cortisol production in adrenal Cushing's syndrome previously was believed to be autonomous. Recent work by our group and others has shown that, in certain patients with bilateral macronodular adrenal hyperplasia or unilateral adrenocortical tumor, cortisol production may be under the control of abnormal or ectopic hormone receptors. The aberrant regulation of cortisol production by GIP, vasopressin, β-adrenergic agonists, hCG/LH, or serotonin illustrates this concept. The identification of an abnormal adrenal receptor offers the possibility of new pharmacological approaches to control hypercortisolism by suppressing the endogenous ligands or by blocking the abnormal receptor with specific antagonists. This review will describe the in vivo investigation protocols utilized by our group to identify the presence of abnormal hormone receptors in primary adrenal 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.

Acute glucocorticoid deficiency is associated with plasma elevations of interleukin-6: does the latter participate in the symptomatology of the steroid withdrawal syndrome and adrenal insufficiency?

The cytokines tumor necrosis factor-alpha (TNF alpha), interleukin-1 (IL-1), and IL-6 are secreted at inflammatory sites in tandem and play a crucial role in the inflammatory and wound-healing processes. All three cytokines are potent activators of the hypothalamic-pituitary-adrenal axis, through which they restrain inflammation, whereas IL-6 itself plays a role in the termination of inflammation as well. To test the hypothesis that endogenous glucocorticoids exert a negative tonic effect on the secretion of these cytokines, we studied 17 patients with Cushing's disease and 2 patients with primary adrenal Cushing's syndrome before and after surgery. Plasma TNF alpha, IL-1 beta and IL-6 were measured before surgery, while the patients were hypercortisolemic; on postoperative day 4 or 5, when they were hypocortisolemic; and on postoperative day 9 or 10, when they were receiving glucocorticoid replacement. During severe hypocortisolism, on postoperative day 4 or 5, plasma IL-6 levels rose significantly, compared to the preoperative values (P < 0.001). During the same interval, TNF alpha and IL-1 beta also rose, albeit to a lesser extent. Over the same interval, patients with severe hypocortisolism experienced temperature elevation, fatigue, somnolence, flu-like symptoms, and anorexia, symptoms that have been traditionally attributed to glucocorticoid deficiency; these were also experienced by subjects that received recombinant human IL-6. There was no postoperative increase in any of the cytokines studied in the patients who were not hypocortisolemic after surgery and who also lacked the corresponding symptomatology. Plasma IL-6 concentrations decreased significantly, albeit not to normal levels, in the hypocortisolemic group of patients on postoperative day 9 or 10, when they were receiving glucocorticoid replacement. We conclude that the peripheral levels of IL-6 and to a lesser extent, those of TNF alpha and IL-1 beta are tonically inhibited by basal levels of glucocorticoids. The increased IL-6 production that occurs when cortisol levels fall might explain the symptomatology of acute glucocorticoid deficiency.