Cortisol-secreting Adrenal Adenoma Research Articles

Pregnancies complicated with functioning adrenal adenomas causing severe obstetric outcomes: a 20-year experience at a tertiary center

BackgroundFunctioning adrenal adenoma during pregnancy is rare, and the diagnosis is challenging owing to unspecific symptoms and restricted investigations. The obstetric outcomes of patients who undergo surgery during pregnancy or who receive only medical treatment are poorly described.ObjectiveThe aim was to investigate the associations between functioning adrenal adenomas and obstetric outcomes.MethodsA retrospective study was performed in a tertiary center over 20 years. The clinical characteristics, management and obstetric outcomes of the diagnosed pregnant women were reviewed.ResultsA total of 12 women were diagnosed with functioning adrenal adenomas during pregnancy from January 2002 to September 2022. Eight women had cortisol-secreting adrenal adenomas, two had excessive catecholamine secretion, and two had primary aldosteronism. The initial symptoms of adrenal adenoma during pregnancy included hypertension or preeclampsia, gestational diabetes mellitus or prepregnancy diabetes mellitus, hypokalemia and ecchymosis. Four women underwent adrenalectomy during pregnancy, while 8 women received only medical therapy. Preterm birth occurred in all patients who received medicine, whereas 1 patient who underwent surgery experienced preterm birth. Among the 8 women in the medical treatment group, 3 had neonates who died.ConclusionsOnce hypertension, hyperglycemia and hypokalemia occur during the 1st or 2nd trimester, pregnant women with adrenal adenomas should be evaluated via laboratory and imaging examinations. The maternal and fetal outcomes were unpredictable owing to the severity of adrenal adenoma, particularly in patients who received only medical treatment. Adrenalectomy should be recommended during pregnancy.

Epidemiology and blood parameter changes in Cushing's syndrome - a population-based study.

To provide complete epidemiological data on Cushing's syndrome (CS) with analysis and differentiation of biochemical parameters, including blood count indices and serum inflammation-based scores. Clinical records of 35 patients diagnosed with CS between 2008 and 2020 at Malta's only central National Health Service hospital were retrospectively analyzed. Detailed clinical and biochemical data were obtained for each patient. Correlation and receiver operator characteristics (ROC) curve analyses were used to establish a threshold value for different variables to predict malignant CS. Standardized incidence rate (SIR) (/million/year) of CS was 4.5, and SIR of Cushing's disease (CD) was 2.3, 0.5 for ectopic CS, 1.5 for cortisol secreting adrenal adenoma, and 0.3 cases for cortisol-producing ACC. Malignant cause of CS had statistically significantly higher cortisol levels and size of tumor and lower potassium at diagnosis (P < 0.001). Additionally, malignant causes had a higher neutrophil-to-lymphocyte ratio (NLR) (P = 0.001) and systemic immune inflammation index (P = 0.005) and a lower lymphocyte-to-monocyte ratio (P < 0.001). Using ROC curve analysis to predict malignant cause of CS, a potassium level of < 3.05 was 75% sensitive and 100% specific (ROC-AUC 0.907, P = 0.001), a post-ODST cortisol level of > 841nmol/L was 100% sensitive and 91% specific (ROC-AUC 0.981, P < 0.001), while a NLR ratio > 3.9 was 100% sensitive and 57.7% specific (ROC-AUC 0.885, P = 0.001). Biochemical and blood count indices and serum inflammatory-based scores differ remarkably between benign and malignant causes of endogenous CS. Such indices can help predict the severity of disease and prognosis.

Intracranial hypertension and empty Sella from adrenal adenoma and excessive and prolonged steroid usage: a case report

BackgroundThere is only one documented case of intracranial hypertension (IH) and empty sella from cortisol-producing adrenal adenoma so far. And IH and empty sella caused by long-term exogenous hypercortisolism has never been reported before. The purpose of this case report is to alert clinicians to glucocorticoid-induced IH.Case presentationWe present retrospectively a 50-year-old woman with cortisol-secreting adrenal adenoma, who progressed to intractable intracranial hypertension and a markedly expanded empty sella due to improper treatment. In 2011, the patient presented with hypertension, lack of cortisol circadian rhythm, low ACTH, a left adrenal adenoma and a partial empty sella, but did not receive low-dose dexamethasone suppression test (LDDST) and 24-h urinary cortisol. In 2014, she exhibited truncal obesity, raised cortisol, LDDST non-suppression, high urinary free cortisol and low ACTH, proving her cortisol-producing adrenal adenoma. She was simultaneously diagnosed with unexplained IH because of papilledema and elevated intracranial pressure, and her partial empty sella changed to a complete empty sella. In 2015, she underwent adrenal adenoma resection. From 2015 to 2018, she kept taking dexamethasone at least 2 mg daily without her doctors’ consent. During this period, she developed transient cerebrospinal fluid rhinorrhea, and her empty sella further worsened. After switching to low dose hydrocortisone, her papilledema disappeared completely, but optic atrophy has become irreversible.ConclusionsThe patient seems to be just an extreme case, but it may reveal and illustrate a general phenomenon: Both cortisol-producing adrenal adenoma and long-term exogenous hypercortisolism could cause varying degrees of elevated intracranial pressure and empty sella. Clinicians should remain vigilant for this phenomenon in patients with cortisol-producing adrenal adenoma or excessive and prolonged steroid usage and give them corresponding examinations to identify this complication.

Analysis of clinical and pathological features of primary bilateral macronodular adrenocortical hyperplasia compared with unilateral cortisol-secreting adrenal adenoma.

BackgroundPrimary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a rare condition with untypical subclinical symptoms of Cushing’s syndrome (CS). This study aimed to compare the clinical and pathological features of PBMAH with unilateral cortisol-secreting adrenal adenoma (UAA).MethodsWe prospectively included 46 PBMAH patients and 205 UAA patients from January 2000 to February 2014. Cortisol levels and 24 hours urine free cortisol (UFC) were determined at baseline and during dexamethasone suppression test (DST) using the chemiluminescence method. Computed tomography (CT) examination of the adrenal glands was performed in all patients. For patients treated with adrenalectomy, hematoxylin, and eosin, staining was performed for pathological examination.ResultsThe proportion of patients with autonomous cortisol secretion was significantly higher in PBMAH patients (39.1%) than UAA patients (6.8%). The PBMAH patients showed significantly lower levels of basal cortisol, low dose dexamethasone suppressed cortisol, and high dose dexamethasone suppressed cortisol than the UAA patients (452.6±183.3 vs. 578.7±166.4 nmol/L, P=0.003; 394.5±298.9 vs. 549.2±217.7 nmol/L, P=0.002; 397.3±282.3 vs. 544.3±187.6 nmol/L, P=0.003). Similarly, the PBMAH patients had significantly lower levels of basal 24 hours UFC, low dose dexamethasone suppressed 24 hours UFC, and high dose dexamethasone suppressed 24 hours UFC than the UAA patients (1,144.4±1,048.1 vs. 1,674.9±1,520.4 nmol/24 h, P=0.032; 1,157.3±1,483.5 vs. 1,940.1±1,360.9 nmol/24 h, P=0.003; 1,256.4±1,767.0 vs. 1,969.9±1,361.7 nmol/24 h, P=0.011).ConclusionsPBMAH is often associated with atypical CS symptoms. The clinical and imaging features of PBMAH are useful for the differential diagnosis of this disease.

A double-blind, randomized, placebo-controlled phase 3 study to assess the efficacy and safety of relacorilant, a selective glucocorticoid receptor modulator, in patients with hypercortisolism due to cortisol-secreting adrenal adenoma(s)/hyperplasia

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

MON-163 A Phase 3, Double-Blind, Randomized, Placebo-Controlled Study to Assess the Efficacy and Safety of a Selective Glucocorticoid Receptor Modulator, Relacorilant, in Patients with Autonomous Cortisol Secretion Due to Cortisol-Secreting Adrenal Adenoma(s)/Hyperplasia

Relacorilant is a highly selective glucocorticoid receptor antagonist that modulates the effects of excess cortisol without interacting with the mineralocorticoid or progesterone receptor. A Phase 2 relacorilant study in patients with endogenous Cushing syndrome (CS) demonstrated improvements in glycemic control and hypertension with no instances of drug-related hypokalemia or antiprogesterone effects.An international, multicenter, Phase 3 clinical trial of relacorilant is currently underway to evaluate the efficacy and safety of relacorilant in CS of various etiologies with evidence of hypercortisolism documented through two independent biochemical tests and at least two clinical signs and symptoms of CS. It uses a randomized-withdrawal design after 22-weeks (22wk) of open-label treatment with relacorilant (GRACE Study: NCT03697109).Here we introduce a double-blind, randomized, placebo-controlled study in patients with less severe CS secondary to adrenal adenoma(s) or hyperplasia. Approximately 130 eligible patients 18-80 years old with a radiologically confirmed adrenal lesion, a biochemical diagnosis of autonomous cortisol secretion and either impaired glucose tolerance/diabetes mellitus (IGT/DM) or hypertension will receive relacorilant (100 mg/day, titrated to 400 mg/day, as tolerated) or placebo over 22WK.Biochemical criteria for entry into the study include a serum cortisol >1.8 µg/dL after dexamethasone suppression testing (DST) and low (<10 pg/dL) or suppressed morning ACTH levels. Patients must be stable on their antidiabetic and/or antihypertensive agents for at least 4 weeks prior to the first dose of relacorilant.The primary efficacy endpoints are the between-treatment difference in change from Baseline to 22wk in AUCglucose for the IGT/DM group and mean systolic blood pressure (based on ambulatory blood pressure monitoring) for the hypertension group. Secondary endpoints include changes in weight, waist circumference, quality of life and coagulation markers. The safety analysis will be performed for all patients who received at least one dose of study drug.This will be the first randomized, double-blind, placebo-controlled study to test if patients with adrenal autonomous hypercortisolism benefit from medical treatment.

MON-413 First Reported Case of Combined High-Dose Mifepristone Therapy and Oral Contraceptive in Inducing Reversible Cholestatic Hepatitis in a Patient with Cushing Disease

Background: Cushing syndrome is predisposed to hepatocellular disease due to increased visceral fat resulting in NAFLD, and direct effects of medical therapy, notably ketoconazole. Mifepristone (MIFE) (a competitive glucocorticoid receptor antagonist) is a CYP3A4 inhibitor, whereas loestrin (an oral contraceptive) is a CYP3A4 substrate. Recently, MIFE has been shown to improve liver enzymes in a patient with NAFLD and cortisol-secreting adrenal adenoma (Ragucci E, et al. Case Rep Endocrinol. 2017). Herein, we present a case of high-dose MIFE with loestrin in inducing cholestatic hepatitis that resolved spontaneously upon drug discontinuation. Case: A 35 year-old woman with Cushing disease (CD) underwent transsphenoidal surgery (TSS) twice (April 2014 and November 2017). Upon re-testing in January 2018, persistent hypercortisolemia was confirmed with 24-hr UFCs x 2 and late-night salivary cortisols x 2 that were > 2 ULN, and nonsuppressed AM cortisol after a 1 mg overnight dexamethasone suppression test. The patient declined pasireotide and ketoconazole due concerns of hyperglycemia and potential liver toxicity, respectively. After her first TSS, she developed secondary hypothyroidism, secondary hypogonadism and DI, and was placed on levothyroxine, loestrin and DDAVP. She agreed to consider MIFE therapy in February 2018. Baseline serum potassium and LFTs were normal, and she was initiated on MIFE 300 mg/d. Her dose was escalated to 600 mg/d in March 2018, 900 mg/d in May 2018, and alternating 900 mg/d and 1200 mg/d in June 2018. Fourteen days after being on alternating high-dose MIFE therapy, the patient presented to the ER with abdominal pains, nausea, vomiting, pruritus, jaundice and dark urine, and abnormal LFTs (hyperbilirubinemia, and mild increases in AST and ALP). She was hospitalized, and ultrasound of her abdomen revealed normal liver architecture, whereas liver biopsy confirmed diffuse canalicular and cytoplasmic bile stasis without zonal predilection consistent with acute drug-induced cholestasis. She had not taken any new medications or supplements after MIFE was initiated. Other causes of liver dysfunction were excluded including normal anti-ANA, anti-Sm and anti-mitochondrial antibodies, and normal viral hepatitis screen. She was treated symptomatically for her pruritus, MIFE and loestrin were discontinued, and she was discharged from hospital after 3 days. Her pruritus resolved and LFTs normalized 5 and 11 weeks, respectively, post-discharge. Conclusion: We report the first case of high-dose MIFE with loestrin in inducing reversible cholestatic hepatitis in CD, which contrasts to the direct hepatocellular toxicity induced by ketoconazole. Our case highlights the importance of knowledge of drugs that behave as CYP3A4 substrates or inhibitors, and close monitoring of LFTs, especially when MIFE dosing is escalated in combination with oral contraceptives.

Alterations in hypothalamic-pituitary-adrenal function immediately after resection of adrenal adenomas in patients with Cushing's syndrome and others with incidentalomas and subclinical hypercortisolism.

Patients with cortisol secreting adrenal adenomas present with Cushing's syndrome (CS), while 5-15% of subjects with adrenal incidentalomas have subclinical hypercortisolism (SH) as they have biochemical abnormalities suggesting autonomous cortisol secretion without associated clinical features of CS. Examine HPA function immediately after resection of either of these adenomas and utilize the data to decide on initiating glucocorticoid replacement. ACTH, cortisol, and DHEA-S levels were measured frequently for 8 h after adrenalectomy in 14 patients with CS and 19 others with incidentalomas + SH. Glucocorticoids were withheld before/during surgery and administered 6-8 h postoperatively to those who had cortisol levels of <3 ug/dL (83 nmol/L). Preoperatively, incidentalomas + SH patients had larger tumors, higher ACTH, and DHEA-S but lower dexamethasone-suppressed serum cortisol levels than those with CS. Postoperatively, ACTH levels increased in both groups: (90.1 ± 31.6; 24.1 ± 14.4 ng/L, respectively; P < 0.001). Postoperative ACTH levels correlated negatively with preoperative Dexamethasone-suppressed cortisol concentrations in both groups. Patients with CS had steeper decline in cortisol concentrations than those with incidentalomas + SH. All patients with CS had hypocortisolemia requiring glucocorticoid therapy for several months, while only 5/19 with incidentalomas + SH had cortisol levels <3 ug/dL;(83 nmol/L) 6-8 h after adrenalectomy and received hydrocortisone replacement therapy for ≤4 weeks. Surgical stress stimulates HPA function even in patients with hypercortisolemia. Patients with incidentalomas + SH have incomplete HPA suppression that allows more robust response to surgical stress than that observed in patients with CS. HPA assessment immediately after surgical resection of adrenal incidentalomas identified those requiring glucocorticoid replacement before discharge.

Multiple myeloma concealed by adrenal Cushing syndrome: a case report and review of the literature

BackgroundCushing syndrome coexisting with multiple myeloma has been previously described in a few reports. Overlapping clinical manifestations can lead to misdiagnoses.Case presentationWe presented an extremely rare case of a 33-year-old Thai woman with concomitant kappa light chain myeloma with adrenal Cushing syndrome, both of which were related to skeletal manifestations. A precedence report indicated that treatment of the Cushing syndrome could exacerbate the myeloma symptoms. Therefore, we were faced with the dilemma of which disease should be addressed first. We decided to treat our patient with a combination chemotherapy followed by an autologous stem cell transplant. Subsequently, a left laparoscopic adrenalectomy was successfully undertaken.ConclusionWe have reported the first association between adrenocorticotropic hormone-independent Cushing syndrome resulting from a left autonomous cortisol-secreting adrenal adenoma, and multiple myeloma.

ACTH-independent Cushing\u2019s syndrome with bilateral cortisol-secreting adrenal adenomas: a case report and review of literatures

BackgroundAdrenocorticotropic hormone (ACTH)-independent Cushing’s syndrome (CS) with bilateral cortisol-secreting adenomas has been rarely reported in the literatures. Precise recognition and management of this disorder constitute a challenge to clinicians due to the difficulty of exact location of the functional lesions.Case presentationWe herein report a new case of a Chinese female patient with a complaint of exertional dyspnea for over 10 years. ACTH-independent CS was diagnosed based on undetectable ACTH and unsuppressed cortisol levels by dexamethasone. Computed tomography (CT) scan indicated bilateral adrenal masses, and adrenal venous sampling (AVS) adjusted by plasma aldosterone revealed hypersecretion of cortisol from both adrenal glands. Bilateral cortisol-secreting adrenal adenomas were suspected and confirmed by the postoperative pathology in subsequent two-step bilateral laparoscopic adrenalectomy. The symptoms and signs of CS relieved after surgery with continuous glucocorticoid replacement.ConclusionsAVS adjusted by plasma aldosterone could be a useful technique in diagnosing ACTH-independent CS with bilateral adrenal adenomas prior to surgery. And the aldosterone ratio could be used to confirm the success of adrenal vein cannulation in this situation.

Intracellular Molecular Differences in Aldosterone- Compared to Cortisol-Secreting Adrenal Cortical Adenomas.

The adrenal cortex is a major site of steroid hormone production. Two hormones are of particular importance: aldosterone, which is produced in the zona glomerulosa in response to volume depletion and hyperkalemia, and cortisol, which is produced in the zona fasciculata in response to stress. In both cases, acute stimulation leads to increased hormone production, and chronic stimulation causes hyperplasia of the respective zone. Aldosterone- and cortisol-producing adenomas (APAs and CPAs) are benign tumors of the adrenal cortex that cause excess hormone production, leading to primary aldosteronism and Cushing’s syndrome, respectively. About 40% of the APAs carry somatic heterozygous gain-of-function mutations in the K+ channel KCNJ5. These mutations lead to sodium permeability, depolarization, activation of voltage-gated Ca2+ channels, and Ca2+ influx. Mutations in the Na+/K+-ATPase subunit ATP1A1 and the plasma membrane Ca2+-ATPase ATP2B3 similarly cause Na+ or H+ permeability and depolarization, whereas mutations in the Ca2+ channel CACNA1D directly lead to increased calcium influx. One in three CPAs carries a recurrent gain-of-function mutation (L206R) in the PRKACA gene, encoding the catalytic subunit of PKA. This mutation causes constitutive PKA activity by abolishing the binding of the inhibitory regulatory subunit to the catalytic subunit. These mutations activate pathways that are relatively specific to the respective cell type (glomerulosa versus fasciculata), and there is little overlap in mutation spectrum between APAs and CPAs, but co-secretion of both hormones can occur. Mutations in CTNNB1 (beta-catenin) and GNAS (Gsα) are exceptions, as they can cause both APAs and CPAs through pathways that are incompletely understood.

Mifepristone Accelerates HPA Axis Recovery in Secondary Adrenal Insufficiency.

Context. Transient secondary adrenal insufficiency (SAI) is an expected complication following successful adenomectomy of ACTH-secreting pituitary adenomas or unilateral adrenalectomy for cortisol-secreting adrenal adenomas. To date, no pharmacological therapy has been shown to hasten recovery of the hypothalamic-pituitary-adrenal (HPA) axis in this clinical scenario. Case Description. A 33-year-old woman underwent uncomplicated unilateral adrenalectomy for a 3.7 cm cortisol-secreting adrenal adenoma. Postoperatively, she developed SAI and was placed on hydrocortisone 15 mg/day, given in divided doses. In the ensuing six years, the patient's HPA axis failed to recover and she remained corticosteroid-dependent. Quarterly biochemical testing (after withholding hydrocortisone for 18 hours) consistently yielded undetectable serum cortisol and subnormal plasma ACTH levels. While she was on hydrocortisone 15 mg/day, mifepristone was initiated and gradually titrated to a maintenance dose of 600 mg/day after 5 months. Rapid recovery of the HPA axis was subsequently noted with ACTH rising into the supranormal range at 4 months followed by a subsequent rise in cortisol levels into the normal range. After 6 months, the dose of hydrocortisone and mifepristone was lowered and both were ultimately stopped after 8 months. The HPA axis remains normal after an additional 16 months of follow-up. Conclusion. Mifepristone successfully restored the HPA axis in a woman with prolonged secondary adrenal insufficiency (SAI) after adrenalectomy for Cushing's syndrome (CS).

A Pregnant Woman Who Underwent Laparoscopic Adrenalectomy due to Cushing's Syndrome.

Cushing's syndrome (CS) may lead to severe maternal and fetal morbidities and even mortalities in pregnancy. However, pregnancy complicates the diagnosis and treatment of CS. This study describes a 26-year-old pregnant woman admitted with hypertension-induced headache. Hormonal analyses performed due to her cushingoid phenotype revealed a diagnosis of adrenocorticotropic hormone- (ACTH-) independent CS. MRI showed a 3.5 cm adenoma in her right adrenal gland. After preoperative metyrapone therapy, she underwent a successful unilateral laparoscopic adrenalectomy at 14-week gestation. Although she had a temporary postoperative adrenal insufficiency, hormonal analyses showed that she has been in remission since delivery. Findings in this patient, as well as those in previous patients, indicate that pregnancy is not an absolute contraindication for laparoscopic adrenalectomy. Rather, such surgery should be considered a safe and efficient treatment method for pregnant women with cortisol-secreting adrenal adenomas.

Bone complications in patients with Cushing’s syndrome: looking for clinical, biochemical, and genetic determinants

This is the first study examining the impact of both clinical, biochemical, and genetic determinants in the occurrence of bone complications in patients with overt Cushing's syndrome (CS). It demonstrates that the degree and duration of hypercortisolism seem to play a major role in bone loss and fractures development in these patients. Bone loss and fractures are a common complication of CS. We investigate the role of gender, disease etiology, duration, and degree of hypercortisolism as well as the impact of glucocorticoid receptor (GR) polymorphisms on the development of bone complications in CS. Fifty-two patients with active CS (38 Cushing's disease and 14 with cortisol-secreting adrenal adenoma) were genotyped for GR polymorphisms (BclI, N363S, ER22/23EK, and A3669G). In all patients, clinical, hormonal, and biochemical markers of bone turnover, densitometric parameters [lumbar spine and left femur bone mineral density (BMD), T-score, Z-score] as well as the prevalence of bone demineralization and both vertebral and peripheral fractures were assessed. No differences were found in bone complications according to gender, disease etiology, and genetic variants distribution. Fractured patients compared to non-fractured ones showed increased levels of urinary free cortisol (UFC) and a more compromised densitometric profile. UFC levels correlated with the occurrence of vertebral fractures (r = 0.43, p = 0.009) while midnight serum cortisol correlated with L1-L4 BMD values (r = -0.35, p = 0.04). Disease duration correlated with the presence of peripheral fractures (r = 0.36, p = 0.04). While GR gene variants as well as gender and disease etiology seem not to play a role, the degree and duration of hypercortisolism seem to be the major determinants of bone loss and fractures in this group of patients. More investigations are needed to understand the real impact of these determinants on the development of bone complications in patients with hypercortisolism.

Adrenal tumours in pregnancy: diagnostic challenge and management dilemma

Adrenal gland tumours in pregnancy are very rare occurrences and have highly variable clinical presentations. The timely diagnosis of adrenal tumours in pregnancy is extremely important, as failure to do so may lead to fatality. As there is limited published literature on adrenal tumours in pregnancy and no consensus on its management, the management of such patients with regard to medical and surgical treatments, as well as timing of delivery, must therefore be individualised and carried out with multidisciplinary expertise. We present two cases of adrenal tumours in pregnancy, both with favourable outcomes and variable gestations. Our first and second cases discuss a large phaeochromocytoma and a cortisol-secreting adrenal cortical adenoma in pregnancy, respectively.

Metabolic complications of endogenous Cushing: patient selection for screening

Aims: this study evaluates the most common associations of symptoms and complications in patients with Cushing’s syndrome (CS) in order to choose a potential population to be screened for CS and estimates the diagnostic accuracy of first line screening tests (cortisol, ACTH) to differentiate ACTH-ectopic CS from Cushing’s disease. Materials and Methods: The clinical data of 259 patients with proven CS during 2001–2011 was analyzed. The clinical presentations of 197 patients (159 Cushing’s disease, 28 ACTH-ectopic CS and 10 cases of benign cortisol-secreting adrenal adenoma) were compared according to the cause of hypercortisolism. ROC-analysis was performed to estimate the diagnostic accuracy of the first line tests (cortisol, ACTH) to suggest ACTH-ectopic CS. A threshold for the test with the highest area under the curves was chosen based on the maximum sum of the sensitivity and specificity. Results: The most frequent complaints were related to fatigue, muscle weakness, weight gain and changes in appearance (facial plethora and fullness, striae). Among the complications of CS the most frequent were being overweight or obese (71%), hypertension (63%), dislipoproteinemia (41%), low traumatic fractures (43%) and steroid-induced diabetes (31%). In women, 16% were older than 50, in those who were younger amenorrhea was registered in 43%. The patients with ACTH-ectopic CS had higher rate of low traumatic fractures (p=0.04), increased serum late-night cortisol, 24 hours urinary free cortisol, morning and evening ACTH and lower levels of potassium (p0.01 for all parameters). Plasma late-night ACTH measurements showed the highest AUC (0,811 (95% CI 0,712–0,909)) to differentiate ACTH-ectopic CS from Cushing’s disease. A cut off value of 108.9 pg/ml for late-night ACTH yielded a sensitivity of 60,7% and a specificity of 79%. Conclusions: patients with a coexistence of obesity, muscle weakness, fatigue, some components of metabolic syndrome and especially low traumatic fractures should be screened for CS. High plasma late night ACTH values in patients with proven CS value suggest ACTH-ectopic syndrome.

Plasma and Urinary Metanephrines Determined by an Enzyme Immunoassay, but not Serum Chromogranin A for the Diagnosis of Pheochromocytoma in Patients with Adrenal Mass

Adrenal pheochromocytomas are neoplasms characterized by catecholamine excess. Determination of metanephrines by high-pressure liquid chromatography has been well established for the diagnosis of pheochromocytomas, demonstrating high sensitivity and specificity. This study evaluates the diagnostic value of newly available enzyme immunoassays for metanephrines in plasma and urine. Chromogranin A was studied as a potential additional diagnostic tool. Spontaneous blood samples and 24-h urine samples were collected in 149 subjects, including 24 histologically proven pheochromocytomas, 17 aldosterone-secreting and 21 cortisol-secreting adrenal adenomas, 30 nonfunctioning adrenal masses, 15 patients with essential hypertension and 42 healthy normotensive volunteers. Plasma and urinary metanephrine and normetanephrine as well as chromogranin A were determined and putative thresholds were calculated by ROC analysis. Plasma free normetanephrine was found to be the best single parameter with the highest sensitivity (89.5%) and specificity (98.3%) using a threshold of 167 pg/ml. Analysis of the combination of plasma free metanephrines revealed a similar sensitivity with lower specificity of 90.0%. Considering both urinary parameters demonstrated a slightly higher sensitivity (92.9%) with lower specificity (77.6%). ROC analysis revealed a threshold of 215 µg/l for chromogranin A with rather low sensitivity (73.9%) and specificity (74.2%). A weak positive correlation was found between the tumor size of pheochromocytomas and plasma metanephrine (r = 0.53, p ≤ 0.05) as well as chromogranin A (r = 0.60, p ≤ 0.01). In conclusion, plasma free and urinary metanephrines measured by enzyme immunoassays are convenient and reliable parameters for the diagnosis of pheochromocytoma. In contrast, CgA demonstrated poor sensitivity and specificity.

Glucose Intolerance and Diabetes Mellitus in Endocrine Disorders – Two Case Reports and a Review

Impaired glucose tolerance and diabetes mellitus are a manifestation of several well recognised endocrine disorders. Hyperglycaemia subsides upon removal of the underlying cause in these conditions - usually a hormone secreting tumour. We describe two subjects who were cured of their poorly controlled diabetes mellitus following surgical removal of a phaeochromocytoma and a cortisol secreting adrenal adenoma and review the mechanisms underlying glucose intolerance in endocrine disorders. The reported incidence of diabetes is variable in these conditions and may range between 2-95%. The severity is also variable as some affected individuals have only minor glucose intolerance while others have frank symptomatic diabetes mellitus which forms a major manifestation of their illness. The mechanisms causing hyperglycaemia are (a) insulin resistance, (b) increased hepatic glucose production and output, (c) decreased insulin production and release and (d) increased intestinal glucose absorption. Multiple intermediate mechanisms which include electrolyte perturbations and hormone receptor and post receptor mediated effects are responsible for these abnormalities. An understanding of these mechanisms and diagnostic strategies is important as these may be used to advantage in managing these patients. We describe some of these in greater detail below.

Late-night and low-dose dexamethasone-suppressed cortisol in saliva and serum for the diagnosis of cortisol-secreting adrenal adenomas

In patients with adrenal incidentalomas, hormonally active masses need to be considered, particularly cortisol-producing adenomas (CPA), aldosterone-producing adenomas, and pheochromocytomas. The screening for hypercortisolism relies on confirming excess cortisol secretion and insufficient suppression after dexamethasone. Because of its high correlation with free cortisol and its stress-free collection, salivary cortisol (SaC) may offer advantages over serum cortisol (SeC). We evaluated the value of SaC and SeC for the diagnosis of CPA. Design Comparative study between 2001 and 2006. Thirty-eight patients with confirmed CPA were compared with 18 healthy subjects as well as 48 control patients suffering from aldosterone-producing adenomas (n=13), pheochromocytomas (n=16), or nonfunctioning adenomas (n=19). Sampling of saliva and serum was performed at 2300 and at 0800 h following low-dose dexamethasone suppression. Receiver operating characteristics analysis was used to calculate thresholds with at least 95% sensitivity for CPA. Regarding the cutoffs for late-night cortisol, SaC (4.8 nmol/l, sensitivity 97%, specificity 69%) was slightly more specific than SeC (115 nmol/l, sensitivity 97%, specificity 63%). In contrast, the cutoff for dexamethasone-suppressed SaC (3.7 nmol/l, sensitivity 97%, specificity 83%) was slightly less specific than SeC (94 nmol/l, sensitivity 97%, specificity 88%). However, the latter cutoffs demonstrated greater specificity when compared with the cutoffs for late-night cortisol. The diagnostic accuracy of SaC is as good as SeC. Owing to its higher specificity, dexamethasone-suppressed cortisol is preferable to late-night cortisol when screening for Cushing's syndrome in patients with adrenal incidentalomas.

The value of corticotropin-releasing hormone (CRH) test for differential diagnosis of Cushing’s syndrome

Diagnosis and differential diagnosis of Cushing's syndrome (CS) remain considerable challenge in endocrinology. For more than 20 years, CRH has been widely used as differential diagnostic test. Following the CRH administration, the majority of patients with ACTH secreting pituitary adenoma show a significant rise of plasma cortisol and ACTH, whereas those with ectopic ACTH secretion characteristically do not. The aim of our study was to assess the value of CRF test for differential diagnosis of CS using the ROC (receiver operating characteristic) curve method. A total of 30 patients with CS verified by pathological examination and postoperative testing were evaluated. CRH test was performed within diagnostic procedures. ACTH secreting pituitary adenoma was found in 18, ectopic ACTH secretion in 3 and cortisol secreting adrenal adenoma in 9 of all patients with CS. Cortisol and ACTH were determined -15.0, 15, 30, 45, 60, 90 and 120 min. after i.v. administration of 100 microg of ovine CRH. Cortisol and ACTH were determined by commercial RIA. Statistical data processing was done by ROC curve analysis. Due to small number, the patients with ectopic ACTH secretion were excluded from test evaluation by ROC curve method. In evaluated subgroups, basal cortisol was (1147.3 +/- 464.3 vs. 1589.8 +/- 296.3 vs. 839.2 +/- 405.6 nmol/L); maximal stimulated cortisol (1680.3 +/- 735.5 vs. 1749.0 +/- 386.6 vs. 906.1 +/- 335.0 nmol/L); and maximal increase as a percent of basal cortisol (49.1 +/- 36.9 vs. 9.0 +/- 7.6 vs. 16.7 +/- 37.3%). Consequently, basal ACTH was (100.9 +/- 85.0 vs. 138.0 +/- 123.7 vs. 4.8 +/- 4.3 pg/mL) and maximal stimulated ACTH (203.8 +/- 160.1 vs. 288.0 +/- 189.5 vs. 7.4 +/- 9.2 pg/mL). For cortisol, determination area under ROC curve was 0.815 +/- 0.083 (CI 95% 0.652-0.978). For cortisol increase cut-off level of 20%, test sensitivity was 83%, with specificity of 78%. For ACTH, determination area under ROC curve was 0.637 +/- 0.142 (CI 95% 0.359-0.916). For ACTH increase cut-off level of 30%, test sensitivity was 70%, with specificity of 57%. Determination of cortisol and ACTH levels in CRH test remains reliable tool in differential diagnosis of Cushing's syndrome.