Urinary Free Cortisol Excretion Research Articles

Luteinizing hormone correlates with adrenal function in postmenopausal women

In postmenopausal women, a relationship between luteinizing hormone (LH) and cortisol levels has been suggested. Furthermore, LH receptors in the adrenal gland have been shown to mediate adrenocorticotropic hormone-independent Cushing syndrome. In contrast, follicle-stimulating hormone (FSH) receptors have not been found in the adrenal gland. Our objective was to explore the relationship of LH with adrenal function in postmenopausal women, as assessed by 24-hour urinary free cortisol (UFC) and aldosterone excretion rate (AER). Participants were studied at a single time point in the fasting state in the Clinical Research Center of Brigham and Women's Hospital. We studied 36 postmenopausal women in sodium balance to control for variation in endogenous levels of plasma renin activity and angiotensin II. Serum cortisol, aldosterone, LH, and FSH levels were measured, as were 24-hour UFC and AER. Correlations were performed by calculation of Pearson's correlation coefficient. Serum LH correlated significantly with log-transformed UFC (r = 0.43, P = 0.01) and inversely with log AER (r = -0.50, P = 0.002). We found no correlation of serum LH with serum cortisol or aldosterone, nor did we find correlation of FSH with these parameters. In postmenopausal women, serum LH levels correlate significantly with UFC (positively) and AER (negatively). LH stimulation may induce subtle shifts in adrenal function toward cortisol secretion.

Ectopic Cushing's syndrome caused by a pulmonary ACTH-secreting tumor in a patient treated with octreotide

Ectopic ACTH syndrome is a rare disease often associated with severe hypercortisolism. When feasible, optimal management is surgical excision of the tumor. A 33-year-old male patient was admitted to the hospital in 1993 with clinical manifestations suggestive of Cushing's syndrome. He presented high plasma ACTH and markedly elevated urinary free cortisol excretion that was not suppressed with high-dose dexamethasone administration. Pituitary MRI scan was normal. No central-to-peripheral ACTH gradient was present in bilateral inferior petrosal sinus sampling. Thoracic CT scan showed a 1.7 cm nodule at the left lung. Pulmonary fine needle cytology and immunocytochemical and ultrastructural studies, together with the presence of bone metastases, led to the diagnosis of an ACTH-producing neuroendocrine carcinoma. He was initially submitted to chemotherapy and has been on treatment with octreotide LAR since 1998, having shown a favorable clinical, biochemical and imaging response. We highlight the excellent long-term response to medical therapy with octreotide LAR, without tachyphylaxis, probably due to its antiproliferative effect.

Validation and application of a highly specific and sensitive ELISA for the estimation of cortisone in saliva, urine and in vitro cell-culture media by using a novel antibody

It is generally acknowledged that local tissue concentrations of cortisol and cortisone are modulated by site-specific actions of 11β-hydroxysteroid dehydrogenase (11β-HSD) isoenzymes 1 and 2. Cortisone, the inactive metabolite of cortisol is produced by 11βHSD type 2. To assess 11β-HSD types 1 and 2 activities, the cortisol/cortisone ratio has to be accurately determined. Immunoassays to measure cortisone levels are not widely available and tend to lack specificity. The aim of this project was to develop a highly specific and sensitive ELISA method for the estimation of free cortisone levels in urine, saliva and in vitro media samples without chromatographic separation. Antibodies against cortisone were raised in rabbits using cortisone-3-CMO-KLH as immunogen. HRP-goat anti-rabbit IgG conjugate was used as enzyme tracer. Cross-reactivities of the untreated cortisone antiserum with major interfering steroids were minimal except for cortisol (3.15%). However, following an immune-affinity purification of the antibodies using CNBr-activated sepharose-cortisol-3-CMO-BSA, cross-reactivity of the purified cortisone antibody with cortisol was reduced to 0.27%. The minimum detection limit of cortisone ELISA was 28pg/mL (77.7pM). The validity of the cortisone ELISA was confirmed by the excellent correlation obtained before and after an HPLC fractionation step (Y=1.09X−0.21, R2=0.98). Intra-assay and inter-assay imprecision were 5.5–11.7% and 8.7–12.8% CV, respectively. Using this assay, salivary cortisone levels showed a circadian rhythm in men and women (11.2±7.3nM at 08.00h and 5.1±3.6nM at 18.00h), and the levels were reduced following liquorice ingestion. In media of adrenocortical H295 cell line incubations, basal cortisone levels were 4.24±0.22nM that increased to 8.6±1.2nM post forskolin treatment. Urinary free cortisone excretion levels in healthy subjects were 56.66±36.9nmol/day. In human volunteers following ingestion of green coffee bean extract for 2weeks, urinary free cortisol excretion reduced significantly from 66.67±22.3 to 42.66±17.5nmol/day (p=0.02) and the cortisol/cortisone ratio from 2.04±1.33 to 1.49±1.13, p=0.05. In conclusion, a simple and highly specific and sensitive ELISA has been developed and applied to estimate cortisone levels in biological fluids and culture media.

Perioperative management of high risk ACTH-independent macronodular adrenal hyperplasia: Report of one case

Objective To improve the diagnosis and treatment of ACTH-independent macronodular adrenal hyperplasia(AIMAH).Methods A 51-year-old female patient with Cushing's syndrome caused by AIMAH was reported.Elevated early morning plasma cortisol levels,increased 24 h urinary free cortisol excretion,and loss of the normal circadian rhythm in cortisol secretion were presented.There was no suppression of cortisol secretion by administration of low-and high-dose overnight dexamethasone suppression test.Cardio-pulmonary function was very bad with the highest blood pressure reaching 300/120 mm Hg( 1 mm Hg=0.133 kPa).Initially,she was treated with mitotane(60 mg/d),but was not effective.After taking ketoconazole (800 mg/d)for 5 days,cardio-pulmonary function was not effectively improved with blood pressure only descending to 180/120 mm Hg.Orthopnoea appeared and Spo2fell once to 75％.The patient had to undergo right total adrenalectomy immediately.Results The mass resected was 10 cm× 10 cm in size and weighted 67.5 g.Histological examination of the removed adrenal revealed nonpigmented macronodular cortical hyperplasia.The patient continued to take ketoconazole (400-800 mg/d)from the 6th day of the operation without steroid replacement therapy in that period.With normal cortisol levels( plasma cortisol at 8:00 was 18.65 μg/dl,24 h urinary free cortisol was 78.75 μmol),she left hospital after the general condition had been improved.During the following updated 10 months follow up,the indexes of her laboratory examination were maintained normal.Conclusion Individualized therapy should be adopted for the patient with AIMAH.The medication is useful to suppress the adrenal gland cortisol production for those with progression of symptoms,very high blood pressure,hypokalemia and hypoproteinemia.Once the cardio-pulmonary function improves,the target organ should be resected as soon as possible.The supplement of cortisol is not appropriate during the perioperative period.The unilateral adrenalectomy is an effective treatment for AIMAH. Key words: ACTH-independent macronodular adrenal hyperplasia; Surgery; Ketoconazole; Plasma cortisol

The Hypercoagulable State in Cushing's Disease Is Associated with Increased Levels of Procoagulant Factors and Impaired Fibrinolysis, But Is Not Reversible after Short-Term Biochemical Remission Induced by Medical Therapy

Cushing's disease (CD) is accompanied by an increased risk of venous thromboembolism. Surgery is the primary treatment of CD. The aim of the study was to compare hemostatic parameters between patients with CD and controls and to evaluate the effect of medical treatment of CD on hemostasis. During 80 d, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline, and ketoconazole, which suppresses adrenocortical steroidogenesis, at four university medical centers in The Netherlands. Seventeen patients with de novo, residual, or recurrent CD were included. We measured urinary free cortisol and parameters of coagulation and fibrinolysis. Patients with CD had significantly higher body mass index (P < 0.001), shortened activated partial thromboplastin time (P < 0.01), and higher levels of fibrinogen, Factor VIII, and protein S activity (P < 0.05) compared to healthy control subjects. In addition, fibrinolytic capacity was impaired in patients with CD as reflected by prolonged clot lysis time (P < 0.001) and higher levels of plasminogen activator inhibitor type 1, thrombin-activatable fibrinolysis inhibitor, and α2-antiplasmin (P < 0.01). There were no statistically significant differences in von Willebrand factor:antigen, antithrombin, and protein C activity. After 80 d, 15 of 17 patients had normalized urinary free cortisol excretion. Despite biochemical remission, only slight decreases in antithrombin (P < 0.01) and thrombin-activatable fibrinolysis inhibitor (P < 0.05) levels were observed. Other parameters of coagulation and fibrinolysis did not change significantly. The hypercoagulable state in patients with CD, which is explained by both increased production of procoagulant factors and impaired fibrinolysis, is not reversible upon short-term biochemical remission after successful medical therapy. This may have implications for the duration of anticoagulant prophylaxis in patients with (cured) CD.

Obesity and the hypothalamic-pituitary-adrenal axis in adolescent girls

Stress and stress-related concomitants, including hypothalamic-pituitary-adrenal (HPA) axis activation, are implicated in obesity and its attendant comorbidities. Little is known about this relationship in adolescents. To begin to address this important knowledge gap, we studied HPA axis activity in 262 healthy adolescent girls aged 11, 13, 15, and 17 years. We hypothesized that obesity would be correlated with increased HPA axis activity and reactivity. Measures of HPA axis activity included 3 blood samples obtained midday (between 1:00 and 2:00 pm) over the course of 40 minutes; overnight urine free cortisol; and cortisol levels 0, 20, and 40 minutes after venipuncture (cortisol reactivity). Measures of adiposity included body mass index (BMI), BMI z score (BMI-Z), percentage body fat, and fat distribution (central adiposity) assessed by dual-energy x-ray absorptiometry. Daytime levels of serum cortisol were inversely associated with BMI-Z and central adiposity (P < .05). The urine free cortisol excretion rate was positively correlated with BMI, BMI-Z, and central adiposity. There was blunting of cortisol response to venipuncture with increasing adiposity. Our results suggest that there may be reduced cortisol levels during the day and increased levels at night with increasing degree of adiposity. This study provides preliminary findings indicating an alteration of the circadian rhythm of cortisol with obesity. We conclude that obesity is associated with altered HPA activity in adolescent girls. The clinical implications of our findings require further investigation.

Failure of functional imaging with gallium-68-DOTA-D-Phe1-Tyr3-octreotide positron emission tomography to localize the site of ectopic adrenocorticotropic hormone secretion: a case report

IntroductionThe diagnostic efficacy of biochemical and imaging modalities for investigating the causes of Cushing's syndrome are limited. We report a case demonstrating the limitations of these modalities, especially the inability of functional imaging to help localize the site of ectopic adrenocorticotropic hormone secretion.Case presentationA 37-year-old Arabian woman presented with 12 months of progressive Cushing's syndrome-like symptoms. Biochemical evaluation confirmed adrenocorticotropic hormone -dependent Cushing's syndrome. However, the anatomical site of her excess adrenocorticotropic hormone secretion was not clearly delineated by further investigations. Magnetic resonance imaging of our patient's pituitary gland failed to demonstrate the presence of an adenoma. Spiral computed tomography of her chest only revealed the presence of a non-specific 7 mm lesion in her left inferobasal lung segment. Functional imaging, including a positron emission tomography scan using 18-fluorodeoxyglucose and gallium-68-DOTA-D-Phe1-Tyr3-octreotide, also failed to show increased metabolic activity in the lung lesion or in her pituitary gland. Our patient was commenced on medical treatment with ketoconazole and metyrapone to control the clinical features associated with her excess cortisol secretion. Despite initial normalization of her urinary free cortisol excretion rate, levels began to rise eight months after commencement of medical treatment. Repeated imaging of her pituitary gland, chest and pelvis again failed to clearly localize a source of her excess adrenocorticotropic hormone secretion. The bronchial nodule was stable in size on serial imaging and repeatedly reported as having a nonspecific appearance of a small granuloma or lymph node. We re-explored the treatment options and endorsed our patient's favored choice of resection of the bronchial nodule, especially given that her symptoms of cortisol excess were difficult to control and refractory. Subsequently, our patient had the bronchial nodule resected. The histological appearance of the lesion was consistent with that of a carcinoid tumor and immunohistochemical analysis revealed that the tumor stained strongly positive for adrenocorticotropic hormone. Furthermore, removal of the lung lesion resulted in a normalization of our patient's 24-hour urinary free cortisol excretion rate and resolution of her symptoms and signs of hypercortisolemia.ConclusionThis case report demonstrates the complexities and challenges in diagnosing the causes of adrenocorticotropic hormone -dependent Cushing's syndrome. Functional imaging may not always localize the site of ectopic adrenocorticotropic hormone secretion.

Clinical outcome of subclinical Cushing's syndrome after surgical and conservative treatment

Subclinical Cushing's syndrome (SCS), a subtle cortisol hypersecretion from an adrenal tumor, may be a common adrenal disease. However, the cardiovascular prognosis and the optimal surgical and conservative treatment in SCS remain elusive. The present study was undertaken to evaluate the prevalence of cardiovascular risk factors in 16 SCS cases, their relationships to cortisol secretory activities, and the clinical outcome after surgical and medical treatment. The prevalence of hypertension, impaired glucose tolerance (IGT), diabetes mellitus (DM), dyslipidemia and obesity in our SCS cases were 56%, 50%, 50%, and 19%, respectively, and 75% of cases were associated with two or more cardiovascular risk factors. In our series, 24-h urinary free-cortisol excretion showed a significant positive correlation with HbA1c and a negative correlation with high-density lipoprotein-cholesterol, but no correlation with age, body mass index, blood pressure or glycemic and lipid profile was found. Eight cases underwent unilateral adrenalectomy (operated (OP) group); the remaining eight cases were a conservative-treatment group (non-OP group). The number of cardiovascular risk factors decreased significantly in the OP group, but not in the non-OP group. In terms of differential changes in risk factors between the groups, more significant improvements of hypertension, dyslipidemia and IGT/DM were observed in the OP group than in the non-OP group. In conclusion, the present study showed the increased prevalence of cardiovascular risk factors in SCS patients with mild hypercortisolism related to impaired glucose/lipid metabolism. Adrenalectomy decreased accumulated cardiovascular risk factors in certain SCS patients, suggesting the possible involvement of mild hypercortisolism in the development of cardiovascular risk factors in SCS.

A rare cause of hypokalaemia and metabolic alkalosis.

A 72-year-old man with a medical history of diabetes mellitus Type II, paroxysmal atrial fibrillation and heart failure was hospitalized after a syncope. Pitting oedema in both legs were the only abnormal finding on physical examination, in particular the patient had no cushinoid features. The blood pressure was slightly elevated at 160/90 mmHg. Regular medications consisted of furosemid 100 mg, digoxin 0.125 mg, warfarin, enalapril 10 mg, metoprolol 50 mg, aldactone 25 mg and insulin. He was not overweight. Routine blood tests were normal, except for potassium 1.7 mmol/L, creatinine 122 μmol/L and albumin 29 g/L. Blood gas test showed a pronounced metabolic alkalosis, with pH 7.54, bicarbonate 41 mmol/L, base excess 17 mmol/L, PCO2 5.79 kPa and PO2 12.3 kPa. Urine levels of sodium and potassium on admission in a spot urine were 86 and 41 mmol/L, respectively. Both at 8 am and at 8 pm, cortisol levels were elevated. Dexamethasone suppression tests showed no ability of suppression. Despite treatment with intravenous (i.v.) and oral potassium, i.v. MgSO4 and an incremental increase in the aldactone dosage from 25 to 600 mg daily, he remained hypokalaemic with metabolic alkalosis. Magnetic resonance imaging (Figure 1), revealed an expansive process in the sinonasal cavity, exerting compression into the medial walls in both orbita. A biopsy taken from the tumour in the sinonasal cavity (Figure 2) showed neuroendocrine tumour, probably a neuroblastoma, with a strongly positive reaction for neuroendocrine markers, later also shown to stain positively for adrenocorticotropic hormone (ACTH). Fig. 1. MRI caput. Fig. 2. Tumour histology. Chest X-ray did not show any lesions, and the cancer marker neuron specific enolase was negative, so we did not find it likely that the tumour was metastatic originating from primary lung cancer. The patient’s condition, including cognitive status, was rapidly deteriorating. Five weeks after hospitalization, the tumour was surgically removed. Histology showed infiltration to dura, no signs of metastasis. Three months after admission he died, assumed cause of death being sepsis, most probably due to pneumonia. The relatives refused autopsy. The location of the ACTH-producing tumour in the paranasal sinuses is uncommon and often not recognized (1). Ectopic ACTH production is usually suggested by cushinoid appearance, which this patient did not have, marked hypokalaemia, increased 24-h urinary-free cortisol excretion and elevated serum ACTH (2).

Mitotane, Metyrapone, and Ketoconazole Combination Therapy as an Alternative to Rescue Adrenalectomy for Severe ACTH-Dependent Cushing's Syndrome

Mitotane is highly effective in the long-term management of Cushing's syndrome but has a slow onset of action. Mitotane combined with fast-acting steroidogenesis inhibitors might avoid the need for emergency bilateral adrenalectomy in patients with severe hypercortisolism. Our objective was to assess the efficacy and safety of combination therapy with mitotane, metyrapone, and ketoconazole in severe ACTH-dependent Cushing's syndrome. Eleven patients with severe Cushing's syndrome participated in this follow-up study in a tertiary referral hospital. High-dose therapy combining mitotane (3.0-5.0 g/24 h), metyrapone (3.0-4.5 g/24 h), and ketoconazole (400-1200 mg/24 h) was initiated concomitantly. Twenty-four-hour urinary free cortisol (UFC) excretion (normal values 10-65 μg/24 h) was monitored. Data are reported as medians (range). All 11 patients experienced a marked clinical improvement. UFC excretion fell rapidly from 2737 μg/24 h (range 853-22,605) at baseline to 50 μg/24 h (range 18-298) (P = 0.001) within 24-48 h of treatment initiation and remained low to normal on the combination therapy. In seven patients, metyrapone and ketoconazole were discontinued after 3.5 months (range 3.0-6.0) of combination therapy, and UFC excretion remained controlled by mitotane monotherapy (UFC 17 μg/24 h, range 5-85; P = 0.016). Five patients became able to undergo etiological surgery and are presently in remission. Four of them recovered normal adrenal function after mitotane discontinuation. Adverse effects were tolerable, consisting mainly of gastrointestinal discomfort and a significant rise in total cholesterol and γ-glutamyl transferase levels (P = 0.012 and P = 0.002, respectively). When surgical treatment for severe ACTH-dependent Cushing's syndrome is not feasible, combination therapy with mitotane, metyrapone, and ketoconazole is an effective alternative to bilateral adrenalectomy, a procedure associated with significant morbidity and permanent hypoadrenalism.

Intraoperative multiple-staged resection and tumor tissue identification using frozen sections provide the best result for the accurate localization and complete resection of tumors in Cushing’s disease

The treatment of choice in Cushing's disease (CD) is surgical removal; however, most tumors are too small to be detected. The objective was to establish a method to achieve the complete removal of tumors on the basis of the results of high-resolution magnetic resonance imaging (MRI), inferior petrosal sinus sampling (IPSS), and a surgical resection technique using frozen biopsy. Eighteen patients who underwent transsphenoidal surgery from 2004 to 2010 were included. High-resolution MRI and IPSS, multiple-staged resection, and tumor tissue identification in frozen sections (surgical and histological identification, SHI) were performed. All patients achieved surgical remission, as confirmed by 24h urinary free cortisol excretion tests. Visible microlesions were identified on the initial MRI in 11 patients (61%). The SHI findings agreed with the MRI findings in 10 of the 11 patients (90.9%) and with IPSS lateralization in 6 of the 11 patients (54.5%). In the 7 patients whose lesions were not visible on the initial MRI, only 1 (14.3%) showed an agreement between IPSS and SHI. In 3 of the 7 patients, the microlesions were identified by additional MRI. The rate of concordance with SHI was 77.8% for the overall MRI and 38.9% for IPSS. High-resolution MRI is better than IPSS for localizing corticotroph adenomas. In patients with lesions not visible on the initial MRI, additional MRI should be performed using a different protocol. Although high-resolution MRI is better for localizing tumors, SHI remains an important approach for removing the tumors completely.

Safety of Proactive Topical Corticosteroid Therapy About Adrenal Function and Growth Velocity of Childhood Severe Atopic Dermatitis

S A T U R D A Y 129 Safety of Proactive Topical Corticosteroid Therapy About Adrenal Function and Growth Velocity of Childhood Severe Atopic Dermatitis T. Fukuie, I. Nomura, M. Futamura, M. Narita, Y. Nakagawa, T. Ohzeki, K. Matsumoto, H. Saito, Y. Ohya; National Center for Child health and Development, Tokyo, JAPAN, Hamamatsu University School of Medicine, Shizuoka, JAPAN, National Research Institute for Child Health and Development, Tokyo, JAPAN. RATIONALE:We have reported about decline of serum IgE titer by proactive treatment of atopic dermatitis (AAAAI 2009, BJD 2010 in press). But safety of long-term proactive treatment with using topical corticosteroid about adrenal and growth suppression in children with atopic dermatitis (AD) has not been enough described. METHODS: Growth measurement of the patients with severe AD who admitted to National Center for Child Health and Development (Tokyo, Japan) from April 2006 to March 2008 and continued the proactive administration of topical corticosteroid over 2 years were studied retrospectively and compared with the normal value of Japanese children. Height and annual height velocity were converted to standard deviation scores (SDS). Hypothalamic-Pituitary-Adrenal (HPA) axis function was assessed by serum cortisol and 24-hour urinary free cortisol excretion before and after receiving continuous therapy with proactive management. RESULTS: Eleven girls and 15 boys who could have continued the proactive therapy between the study periods were eligible for this study. The mean (range) agewas 4.4 yrs (0-10) and the mean baseline height SD score was -0.54. Mean baseline serum and urinary cortisol levels were once reduced significantly with everyday use of topical corticosteroids (remission-induction phase), however improved at intermittent proactive treatment phase.Mean height SD scores after 1 and 2 years were not aggravated (-0.54 and -0.47, respectively), and mean annual height velocity SD scores (height-adjusted) after 1 and 2 years were -0.23 and 0.50. CONCLUSIONS:We found that proactive intermittent application of topical corticosteroid does not have negative effects on HPA axis function and height velocity.

Transient Efficacy of Octreotide and Pasireotide (SOM230) Treatment in GIP-dependent Cushing's Syndrome

We studied a 55-year old woman presenting with features of Cushing's syndrome associated with metabolic abnormalities including severe hypertension and type 2 diabetes. Urinary free cortisol excretion was within normal limits, but an unusual diurnal cortisol rhythm was observed with low morning and high postprandial levels, associated with the absence of cortisol suppression after dexamethasone, suggesting the possibility of GIP-dependent Cushing's syndrome. The diagnosis was confirmed by further investigations, showing significant plasma cortisol responses after a mixed meal test and after oral, but not intravenous glucose administration, as well as ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH). An aberrant increase in cortisol was also observed after glucagon and terlipressin injections. The patient was first treated with octreotide 100-250 μg thrice daily for 6 months, then with the new multi-ligand somatostatin analogue (SOM 230) 450-900 μg twice daily for 3 months. Although inducing a significant acute suppression of post-prandial cortisol response, both drugs had no effects on the clinical and metabolic abnormalities associated with Cushing's syndrome and new tests performed at the end of each treatment period confirmed escape of post-meal cortisol suppression to therapy. The patient finally underwent a bilateral adrenalectomy, which markedly improved her medical condition and allowed in vitro confirmation by real time RT-PCR quantification of a high aberrant expression of GIP receptor mRNA in adrenal tissue. This case report illustrates the lack of sustained efficacy of somatostatin analogues on GIP-dependent Cushing's syndrome, independent of their affinity for the different somatostatin receptor subtypes.

Free cortisol/cortisone ratio in pooled urine was increased after rapid-ACTH stimulation test under dexamethasone suppression

We employ rapid-ACTH stimulation test under dexamethasone (DEX) suppression to assess the adrenal function in daily clinic. However, we have little knowledge about the excretion of urinary free cortisol (FF) and cortisone (FE) in pooled urine in this setting. The purpose was to examine the changes of FF and FE as well as FF/FE ratio in pooled urine after rapid-ACTH stimulation test under DEX suppression using stable isotope dilution-gas chromatography/mass spectrometry (SID-GC/MS). Pooled urine samples were collected from 8 patients (age 33-71 years) who were suspected to have primary aldsteronism. They all were finally diagnosed as having normal glucocorticoid secretion. We performed rapid-ACTH stimulation test with DEX suppression for consecutive 4 days as follows. (1) 24 hour urine samples were serially collected from 2300 h on day 1 for 72 hours (Basal, DEX1mg, and DEX8mg-ACTH). (2) 1 and 8 mg DEX was given at 2300 h on day 2 and 3, respectively. (3) 250 µg of ACTH was given at 0900 h on day 4. Urine free steroids were delivered with bismethylenedioxy-heptafluorobutyric anhydride and analyzed by SID-GC/MS (µg/day). From DEX1mg to DXE8mg-ACTH, (1) FF and FE were significantly increased (3.9±1.3 to 21.3±14.6 and 12.4±4.8 to 26.1±11.0 µg/day, respectively), but (2) FF/FE ratio significantly increased (0.32±0.05 to 0.77±0.23). These data suggested that newly synthesized cortisol by ACTH stimulation was not efficiently metabolized to cortisone.

Cortisol, energy intake, and food frequency in overweight/obese women

Objective This retrospective study investigated the relation between daily urinary free cortisol excretion rate, as a marker of cortisol production rate, to daily caloric intake, food choice, body mass index (BMI), and waist circumference. Methods One hundred twenty-seven overweight/obese women and 21 normal-weight subjects were enrolled in the study. Fasting blood samples for metabolic parameters were taken from each subject, followed by an oral glucose tolerance test. Cortisol excretion rate was assessed on 24-h urine collection (UFC/24 h). In obese patients, the daily caloric intake was calculated, and a weekly food-frequency questionnaire was assessed. Analysis of variance was used to assess the differences between groups. The relations between parameters were investigated by simple and multiple regressions. Results Obese women had significantly higher UFC/24 h than the normal-weight women ( P < 0.001). The obese subjects had an unbalanced diet, particularly rich in saturated lipids, and weekly food choice showed a preference for highly caloric foods. UFC/24 h values and waist circumference were significantly correlated ( P < 0.001), regardless of BMI. In the obese group, after adjustment for BMI, the UFC/24 h values were also significantly and positively correlated to daily carbohydrate and lipid intake and to weekly starchy food consumption. Conclusion We demonstrated a significant association between higher UFC/24 h and energy intake, fats, and consumption of starchy foods, and that these relations were independent of BMI.

Pasireotide Alone or with Cabergoline and Ketoconazole in Cushing's Disease

To the Editor: Cushing's disease, which is caused by an adrenocorticotropin-secreting pituitary adenoma, is associated with increased morbidity and mortality.1 Currently, there is no effective medical therapy for Cushing's disease. However, recent studies identified the somatostatin-receptor subtype 5 and dopamine-receptor subtype 2 as potential therapeutic targets in Cushing's disease.2 Pasireotide is a new somatostatin analogue that binds with high affinity to somatostatin-receptor subtypes 1, 2, and 3, and it especially has high-affinity binding to somatostatin-receptor subtype 5.3 In a recent 15-day pilot study, pasireotide normalized the excretion of urinary free cortisol in 17% of patients with Cushing's disease.4 Cabergoline, a . . .

Sudden Respiratory Failure in a Patient with Cushing`s Syndrome

A 79 year-old patient with prostate cancer related Cushing's syndrome was referred to ICU for acute respiratory distress occurring two days after introduction of mifepristone. Pneumocystis jirovecii pneumonia was diagnosed. Despite anti pneumocystis therapy and supportive treatment, the patient died of multiple organ failure. The relationship between mifepristone and Cushing's syndrome and potential implications are discussed. Cushing's syndrome is a classical but rare disease resulting from exposure to excessive concentrations of glucocorticoid. When surgery is not feasible medical therapy should be discussed. A 79 year-old man was admitted to intensive care unit for acute respiratory distress. He had been treated for prostate cancer for 12 years, with radiotherapy and hormonotherapy. The last prostate-specific antigen (PSA) level was (0, 24 ng/ml) while pelvis MRI disclosed irregular prostate consistent with radiotherapy after-effects without any sign of recurrence of malignancy. He was referred 3 months before to the general ward because of depression, severe systemic hypertension, hypokalaemia and diabetes mellitus. Endogenous hypercortisolism was diagnosed. Static and dynamic analysis: (plasma cortisol level at 8 am : 1564 nmol/l (normal<200 nmol/l), 24h urinary free cortisol excretion: 20200 nmol/24h (normal <270 nmol/24h), no suppression of plasma cortisol with low dose of dexamethasone, adrenocorticotropic hormone (ACTH) : 145 ng/l.(normal<50 ng/l)) were in favour of an ACTH dependent Cushing's syndrome. Considering normal pituitary MRI, final diagnosis was paraneoplastic Cushing's syndrome. CT scan imaging of the thorax (Fig. 1), abdomen and pelvis disclosed bilateral adrenal hyperplasia but did not show any thoracic or pancreatic tumours which are the most common tumours responsible for ectopic ACTH secretion.

Endothelial Dysfunction Aassociated with Hypercortisolism is Reversible in Cushing's Syndrome

Cushing's syndrome (CS) as represented by chronic glucocorticoid excess is associated with increased rate of cardiovascular morbidity and mortality. Because endothelial dysfunction is an early event of atherosclerosis, we investigated whether endothelial dysfunction is associated with CS and reversible. Twenty-one CS patients due to different causes were studied for vascular endothelial function by ultrasound measurement of flow-mediated vasodilation (FMD), among whom 12 patients were re-evaluated after surgical and medical treatment; 12 age- and gender-matched subjects served as control. Percent (%) FMD in CS patients (5.8+/-1.9 %) was significantly (p =0.0014) lower than that in control subjects (8.1+/-1.7 %). In CS patients, %FMD showed significant (p < 0.01) negative correlations with morning serum cortisol levels (r =-0.58) and 24-h urinary free cortisol excretion (r =-0.58). After surgical and medical treatment in CS patients, morning cortisol levels significantly (p =0.0025) decreased from 23.4 [15.6-37.3] to 10.2 [7.7-12.9] microg/dL, whereas %FMD significantly (p =0.0024) increased from 5.2+/-1.9 to 7.8+/-2.3 %; changes of %FMD after treatment significantly (p =0.0004) and inversely correlated with those of morning cortisol levels (r =-0.85), but not with those of body mass index, blood pressure, glycemic or lipid profiles. Taken together, the present study clearly revealed that endothelial dysfunction in CS patients is related to hypercortisolemia and reversible after treatment, suggesting the possible role of cortisol excess in the development of endothelial dysfunction, thereby possibly leading to increased cardiovascular complications.

Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease

The expression of dopamine receptor subtypes has been reported in corticotroph adenomas, and this finding support the possibility for medical treatment of Cushing's disease (CD) with dopamine agonists when conventional treatment has failed. The aim of this study was to evaluate the effectiveness of cabergoline (at doses of up 3 mg/week), alone or combined with relatively low doses of ketoconazole (up to 400 mg/day), in 12 patients with CD unsuccessfully treated by transsphenoidal surgery. After 6 months of cabergoline therapy, normalization of 24 h urinary free cortisol (UFC) levels occurred in three patients (25%) at doses ranging from 2-3 mg/week, whereas reductions ranging from 15.0 to 48.4% were found in the remaining. The addition of ketonocazole to the nine patients without an adequate response to cabergoline was able to normalize UFC excretion in six patients (66.7%) at doses of 200 mg/day (three patients), 300 mg/day (two patients) and 400 mg/day (one patient). In the remaining patients UFC levels did not normalize but a significant reduction ranging from to 44.4 to 51.7% was achieved. In two of the six responsive patients to combination therapy, the weekly dose of cabergoline could be later reduced from 3 to 2 mg. Our findings demonstrated that cabergoline monotherapy was able to reverse hypercortisolism in 25% of patients with CD unsuccessfully treated by surgery. Moreover, the addition of relatively low doses of ketoconazole led to normalization of UFC in about two-thirds of patients not achieving a full response to cabergoline.

The Relationship Between 24-h Urinary Cortisol and Bone in Healthy Young Women

Cortisol within the normal range has been associated with reduced bone density in the elderly, but little is known about this relationship in healthy young women. The purpose of this study is to assess whether 24-h urinary free cortisol excretion (UFC) is related to bone density in 132 healthy, non-obese, regularly menstruating women, aged 19-35. Participants completed questionnaires (food frequency, demographics, physical activity, dietary restraint, perceived stress, and daily stress) and a 24-h urine collection. UFC was determined by high-throughput liquid chromatography and tandem mass spectrometry. Anthropometrics were completed and a dual energy X-ray absorptiometry scan measured areal bone mineral density (aBMD, g/cm(2)) and bone mineral content (BMC, g) at the lumbar spine (L1-4), hip, and total body (TB) as well as total body lean (LBM) and fat mass. aBMD and BMC were significantly positively associated with height, LBM, physical activity, calcium intake, and duration of previous oral contraceptive use (except L1-4) and negatively with perceived stress. UFC was not correlated with any measured variables except urine volume (r = 0.17, p = 0.046). After adjusting for urine volume, height, LBM, ethnicity, and prior oral contraceptive use, UFC was significantly inversely associated with TB BMC (r = -0.30, p < 0.001) and aBMD (r = -0.27, p = 0.003), L1-4 aBMD (r = -0.19, p = 0.035) and BMC (r = -0.18, p = 0.049), and hip BMC (r = -0.23, p = 0.011). Further adjustment for sport activity, calcium intake and perceived stress did not change these relationships meaningfully except that L1-4 became nonsignificant (p < 0.07). Cortisol within the normal range appears to have a minor negative influence on bone density in healthy young women.