24-hour Urinary Cortisol Excretion Research Articles

#2026 Hypokalemia associated to neuroendocrine carcinoma of the cervix

Abstract Background and Aims Hypokalemia is one of the most common electrolyte disorders seen in clinical practice. Hypokalemia can be caused by decreased intake of potassium, redistribution of potassium (K+) in cells or by excessive gastrointestinal losses or renal losses. In this setting, hypokalemia may also be caused by the paraneoplastic production of ectopic adrenocorticotropic hormone (ACTH) by some tumors. Cancer of the uterine cervix is the fourth common cancer affecting women worldwide and the fourth most common gynecologic cancer in Spain. Neuroendocrine carcinoma of the cervix represents about 2% of all cervical neoplasms. Method We report the case of a 44-year-old Peruvian woman with hypokalemia who was diagnosed with Cushing syndrome secondary to paraneoplastic production of ACTH by neuroendocrine carcinoma of cervix. Results Patient was overweight and affected by uterine myoma and anemia without further investigations. She was admitted to our hospital due to lower back pain, leg swelling and constipation. Blood pressure was normal, chest radiography did not show abnormal findings and ECG showed the U wave. Laboratory tests at admission revealed hypokalemia (2.3 mmol/L), metabolic alkalosis, anemia (hemoglobin 9.5 g/dL), hyperkaliuria (K+ urine/Creatinine urine 70 mmol/g) with an elevated transtubular potassium gradient (TTKG=12) and normal renal function. Laboratory data are presented in Table 1. She developed hypertension in the first day of hospitalization. Renin, aldosterone and cortisol tests was performed. Hypercortisolism was observed and confirmed with 24-hour urinary cortisol excretion. Because of an elevated ACTH (263 pg/mL), pituitary magnetic resonance imaging was performed without lesions. Whole-body computed tomography revealed a cervical mass. PET scan showed pelvic, adrenal, hepatic and local lymphadenopathy activity (see Fig. 1). After the histopathological study, diagnostic of small cell neuroendocrine carcinoma of the cervix was made. Chemotherapy therapy was initiated with cisplatin/etoposide regimen. The patient decide to return to Peru because of the poor prognosis of her illness. At discharge, potassium level was 3 mmol/L despite the treatment with spironolactone, ramipril, losartan and oral potassium chloride (160 mmol). Conclusion Hypokalemia is a common clinical disorder. In some patients it may be caused by an increased mineralocorticoid activity due to ectopic ACTH-secreting tumors. Applying diagnostic algorithms to electrolyte disorders, beyond their simple treatment, can unmask secondary causes and serious diseases.

SAT-LB23 Paraneoplastic Hypercalcemia in a PTH Producing Adrenocortical Carcinoma - a Rare and Deadly Condition

Background: Hypercalcemia is a commonly encountered paraneoplastic manifestation of certain cancers with or without endocrine differentiation. However, the association between adrenocortical carcinoma (ACC) with paraneoplastic hypercalcemia is very rare, and therefore little is known about the cause and its relevance in the disease. Clinical Case: A 40-year-old woman presented in the hospital with a 5-month history of progressive flank pain with unintentional weight loss of 6 kg. MRI revealed a mass of 9x8.1x4.8 cm of the right adrenal gland with inhomogeneous contrast enhancement. Biochemical investigations provided evidence of endogenous hypercortisolism (24-hour urinary cortisol excretion [490 µg, n<236 µg/l], 1mg dexamethasone suppression test [199 nmol/l, n<50 nmol/l], ACTH [28 ng/l, n<61 ng/l]) although the patient did not show any specific clinical sign of overt hypercortisolism. In addition, laboratory testing revealed an exceptionally high plasma level of calcium [max 3.67 mmol/l (albumin-corrected)] and low phosphate [min 0.26 mmol/l] in the setting of low PTH [6.4 ng/l, n>15 ng/l] and PTHrP levels [<0.50 pmol/l]. However, subsequent dilution unmasked a highly elevated PTH concentration of 2171.5 ng/l with persistent low PTHrP levels, indicating false low values due to a hook effect in the initial measurement. Levels of 1,25-dihydroxy vitamin D and 25-hydroxy vitamin D were in the normal range. A PET-CT provided no indications of metabolically active (osseous) metastases. After correction of the serum calcium towards tolerable values, the tumor was removed by open en bloc adrenalectomy. Histologic evaluation confirmed an ACC (TNM pT4 pN1 (2/3), L1, V1, high grade) despite missing immunohistochemically expression of classical adrenal markers (diagnosis of exclusion). Supplemental quantitative RT-PCR studies support the diagnosis of ACC by detecting significant SF-1 and CYP11B2 expression in the tumor cells. Further analyses provided evidence that the mRNA expression of PTH, but not PTHrP, was moderately increased in the ACC sample compared to NCI H295R cells. Upon tumor resection, serum calcium levels swiftly normalized indicating the tumor as the sole source of PTH secretion. Despite initiation of adjuvant mitotane- and salvage chemo-therapy, the patient died 3 months later upon of a massive tumor relapse with a recurrence of severe hypercalcemia. Conclusion: This case demonstrates paraneoplastic hypercalcemia in a PTH producing ACC. PTH may induce hypercalcemia, impair adrenal steroid synthesis and act as an autocrine growth factor in ACC, as described in few individual cases for PTHrp producing ACC [1]. This suggests a poor prognosis for this rare entity.1. Rizk-Rabin, M., et al., Differential Expression of Parathyroid Hormone-Related Protein in Adrenocortical Tumors: Autocrine/Paracrine Effects on the Growth and Signaling Pathways in H295R Cells. 2008.

The relationship between diurnal cortisol secretion and climacteric-related symptoms

ObjectivesChronic stress, also associated with climacteric-related symptoms, may influence cortisol secretion. We studied cortisol metabolism in peri- and postmenopausal women with diverse climacteric-related symptoms. Study design and main outcome measuresThe study population was 35 women, aged 45–70 years. Plasma cortisol levels were measured from blood samples collected every 20 min over 24 h. Urinary cortisol was analysed from 24-hour urine collections. Climacteric-related symptoms (vasomotor, sleep, depressive, anxiety, cognitive, sexual, menstrual, and somatic) were evaluated with the Women’s Health Questionnaire (WHQ). Associations between cortisol variables (24-hour, night, day, maximum, minimum, morning baseline, cortisol awakening response (CAR), area under the curve, slope, and 24-hour urinary cortisol) and the symptoms were first examined with a correlation analysis. Then, the women were divided into two groups according to their climacteric symptomatology, and differences in cortisol variables between the groups were investigated. Diurnal cortisol curves by symptomatology were also analyzed visually. ResultsIn the correlation analysis, more frequent vasomotor symptoms were associated with a higher CAR (rs = 0.37, p = 0.039) and lower 24-hour urinary cortisol excretion (rs= -0.45, p = 0.012), and more frequent depressive symptoms were associated with a higher minimum cortisol level (rs = 0.33, p = 0.0498). When the women were divided into two groups, women with more frequent vasomotor (p = 0.012) or somatic symptoms (p = 0.021) had a lower 24-hour urinary cortisol excretion than less symptomatic women. ConclusionsAlthough previous studies have reported associations between climacteric-related symptoms and cortisol secretion, these two factors were not substantially interrelated in our study.

Assessment of platelet function in endogenous hypercortisolism.

It is commonly known that glucocorticoids exert a significant effect on haemostasis. Studies that have analysed the plasmatic coagulation system and fibrinolysis parameters in hypercortisolaemic patients are abundant. Platelet function, which plays a vital role in primary haemostasis, is much less clear in this context. We aimed at assessing platelet function in endogenous hypercortisolaemic patients. Twenty-five hypercortisolaemic patients were included in the study. Twelve of them were diagnosed with overt Cushing's syndrome (OCS) and 13 had subclinical Cushing's syndrome (SCS). Thirty healthy volunteers comprised the control group. In all subjects platelet function parameters were examined: ADP- and collagen-induced platelet aggregation (ADP-IPA and Col-IPA, respectively), IMPACT R (expressed as percentage of surface covered (SC) by platelets and average size (AS) of the adhering particles in μm2), as well as closure time (CT) after platelet activation with agonists: ADP and Col or Col and epinephrine (EPI). The statistical significance level was set at 0.05. There was no significant difference in mean values of ADP-IPA, Col-IPA, Col/Epi CT, Col/ADP CT, SC, and AS between hypercortisolaemic subjects and controls. No statistically significant differences in means of examined parameters were found between overt and subclinical Cushing's syndrome patients. Furthermore, no statistically significant relationships were found between these parameters and hormonal indicators of hypercortisolism: 24-hour urinary cortisol excretion, morning and evening serum cortisol level, and overnight-test cortisol concentration. In hypercortisolaemic patients no primary haemostasis disorders are present, as reflected by platelet adhesion and ADP- and collagen-induced aggregation measurements.

Activity of selected coagulation factors in overt and subclinical hypercortisolism

It is universally acknowledged that glucocorticoids are hormones that exert a significant effect on hemostasis. The aim of this study was to analyze the activities of coagulation factors VIII, von Willebrand (vW), IX, X, and XI, in patients with overt and subclinical hypercortisolism, as well as to examine possible associations between activities of these factors and the degree of hypercortisolism. Thirty endogenous hypercortisolemic patients were included in the study. Twelve of them were diagnosed with overt Cushing's syndrome (OCS), and eighteen with subclinical Cushing's syndrome (SCS). Healthy, age- and sex-matched volunteers comprised the control group. Activities of coagulation factors VIII, IX, X, and XI were examined using a coagulometric method, and von Willebrand factor (vWF) using an immunoturbidimetric method. Mean activities of examined coagulation factors were significantly higher in OCS patients in comparison to healthy controls. SCS patients had significantly higher mean vWF activities versus controls; and a clear trend toward higher mean activities of other factors in SCS patients versus controls was recorded (but no significant differences). Furthermore, statistically significant positive correlations were found between activities of factor IX and: morning serum cortisol concentrations, 24-hour urinary cortisol excretion values, cortisol concentrations in the overnight suppression test with 1 mg of dexamethasone. Activities of factors X and XI positively correlated with cortisol levels in the overnight suppression test. In endogenous hypercortisolemic patients the coagulation pathway is hyperactivated as indicated by increased activities of coagulation factors. These disorders are evident among patients with overt hypercortisolism.

Growth Velocity Reduced with Once-Daily Fluticasone Furoate Nasal Spray in Prepubescent Children with Perennial Allergic Rhinitis

The effect of fluticasone furoate nasal spray (FFNS) on growth in prepubescent children has not been evaluated. To characterize the difference in mean prepubescent growth velocities, as determined by stadiometry, between patients treated continuously for 1 year with FFNS 110mcg once daily and placebo nasal spray. This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group 76-week safety study. Nasal symptom assessments were used as a measure of adherence. Eligible patients were ages 5 to <8.5 years at screening and had at least a 1-year clinical history and diagnosis of perennial allergic rhinitis, including a positive skin test or specific IgE to an appropriate perennial allergen within the past year. One hundred eighty-six patients in the FFNS group and 187 patients in the placebo group completed the entire 52-week treatment period. During treatment, the least squares mean growth velocity was 5.19 cm/y for the FFNS group and 5.46 cm/y for the placebo group; mean difference,-0.270 cm/y (95% CI,-0.48 to-0.06 cm/y). Other safety assessments, including 24-hour urinary cortisol excretion, were comparable between the treatment groups. Daily reflective total nasal symptom scores declined similarly in both the FFNS and placebo groups. Once-daily treatment with FFNS over 52 weeks in prepubescent children resulted in a small reduction in growth velocity compared with placebo. Clinicians will need to balance the reduction in growth observed with FFNS to its potential for clinical benefit.

Lower Methylation of Glucocorticoid Receptor Gene Promoter 1F in Peripheral Blood of Veterans with Posttraumatic Stress Disorder

BackgroundEnhanced glucocorticoid receptor (GR) sensitivity is present in people with posttraumatic stress disorder (PTSD), but the molecular mechanisms of GR sensitivity are not understood. Epigenetic factors have emerged as one potential mechanism that account for how trauma exposure leads to sustained PTSD symptoms given that PTSD develops in only a subset of trauma survivors. MethodsCytosine methylation of a relevant promoter of the GR gene (NR3C1-1F promoter) and three functional neuroendocrine markers of hypothalamic-pituitary-adrenal axis function were examined in a sample of 122 combat veterans. ResultsLower NR3C1-1F promoter methylation in peripheral blood mononuclear cells (PBMCs) was observed in combat veterans with PTSD compared with combat-exposed veterans who did not develop PTSD. NR3C1-1F promoter methylation was also associated with three functional measures of glucocorticoid activity that have been associated with PTSD in combat veterans: PBMCs’ lysozyme inhibition on the lysozyme suppression test, plasma cortisol decline on the low-dose (.50 mg) dexamethasone suppression test, and 24-hour urinary cortisol excretion. Finally, NR3C1-1F promoter methylation was inversely correlated with clinical markers and symptoms associated with PTSD. ConclusionsAlterations in NR3C1-1F promoter methylation may reflect enduring changes resulting from combat exposure that lead to functional neuroendocrine alterations. Because epigenetic measures are thought to reflect enduring effects of environmental exposures, they may be useful in distinguishing combat-exposed veterans who do or do not develop PTSD.

Comparison of methods for evaluation of the suppressive effects of prednisolone on the HPA axis and bone turnover: changes in s-DHEAS are as sensitive as the ACTH test

Different hypothalamic-pituitary-adrenal (HPA) axis function tests are used for diagnosing disease and evaluating suppressive effects of corticosteroid treatment. Our objectives were to evaluate sensitivity and precision of different HPA axis tests to be able to select one that combines good performance with good practicability, suitable for investigation of new corticosteroids in clinical trials. In this descriptive, double-blind, parallel-group study, 60 healthy male volunteers were treated with once-daily morning doses of prednisolone for 2 weeks. The volunteers were randomized to 1 of 5 treatment groups (prednisolone 2.5, 5, 7.5, 10, or 15 mg). We compared the plasma-cortisol (p-cortisol) 24-hour average concentration (Cav) with morning (08:00 hours) p-cortisol, daytime p-cortisol Cav, and 24-hour urinary cortisol excretion. Adrenocorticotrophic hormone (ACTH) stimulation tests and the metyrapone test were also performed. Furthermore, we analyzed levels of serum dehydroepiandrosterone sulfate (s-DHEAS), insulin, and markers of bone turnover. Dose-related effects were shown, but the magnitude of effects and sensitivities varied greatly between the tests. P-cortisol measurements over the course of 24 hours were used as the reference method. Low- and standard-dose ACTH tests and morning s-DHEAS levels had similar sensitivity. Urinary cortisol excretion and the metyrapone stimulation test had low sensitivity. The effects of prednisolone on markers of bone turnover were, in general, less than those on the HPA axis. Only osteocalcin, procollagen Type 1 C-peptide and procollagen Type 3 N-peptide were significantly affected. Treatment with prednisolone was well tolerated. Changes in s-DHEAS and the low-dose ACTH test combine good sensitivity and precision for evaluation of the suppressive effect of exogenous corticosteroids on the HPA axis, and they are easy to perform.

Once-daily fluticasone furoate is efficacious in patients with symptomatic asthma on low-dose inhaled corticosteroids

BackgroundFluticasone furoate (FF) is an inhaled corticosteroid (ICS) with 24-hour activity in development as a once-daily treatment for the long-term management of asthma. ObjectiveTo assess the efficacy and safety of 4 doses of once-daily FF administered using a dry powder inhaler in patients (≥12 years) with moderate asthma, uncontrolled on low-dose ICS (fluticasone propionate [FP] 200 μg/day or equivalent). MethodsThis double-blind, placebo-controlled, dose-ranging study randomized 622 patients to 1 of 6 treatments: FF (100, 200, 300, or 400 μg) once daily in the evening, FP 250 μg twice daily (active control), or placebo for 8 weeks. The primary endpoint was the change from baseline in predose evening forced expiratory colume in 1 second (FEV1) at week 8. ResultsAt week 8, relative to placebo, all doses of FF once daily and FP twice daily demonstrated significantly (P < .001) greater increases from baseline and greater than 200-mL increases in predose FEV1. There was no evidence of a dose-response relationship between FF doses. Improvement with once-daily FF was similar to or greater than that for twice-daily FP. Secondary efficacy endpoint findings generally supported the efficacy of FF 100 to 400 μg once daily, although statistically significant improvements versus placebo in symptom-free 24-hour periods were only reported for FF 400 μg. There were few withdrawals due to lack of efficacy. Oral candidiasis was reported in 0 to 4% of patients; 24-hour urinary cortisol excretion ratios were similar across active treatment groups and not significantly different from placebo. ConclusionFF 100 to 400 μg once daily in the evening is effective and well tolerated in patients with asthma uncontrolled on low-dose ICS, with 100 μg and 200 μg, considered the most applicable doses in this asthma population. Trial Registrationclinicaltrials.gov Identifier: NCT00603278.

Efficacy and Safety Profile of Fluticasone Furoate Administered Once Daily in the Morning or Evening: A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled Trial in Adult and Adolescent Patients With Persistent Bronchial Asthma

BackgroundFluticasone furoate (FF) is an inhaled corticosteroid that is structurally and functionally distinct from fluticasone propionate and is under development as a once-daily therapy for asthma. ObjectiveThe objective of this study was to estimate the treatment differences (with 95% CI) in efficacy and safety profile between FF administered once daily in the morning and evening via Rotadisk Diskhaler (see text) in patients with persistent asthma. No hypothesis testing was performed for this comparison. MethodsThis was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group study. Patients (ages 16−55 years; peak expiratory flow [PEF] 50%−90% predicted) were randomized to receive 1 of 3 doses of FF Rotadisk or placebo daily for 4 weeks. The sponsor, GlaxoSmithKline, designed the study and selected the study sites. The primary end point was change from baseline in daily trough (pretreatment, prebronchodilator) PEF during the treatment period with FF Rotadisk 100 μg once daily in the morning compared with 100 μg once daily in the evening. Other end points included change from baseline in forced expiratory volume in 1 second, asthma symptom score, adverse events (AEs), 24-hour urinary cortisol excretion, and FF pharmacokinetics. ResultsFive hundred and seventy-five patients (mean age 36.6 years, 56.9% female) formed the intent-to-treat population and were randomly allocated to FF Rotadisk 100 μg once daily in the morning (n = 144), FF Rotadisk 100 μg once daily in the evening (n = 146), FF Rotadisk 250 μg once daily in the evening (n = 142), or placebo (n = 143). Of these patients, 526 (91.5%) completed the study. A smaller proportion of patients in the placebo group (86.7%) than in the active treatment groups completed the study. Mean difference in PEF change from baseline with FF Rotadisk 100 μg once daily in the morning relative to evening was +13.4 L/min (95% CI, 2.3−24.4). However, morning trough values might have been affected by higher placebo response after morning dosing (18.8 vs 8.8 L/min). Trough PEF improved relative to placebo (P ≤ 0.005), with little difference between FF Rotadisk 100 μg morning (19 L/min) and evening (16 L/min) dosing, as with other efficacy measures. Frequencies of all-cause AEs were similar with FF Rotadisk (32%–39%, 2 serious AEs) and placebo (37%, 1 serious AE). No serious AEs were deemed by the investigator to be related to study treatment. Twenty-four-hour urinary cortisol increased from baseline in all groups, but the increase was significantly lower with FF Rotadisk 250 μg group than placebo. ConclusionFF Rotadisk administered once daily in the morning or evening was well tolerated and associated with improvements in lung function and asthma symptoms compared with placebo. Improvements seen for FF Rotadisk 100 μg appear to be comparable for morning and evening dosing. Clinical.trials.govNCT01499446.

Fluticasone furoate: once-daily evening treatment versus twice-daily treatment in moderate asthma

BackgroundInhaled corticosteroids are the recommended first-line treatment for asthma but adherence to therapy is suboptimal. The objectives of this study were to compare the efficacy and safety of once-daily (OD) evening and twice-daily (BD) regimens of the novel inhaled corticosteroid fluticasone furoate (FF) in asthma patients.MethodsPatients with moderate asthma (age ≥ 12 years; pre-bronchodilator forced expiratory volume in 1 second (FEV1) 40-85% predicted; FEV1 reversibility of ≥ 12% and ≥ 200 ml) were randomized to FF or fluticasone propionate (FP) regimens in a double-blind, crossover study. Patients were not permitted to have used any ICS for ≥ 8 weeks prior to enrolment and subsequently received doses of FF or FP 200 μg OD, FF or FP 100 μg BD and matching placebo by inhalation for 28 days each. Primary endpoint was Day 28 evening pre-dose (trough) FEV1; non-inferiority of FF 200 μg OD and FF 100 μg BD was assessed, as was superiority of all active treatment relative to placebo. Adverse events (AEs) and 24-hour urinary cortisol excretion were assessed.ResultsThe intent-to-treat population comprised 147 (FF) and 43 (FP) patients. On Day 28, pre-dose FEV1 showed FF 200 μg OD to be non-inferior (pre-defined limit -110 ml) to FF 100 μg BD (mean treatment difference 11 ml; 95% CI: -35 to +56 ml); all FF and FP regimens were significantly superior to placebo (p ≤ 0.02). AEs were similar to placebo; no serious AEs were reported. Urinary cortisol excretion at Day 28 for FF was lower than placebo (ratios: 200 μg OD, 0.75; 100 μg BD, 0.84; p ≤ 0.02).ConclusionsFF 200 μg OD in the evening is an efficacious and well tolerated treatment for asthma patients and is not inferior to the same total BD dose.Trial registrationClinicaltrials.gov; NCT00766090.

Diagnosing the Unrecognized Systemic Absorption of Intra-Articular and Epidural Steroid Injections

To present a case series of patients who were misdiagnosed with endocrine disorders because of failure to recognize the systemic absorption of intra-articular and epidural steroids and to discuss the utility of performing a urine screen to detect synthetic glucocorticoids. In this case series, we describe the clinical, laboratory, and imaging findings of 3 patients referred to our clinic, each with a presumed endocrine disorder. Patient 1 was a 54-year-old woman with weakness, loss of appetite, and a hormonal profile suggestive of hypopituitarism. Patient 2 was a 49-year-old woman with chronic fatigue and history of physical abuse, whose history and test results were compatible with growth hormone deficiency secondary to head trauma. Patient 3 was a 46-year-old woman who was diagnosed with endogenous Cushing syndrome despite normal 24-hour urinary cortisol excretion. In each case, we subsequently elicited a history of intra-articular or epidural glucocorticoid injections, and a urine screen documented the presence of synthetic glucocorticoids. Systemic absorption of the injected steroids was thus determined to be the cause of the symptoms and abnormal laboratory findings in each case. The potential for harm from intra-articular and epidural glucocorticoid administration is underrecognized by physicians, leading to expensive investigation, false diagnoses, and unnecessary treatment. A urine screen for synthetic glucocorticoids is a valuable adjunct towards appropriate diagnosis.

Characterization of Resistant Hypertension&lt;subtitle&gt;Association Between Resistant Hypertension, Aldosterone, and Persistent Intravascular Volume Expansion&lt;/subtitle&gt;

Resistant hypertension is a common clinical problem and greatly increases the risk of target organ damage. We evaluated the characteristics of 279 consecutive patients with resistant hypertension (uncontrolled despite the use of 3 antihypertensive agents) and 53 control subjects (with normotension or hypertension controlled by using <or=2 antihypertensive medications). Participants were prospectively examined for plasma aldosterone concentration, plasma renin activity, aldosterone to renin ratio, brain-type natriuretic peptide, atrial natriuretic peptide, and 24-hour urinary aldosterone (UAldo), cortisol, sodium, and potassium values while adhering to a routine diet. Plasma aldosterone (P < .001), aldosterone to renin ratio (P < .001), 24-hour UAldo (P = .02), brain-type natriuretic peptide (P = .007), and atrial natriuretic peptide (P = .001) values were higher and plasma renin activity (P = .02) and serum potassium (P < .001) values were lower in patients with resistant hypertension vs controls. Of patients with resistant hypertension, men had significantly higher plasma aldosterone (P = .003), aldosterone to renin ratio (P = .02), 24-hour UAldo (P < .001), and urinary cortisol (P < .001) values than women. In univariate linear regression analysis, body mass index (P = .01), serum potassium (P < .001), urinary cortisol (P < .001), urinary sodium (P = .02), and urinary potassium (P < .001) values were correlated with 24-hour UAldo levels. Serum potassium (P = .001), urinary potassium (P < .001), and urinary sodium (P = .03) levels were predictors of 24-hour UAldo levels in multivariate modeling. Aldosterone levels are higher and there is evidence of intravascular volume expansion (higher brain-type and atrial natriuretic peptide levels) in patients with resistant hypertension vs controls. These differences are most pronounced in men. A significant correlation between 24-hour urinary aldosterone levels and cortisol excretion suggests that a common stimulus, such as corticotropin, may underlie the aldosterone excess in patients with resistant hypertension.

Lack of effect on adult and adolescent hypothalamic-pituitary-adrenal axis function with use of fluticasone furoate nasal spray

Intranasal corticosteroids are recommended as first-line therapy for allergic rhinitis (AR), and because of their pharmacologic class, hypothalamic-pituitary-adrenal (HPA) axis function is evaluated. To evaluate whether cortisol production was suppressed (as a measure of HPA axis function) by 6 weeks of treatment with fluticasone furoate nasal spray, 110 microg once daily, in patients with perennial AR. A double-blind, randomized, placebo- and active-controlled (prednisone), parallel-group study. Outpatients aged 12 to 65 years with perennial AR for 2 years or more were from 1 center in the United States and 1 center in Canada. Pharmacodynamic and pharmacokinetic samples were collected during 24-hour domiciled visits (overnight in clinic). Measurements included change from baseline in 24-hour serum cortisol weighted mean and 24-hour urinary free cortisol excretion, total 24-hour urinary free cortisol excretion and 6-beta hydroxycortisol excretion, and plasma concentration of fluticasone furoate. A total of 112 of 183 patients were randomized. Fluticasone furoate was noninferior to placebo with respect to the ratio from baseline in serum cortisol weighted mean (treatment ratio, 0.98; 95% confidence interval, 0.89 to 1.07). In contrast, use of prednisone, 10 mg once daily, significantly reduced the ratio from baseline compared with placebo. Change from baseline in 24-hour urinary cortisol excretion was similar in the fluticasone furoate and placebo groups. Plasma levels of fluticasone furoate were undetectable after 6 weeks of treatment. Fluticasone furoate nasal spray, 110 microg once daily, was not associated with HPA axis suppression in patients 12 years and older with perennial AR.

Computertomographischer Nachweis von Leberhämangiomen

A 67-year old woman had noticed increasing growth of hair on the face and extremities for eight months. The testosterone level was raised at 2.6 micrograms/l and 24-hour urinary cortisol excretion was 160 micrograms. Ultrasound scanning showed a tumour measuring 14 x 10 x 10 cm in the left suprarenal, as well as several irregular space-occupying lesions in the liver, some of which were echo-rich. By computed tomography these structures were hypodense and did not concentrate any contrast medium. A provisional diagnosis of suprarenal carcinoma with hepatic metastases was accordingly made. After surgical removal of the suprarenal carcinoma the hormonal parameters unexpectedly returned to normal. Repetition of the computed tomography failed to elucidate the nature of the liver lesions. However, superselective hepatic angiography revealed the typical picture of haemangiomas of the liver. The existing computed tomograms were therefore reviewed. The diagnostic error was found to be due to incorrect timing of the interval between injection of contrast medium and performance of computed tomography.

Systemic Exposure and Urinary Cortisol Effects of Fluticasone Propionate Formulated With Hydrofluoroalkane in 4‐ to 11‐Year‐Olds With Asthma

The systemic exposure of fluticasone propionate with hydrofluoroalkane propellant compared with chlorofluoro-carbon propellant and the effect of fluticasone propionate hydrofluoroalkane on 24-hour urinary cortisol in children aged 4 to 11 years with asthma were evaluated. Study 1 was an open-label, 2-way crossover study in which 16 subjects were randomized to 7.5 days each of fluticasone propionate hydrofluoroalkane 88 mug twice a day or fluticasone propionate chlorofluorocarbon 88 mug twice a day. In study 2, 63 subjects received 13.5 days of placebo followed by 27.5 days of fluticasone propionate hydrofluoroalkane 88 mug twice a day. The main outcome measure for study 1 was the difference between fluticasone propionate hydrofluoroalkane and fluticasone propionate chlorofluorocarbon in fluticasone propionate AUC(last) (area under the plasma fluticasone propionate concentration-time curve from zero up to the last quantifiable plasma concentration), and for study 2, 24-hour overnight urinary cortisol excretion. In study 1, fluticasone propionate systemic exposure was significantly lower (55%) with hydrofluoroalkane metered dose inhaler compared with chlorofluorocarbon metered dose inhaler. Study 2 showed no statistically significant changes in 24-hour overnight urinary cortisol excretion and no relationship to fluticasone propionate systemic exposure at this dose. The results of these 2 studies showed that in children aged 4 to 11 years with asthma, fluticasone propionate hydrofluoroalkane has lower systemic exposure compared with chlorofluorocarbon and no hypothalamic-pituitary-adrenal axis effects as measured by 24-hour urinary cortisol excretion.

Ten‐year follow‐up study of cortisol levels in aging holocaust survivors with and without PTSD

To investigate the longitudinal course of mean 24-hour urinary cortisol excretion in posttraumatic stress disorder (PTSD), the authors evaluated 24-hour cortisol excretion in 28 Holocaust survivors 10 years after obtaining an initial estimate. Cortisol levels increased in participants whose PTSD had remitted (n = 3) but declined in participants who developed PTSD (n = 3) or whose PTSD status did not change over time (PTSD+: n = 14, PTSD-: n = 8). Cortisol levels at Time 1 predicted diagnostic status change better than psychological variables, including exposure to traumatic events between assessments. The authors conclude that cortisol levels are affected by change in PTSD status and age.

Fluticasone propionate hydrofluoroalkane inhalation aerosol in patients receiving inhaled corticosteroids

Inhaled corticosteroids (ICSs) delivered by metered-dose inhalers that contain chlorofluorocarbon propellants are being discontinued because of the harmful effects of chlorofluorocarbon on the ozone layer. Therefore, some metered-dose inhaler products are being reformulated with "ozone-friendly" hydrofluoroalkane propellants. To evaluate treatment with fluticasone propionate hydrofluoroalkane inhalation aerosol, 88, 220, and 440 microg twice daily, vs placebo in patients with asthma receiving an ICS. Randomized, double-blind, parallel-group, 12-week study. Mean morning predose percent predicted forced expiratory volume in 1 second increased by 2.2%, 3.2%, and 4.6% in the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively, compared with an 8.3% decrease for placebo (P < .001 vs placebo for all groups). Secondary pulmonary function end points and asthma symptoms showed similar improvements compared with placebo. Discontinuation from the study due to lack of efficacy was 50% in the placebo group and 11%, 10%, and 6% in the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively. At week 12, the probability of remaining in the study was 0.89, 0.90, and 0.94 for the fluticasone propionate, 88-, 220-, and 440-microg twice-daily, groups, respectively, vs 0.45 for the placebo group (P < .001 for all). Changes in 24-hour urinary cortisol excretion rates were similar among treatment groups. Fluticasone propionate hydrofluoroalkane, previously shown to be a clinically suitable alternative to fluticasone propionate chlorofluorocarbon, was effective and well tolerated. The ability to switch from fluticasone propionate chlorofluorocarbon and other chlorofluorocarbon-containing ICSs to fluticasone propionate hydrofluoroalkane without sacrificing asthma control or tolerability will facilitate a smooth transition to this nonchlorofluorocarbon-containing medicinal.

The safety of twice-daily treatment with fluticasone propionate and salmeterol in pediatric patients with persistent asthma

For children older than 5 years with asthma who remain symptomatic despite inhaled corticosteroid (ICS) therapy, the preferred treatment is to add an inhaled long-acting beta2-agonist vs increasing the ICS dose. To compare the safety of twice-daily treatment with inhaled fluticasone propionate plus the inhaled long-acting beta2-agonist salmeterol with that of fluticasone propionate used alone in children aged 4 to 11 years with persistent asthma. A randomized, multicenter, double-blind, active-controlled, parallel-group study in 203 children with persistent asthma who were symptomatic during ICS therapy. Patients received fluticasone propionate-salmeterol (100/50 microg) or fluticasone propionate (100 microg) alone twice daily for 12 weeks. The safety profile of fluticasone propionate-salmeterol was similar to that of fluticasone propionate alone. The overall incidence of adverse events was 59% for fluticasone propionate-salmeterol and 57% for fluticasone propionate. Both treatments were well tolerated. Two patients receiving fluticasone propionate-salmeterol and 5 receiving fluticasone propionate withdrew from the study because of worsening asthma. Changes in heart rate, blood pressure, and laboratory variables were infrequent and were similar between treatments. No patients had clinically significant abnormal electrocardiographic findings during treatment. Geometric mean 24-hour urinary cortisol excretion at baseline and after 12 weeks of treatment was comparable within and between groups; no patient in either group had abnormally low 24-hour urinary cortisol excretion after 12 weeks of treatment. The incidence of withdrawals due to asthma exacerbations was 2% in the fluticasone propionate-salmeterol group and 5% in the fluticasone propionate group. In pediatric patients with persistent asthma, fluticasone propionate-salmeterol twice daily was well tolerated, with a safety profile similar to that of fluticasone propionate used alone.

Salmeterol/fluticasone and fluticasone alone are well tolerated over 1 year of treatment stepped-up to achieve total control: Safety results of the GOAL study

Rationale The 1-year Gaining Optimal Asthma controL (GOAL) study showed that more patients achieve guideline-defined control with salmeterol/fluticasone (SFC) than fluticasone (FP) alone. The GOAL study provides an opportunity to evaluate safety parameters following long-term treatment stepped-up to achieve total asthma control. Methods Patients with uncontrolled asthma were stratified on prior medication (S1: ICS-naïve; S2: low-dose ICS; S3: moderate-dose ICS), and randomized to SFC (Seretide ®/Advair ®) 50/100-50/500 μg bid or FP (Flixotide ®/Flovent ®) 100-500 μg bid for up to 1 year. Adverse events (AEs) were recorded at each clinic visit and 24-hour urinary free cortisols monitored in a patient subset. Results The safety population for SFC vs FP included: S1, 548 vs 550; S2, 585 vs 578; S3, 576 vs 579 patients. The overall incidence of AEs was similar across all strata for both SFC vs FP: S1, 55% vs 56%; S2, 60% vs 57%; and S3, 69% vs 67%. Drug-related AEs were seen in 10% of patients with both treatments (all strata). The incidence of serious AEs with SFC vs FP alone was low across all strata: S1 2% vs 4%; S2 3% vs 2%; and S3 6% vs 4%. The most common adverse events (incidence ≥5%; all strata) were similar for SFC and FP and were: nasopharyngitis, upper RTI headache, sinusitis and influenza. There were no significant differences between treatments in 24-hour free urinary cortisol excretion at week 52 versus baseline. Conclusions Long-term treatment with salmeterol/fluticasone or fluticasone stepped-up to achieve Total Control is safe and well tolerated.