Baseline Urinary Free Cortisol Research Articles

Personalized Noninvasive Diagnostic Algorithms Based on Urinary Free Cortisol in ACTH-dependant Cushing's Syndrome.

Current guidelines for distinguishing Cushing's disease (CD) from ectopic ACTH secretion (EAS) are questionable, as they use pituitary magnetic resonance imaging (MRI) as first-line investigation for all patients. CRH testing is no longer available, and they suggest performing inferior petrosal sinus sampling (BIPPS), an invasive and rarely available investigation, in many patients. To establish noninvasive personalized diagnostic strategies based on the probability of EAS estimated from simple baseline parameters. Retrospective study. University hospitals. Two hundred forty-seven CD and 36 EAS patients evaluated between 2001 and 2023 in 2 French hospitals. A single-center cohort of 105 Belgian patients served as external validation. Twenty-four-hour urinary free cortisol (UFC) had the highest area under the receiver operating characteristic curve for discrimination of CD from EAS (.96 [95% confidence interval (CI), .92-.99] in the primary study and .99 [95% CI, .98-1.00] in the validation cohort). The addition of clinical, imaging, and biochemical parameters did not improve EAS prediction over UFC alone, with only BIPPS showing a modest improvement (C-statistic index .99 [95% CI, .97-1.00]). Three groups were defined based on baseline UFC: < 3 (group 1), 3-10 (group 2), and > 10 × the upper limit of normal (group 3), and they were associated with 0%, 6.1%, and 66.7% prevalence of EAS, respectively. Diagnostic approaches performed in our cohort support the use of pituitary MRI alone in group 1, MRI first followed by neck-to-pelvis computed tomography scan (npCT) when negative in group 2, and npCT first followed by pituitary MRI when negative in group 3. When not combined with the CRH test, the desmopressin test has limited diagnostic value. UFC accurately predicts EAS and can serve to define personalized and noninvasive diagnostic algorithms.

LBMON176 Management, Safety, And Efficacy Of Osilodrostat Treatment In US Patients With Non-pituitary Cushing's Syndrome: Results From The ILLUSTRATE Study

Abstract Background Osilodrostat, a potent cortisol synthesis inhibitor, demonstrated safety and efficacy in the treatment of Cushing's disease (CD). No information is available describing use of osilodrostat in non-pituitary Cushing's syndrome (CS) in US patients. Data from a real-world study in US patients with non-pituitary CS is presented. Methods The ILLUSTRATE study is a real-world characterization of osilodrostat usage in patients with endogenous CS treated May 1, 2020 - October 29, 2021. Forty-two adult patients with a confirmed diagnosis of endogenous CS and a prescription for osilodrostat were included in this real-world study. We report patient characteristics, osilodrostat dose, efficacy, and safety in the subset of patients with non-pituitary CS (n=8,19%). Results The 8 non-pituitary CS patients enrolled comprised 5 with adrenal CS and 3 with ectopic CS. Baseline urinary free cortisol (UFC) was 2.57–75.2×ULN in patients with ectopic CS, and 0.42–27.76×ULN in the 4 adrenal patients with baseline UFC available. In the adrenal CS patients, starting dose ranged from 1–4 mg daily. In adrenal patients with more than one documented clinical encounter (n=4): 2 remained on starting doses of 1 mg BID and 2 mg BID, 1 increased from 1 mg QD to 2 mg BID on day (D) 50, and 1 increased from 2 mg BID to 4 mg BID on D5 and required down-titration on D18 with treatment interruption on D27. The 3 patients with ectopic CS were all initiated at 2 mg BID: 1 patient's dose was unchanged throughout the observation period, and the other 2 patients were up-titrated, both on D91 to 4 mg BID or 5 mg QD. The two ectopic CS patients with available UFC data experienced substantial UFC | reductions (from 57.1×ULN to 2.9×ULN at D91 and 75.2×ULN to 0. 076×ULN at D134). The one adrenal CS patient with available UFC data and prior medical therapy for CS maintained UFC ≤ ULN during osilodrostat treatment. Osilodrostat was generally well tolerated and one ectopic CS patient had treatment interrupted on D214 for adrenal insufficiency (AI). Two of five adrenal CS patients (40%) had symptoms suggestive of glucocorticoid withdrawal (e. g., fatigue, nausea, and headache) and one had an interruption in therapy. Neither had documented AI. Conclusion In this real-world cohort of patients treated with osilodrostat for non-pituitary CS, large UFC reductions were seen in two patients with ectopic CS. All 8 were initiated on ≤2 mg BID, with 3 (38%) remaining on their original dose. In the majority of those up-titrated, there was an extended titration interval. The observed safety profile in this subset (albeit small) of non-pituitary CS patients was consistent with the known osilodrostat safety profile. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Dehydroepiandrosterone sulfate levels predict weight gain in women with anorexia nervosa.

Anorexia nervosa (AN) is a serious condition characterized by undernutrition, complicated by endocrine dysregulation, and with few predictors of recovery. Urinary free cortisol (UFC) is a predictor of weight gain, but 24-h urine samples are challenging to collect. We hypothesized that serum dehydroepiandrosterone sulfate (DHEAS), which like cortisol is regulated by adrenocorticotropic hormone (ACTH), would predict weight gain and increases in fat mass in women with AN. We prospectively studied 34 women with AN and atypical AN, mean age 27.4 ± 7.7 years (mean ± SD), who received placebo in a 6-month randomized trial. Baseline DHEAS and 24-h UFC were measured by liquid chromatography with tandem mass spectrometry. Body composition was assessed at baseline and 6months by DXA and cross-sectional abdominal CT at L4. Mean baseline DHEAS level was 173 ± 70 μg/dl (0.7 ± 0.3 times the mean normal range for age) and mean baseline UFC (n=15) was 20 ± 18 μg/24 h (normal: 0-50 μg/24 h). Higher DHEAS levels predicted weight gain over 6months (r=0.61, p < .001). DHEAS levels also predicted increases in fat mass (r=0.40, p=.03), appendicular lean mass (r=0.38, p=.04), and abdominal adipose tissue (r=0.60, p < .001). All associations remained significant after controlling for age, baseline BMI, OCP use, duration of AN, and SSRI/SNRI use. DHEAS levels correlated with UFC (r=0.61, p=.02). In women with AN, higher serum DHEAS predicts weight gain and increases in fat and muscle mass. Additional studies are needed to confirm these findings and further elucidate the association between DHEAS and weight gain. Anorexia nervosa is a severe psychiatric condition, and predictors of weight recovery are needed to improve prognostication and guide therapeutic decision making. While urinary cortisol is a predictor of weight gain, 24-h urine collections are challenging to obtain. Like cortisol, dehydroepiandrosterone sulfate (DHEAS) is a hormone produced by the adrenal glands. As a readily available blood test, DHEAS holds promise as more practical biomarker of weight gain in anorexia nervosa.

Effects of Ketoconazole on the Clinical Recovery in Central Serous Chorioretinopathy.

PurposePatients with hypercortisolism have been associated with a higher prevalence of the pachychoroid spectrum including central serous chorioretinopathy (CSCR), which may explain the inconsistency of therapeutic responses of the mineralocorticoid receptor antagonist because hyperaldosteronism has rarely been detected in patients with CSCR. Therefore, this study aimed to evaluate the effects of ketoconazole, the first-line cortisol inhibitor, on the resolution of subretinal fluid (SRF) in CSCR and to analyze correlations between choroidal thickness and steroid hormones.Patients and MethodsThis retrospective cohort study included 41 naïve CSCR eyes of 41 patients categorized into control (20 eyes) and treatment (21 eyes) groups. Patients in the treatment group were administered oral ketoconazole at a daily dose of 400 or 600 mg for 3–6 weeks. At week 12, rescue laser therapy was applied to patients exhibiting persistent SRF. Thus, a survival analysis was performed to determine the time interval from presentation to clinical resolution of SRF. Secondary outcomes consisted of eyes with persistent SRF and factors affecting the therapeutic response.ResultsThe mean 24-hour urinary free cortisol (UFC) levels were elevated at 181 ± 70 and 150 ± 68 µg/day (range: 20–150) in the treatment and control groups, respectively (p = 0.21). After controlling for age and gender, baseline UFC levels were significantly associated with choroidal thickness in both eyes (p < 0.05). Ketoconazole significantly increased the CSCR resolution with the median time to resolution of 7 vs 16 weeks (p < 0.01) and decreased the proportion of eyes receiving rescue therapy at 12 weeks (23.8% vs 50%; p = 0.01). Prolonged CSCR durations were likely found in elderly patients with thick choroids in fellow eyes.ConclusionPatients with CSCR showed elevated glucocorticoids, which further correlated with their choroidal thickness. Using cortisol blockers may shorten the duration of existing SRF.

Selective Serotonin Reuptake Inhibitors Increase Urinary Free Cortisol in Patients with Carney Complex and Primary Pigmented Nodular Adrenocortical Disease

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome predominantly associated with Carney Complex (CNC), a multiple endocrine neoplasia syndrome primarily caused by inactivating defects in PRKAR1A. PPNAD, which has neuroendocrine features, demonstrates cortisol production in response to serotonin as well as increased expression of tryptophan hydroxylase type 2, a serotonin synthesizing enzyme, and the serotonin (5-HT) receptors types 4, 6, and 7. This creates an autocrine/paracrine serotonergic regulatory loop that activates cortisol production. PPNAD can be diagnosed through a 6-day Liddle test (LT) showing a paradoxical increase of >50% from baseline in 24-h urinary free cortisol (UFC) on the 2nd day of high-dose dexamethasone administration (Day 6). Selective serotonin reuptake inhibitors (SSRIs) inhibit the reuptake of serotonin and are widely used for the treatment of depression. We performed a retrospective cohort study of patients with CNC and PPNAD that underwent a LT to evaluate the effect of SSRIs on UFCs, with the hypothesis that SSRI use leads to an exaggerated increase in UFC through presumed activation of the described serotonergic regulatory loop. Of the 34 patients (4–65 y) with CNC and PPNAD that underwent a LT at our institution between 2004 and 2018, 4 took an SSRI during testing. No differences were observed between the SSRI (S) group and the non-SSRI (NS) group in baseline UFCs and the percent increase in UFC on D6. Specifically, the median (IQR) baseline UFC in the S group was 36 (13–252) mcg/24h (nl 4–56) vs 35 (13–98) mcg/24h in the NS group (P=0.95). The percent change in UFC was 208 (93–683)% in the S group and 185 (28–364)% in the NS group (P=0.89). However, there was a difference for overall UFC measurement (across days 1–6 of the LT) in the S group vs the NS group (P=0.03). Age <18 vs 18+ and sex did not have an effect on the outcomes (P=0.17 and P=0.74, respectively). Thus, we conclude that though the percent change in UFC during the LT was similar in both groups, there was a significant difference in overall UFC in the S group when compared to the NS group. These data support an effect of SSRIs and serotonin on UFC and consequently cortisol production in PPNAD. This interesting observation has to be confirmed in more patients with CNC and PPNAD to further elucidate the effects of SSRIs on cortisol production in patents with PPNAD-caused Cushing syndrome, as this may have significant diagnostic and therapeutic implications.

SAT-167 Dehydroepiandrosterone Sulfate (DHEAS) Levels Predict Weight Gain in Women with Anorexia Nervosa

Introduction: Anorexia nervosa (AN) and atypical AN (defined as weight loss and all the psychological features of AN but BMI>18.5 kg/m2) are serious disorders characterized by undernutrition and complicated by endocrine dysregulation. Predictors of recovery, including serum biomarkers, are lacking. Prior studies have suggested that higher urinary free cortisol (UFC) may predict weight gain in women with AN, but 24-hour urine collections are not feasible in a real-world setting. Like cortisol, the adrenal androgen dehydroepiandrosterone (DHEA) and its sulfated form DHEAS, which has a longer half-life, are stimulated by ACTH. We hypothesized that DHEAS levels would correlate with UFC and be a predictor of weight gain in women with AN.Methods: We prospectively studied 34 women with AN and atypical AN, mean age 27.4 ± 7.7 years (mean ± SD), who received placebo in a randomized trial. AN and atypical AN were diagnosed by SCID. Baseline DHEAS and 24-hour UFC were measured by LC-MS/MS (Endocrine Sciences, Calabasas Hills, CA). Weight and body composition were assessed at baseline and 6 months later by DXA and cross-sectional abdominal CT at L4.Results: At baseline, mean weight was 51.3 ± 4.9 kg. Of the 18 subjects who gained weight (range 0.1–10.3 kg), 28% were eumenorrheic, 39% amenorrheic, and 33% on oral contraceptives at baseline; baseline reproductive status was similar for subjects who did not subsequently gain weight. In the group as a whole, mean baseline DHEAS level was 173 ± 70 µg/dL (0.7 ± 0.3 times the mean normal range for age) and mean baseline UFC for subjects who completed testing (n=15) was 20 ± 18 µg/24h (normal range 0–50 µg/24h). Higher DHEAS levels at baseline predicted weight gain over 6 months (r=0.61, p<0.001), which remained significant after controlling for age, baseline BMI, OCP use, and SSRI/SNRI use (p<0.001); none of these covariates were predictors of weight gain. Baseline DHEAS levels predicted an increase in fat mass (r=0.40, p=0.03) and appendicular lean mass (r=0.38, p=0.04) by DXA, and abdominal fat by CT (r=0.60, p<0.001); the associations remained significant after controlling for the above factors. UFC did not predict change in weight (r=0.37, p=0.17) or body composition. DHEAS levels were positively associated with UFC (r=0.61, p=0.02).Conclusion: In women with AN, higher DHEAS levels are a predictor of weight gain and increases in fat mass, skeletal muscle mass, and abdominal fat. Serum DHEAS correlates with UFC, a predictor of weight gain in prior studies. DHEAS may be a more practical biomarker of recovery, as 24-hour urine collections are challenging. Further studies are needed to determine whether higher DHEAS levels are a marker of global adrenal stress response and a reflection of higher cortisol levels, which may stimulate weight gain, or an independent predictor of weight gain in AN and atypical AN, perhaps through neuromodulation.

SUN-356 The Effects of Selective Serotonin Reuptake Inhibitors on Urinary Free Cortisol in Patients with Carney Complex and Primary Pigmented Nodular Adrenocortical Disease

PPNAD is a rare cause of ACTH-independent Cushing syndrome mainly associated with Carney complex (CNC). It is diagnosed by histologic examination or a 6-day Liddle test (LT) showing a paradoxical increase of >50% in 24-h urinary free cortisol (UFC) on the 2nd day of high-dose dexamethasone administration (Day 6 [D6]). PPNAD tissue has neuroendocrine features and can overexpress the serotonin (5-HT) synthesizing enzyme tryptophan hydroxylase type 2 and the 5-HT receptors types 4, 6, and 7, with formation of an illicit stimulatory serotonergic loop whose pharmacological inhibition in vitro decreases cortisol production [1]. SSRIs inhibit the reuptake of 5-HT and are used as 1st-line antidepressants. This is a retrospective cohort study of patients with CNC and PPNAD that underwent a LT with the objective to evaluate the effect of SSRIs on UFCs in these patients. Of the 34 patients (4-65 y) with CNC and PPNAD that had a LT at our institution between 2004 and 2018, 4 patients took an SSRI during testing. No statistically significant differences were demonstrated between the SSRI (S) group and the non-SSRI (NS) group in baseline UFCs and urine 17-hydroxycorticosteroids (17OHS) and the percent increase in UFC and 17OHS on D6. Specifically, the median (IQR) baseline UFC in the S group was 36 (13-252) mcg/24h (nl 4-56) vs 35 (13-98) mcg/24h in the NS group (P=0.95). Baseline 17OHS were 11 (8-18) mg/mg creatinine (Cr) (nl ≤6) in the S group vs 8 (5-11) mg/mgCr in the NS group (P=0.27). The percent change in UFC was 208 (93-683)% in the S group and 185 (28-364)% in the NS group (P=0.89), while the percent change in 17OHS was 56 (40-87)% in the S group and 67 (16-92)% in the NS group (P=0.91). On D6, the S group appeared to have higher UFC [118 (63-635) mcg/24h vs 112 (58-201) mcg/24h; P=0.64] and 17OHS [16 (10-39) mg/mgCr vs 13 (7-17) mg/mgCr; P=0.25] than the NS group, but these were not statistically significant. Though these data do not confirm an effect of SSRIs on UFC and ultimately cortisol production in PPNAD, and the percent change in UFC during the LT was similar between both groups, the higher D6 UFC in the S group, when the baseline UFCs between the 2 groups were similar may suggest a degree of increased cortisol production in the S group. The data are limited by the small number of patients in the S group (n=4). In addition, 50% of patients in the S group vs 77% in the NS group underwent adrenalectomy, which is indicative of more severe disease in the NS group. More data are needed from this cohort to determine if SSRI use affects cortisol production in vivo, as this may have significant diagnostic and therapeutic implications for patients with CNC and PPNAD. Reference: 1. Bram, Z., et al., PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease. JCI Insight, 2016. 1(15): p. e87958.

Factors predicting long-term comorbidities in patients with Cushing\u2019s syndrome in remission

PurposeIn Cushing’s syndrome, comorbidities often persist after remission of glucocorticoid excess. Here, we aim to identify factors predicting long-term comorbidities in patients with Cushing’s syndrome in remission.MethodsIn a retrospective cross-sectional study, 118 patients with Cushing’s syndrome in remission (52 pituitary, 58 adrenal, 8 ectopic) were followed for a median of 7.9 years (range 2–38) after the last surgery. Associations between baseline anthropometric, metabolic, hormonal parameters at diagnosis, and comorbidities (obesity, diabetes, hyperlipidemia, hypertension, osteoporosis, depression) at last follow-up, were tested by uni- and multivariate regression analysis.ResultsIn patients with manifest comorbidities at diagnosis, remission of Cushing’s syndrome resolved diabetes in 56% of cases, hypertension in 36% of cases, hyperlipidaemia in 23%, and depression in 52% of cases. In a multivariate regression analysis, age, fasting glucose, BMI, and the number of comorbidities at diagnosis were positive predictors of the number of long-term comorbidities, while baseline 24-h urinary free cortisol (UFC) negatively correlated with the persistence of long-term comorbidities. The negative relationship between baseline UFC and long-term comorbidities was also found when pituitary and adrenal Cushing’s cases were analyzed separately. Baseline UFC was negatively related to the time of exposure to excess glucocorticoids.ConclusionsLong-term comorbidities after remission of Cushing’s syndrome depend not only on the presence of classic cardiovascular risk factors (age, hyperglycemia, BMI), but also on the extent of glucocorticoid excess. Lower baseline UFC is associated with a higher number of long-term comorbidities, possibly due to the longer exposure to excess glucocorticoids in milder Cushing’s syndrome.

Metyrapone treatment in Cushing's syndrome: a real-life study.

Medical treatment is increasingly used in patients with Cushing's syndrome (CS). Metyrapone (MET) is an inhibitor of 11β-hydroxylase: retrospective studies reported a decrease of cortisol secretion in 50% of cases. We evaluated the effectiveness of MET in an observational study, considering the normalization of urinary-free cortisol (UFC) and late-night salivary cortisol (LNSC) levels. We enrolled 31 patients with CS, treated with MET for at least 1 month (16 for primary treatment and 15 after surgical failure). A planned dose-titration regimen considering baseline UFC levels was adopted; MET dose was uptitrated until UFC normalization, surgery, or side effect occurrence. UFC and LNSC levels were routinely measured by liquid chromatography-tandem mass spectrometry. Patients were treated with a median dose of 1000 mg for 9 months. UFC and LNSC decreased quickly after the first month of treatment (-67 and -57% from baseline), with sustained UFC normalization up to 12 and 24 months (in 13 and 6 patients, respectively). UFC and LNSC normalized later (after 3-6 months) in patients with severe hypercortisolism (>5-fold baseline UFC). Regarding the last visit, 70 and 37% of patients normalized UFC and LNSC, respectively. Body weight reduction (-4 kg) was observed after UFC normalization. Severe side effects were not reported, half of the female patients complained of hirsutism, and blood pressure was not increased. MET therapy is a rapid-onset, long-term effective, and safe medical treatment in CS patients, achieving UFC normalization (in 70% of patients) more than cortisol rhythm recovery (in 37% of subjects).

Cabergoline for Cushing’s disease: a large retrospective multicenter study

The efficacy of cabergoline in Cushing's disease (CD) is controversial. The aim of this study was to assess the efficacy and tolerability of cabergoline in a large contemporary cohort of patients with CD. We conducted a retrospective multicenter study from thirteen French and Belgian university hospitals. Sixty-two patients with CD received cabergoline monotherapy or add-on therapy. Symptom score, biological markers of hypercortisolism and adverse effects were recorded. Twenty-one (40%) of 53 patients who received cabergoline monotherapy had normal urinary free cortisol (UFC) values within 12 months (complete responders), and five of these patients developed corticotropic insufficiency. The fall in UFC was associated with significant reductions in midnight cortisol and plasma ACTH, and with clinical improvement. Compared to other patients, complete responders had similar median baseline UFC (2.0 vs 2.5xULN) and plasma prolactin concentrations but received lower doses of cabergoline (1.5 vs 3.5 mg/week, P < 0.05). During long-term treatment (>12 months), cabergoline was withdrawn in 28% of complete responders because of treatment escape or intolerance. Overall, sustained control of hypercortisolism was obtained in 23% of patients for 32.5 months (19-105). Nine patients on steroidogenesis inhibitors received cabergoline add-on therapy for 19 months (1-240). Hypercortisolism was controlled in 56% of these patients during the first year of treatment with cabergoline at 1.0 mg/week (0.5-3.5). About 20-25% of CD patients are good responders to cabergoline therapy allowing long-term control of hypercortisolism at relatively low dosages and with acceptable tolerability. No single parameter, including the baseline UFC and prolactin levels, predicted the response to cabergoline.

Pasireotide monotherapy in Cushing’s disease: a single-centre experience with 5-year extension of phase III Trial

A recent phase III randomized controlled trial (NCT00434148) showed efficacy of pasireotide in the treatment of patients with Cushing's disease (CD). Patients were invited to participate in an extension phase of the protocol and a subgroup had a sustained response. We report the experience with 4 patients in our center of which 2 full responders have completed 5.5 and 4.25 years of treatment with disease control. The trial protocol was described previously. The extension phase consisted of 3-monthly visits with clinical, biochemical, and imaging evaluation and investigator-driven pasireotide titration. Research charts were retrospectively analyzed. Four patients with persistent CD following pituitary surgery completed the first 6 months of the trial and 3 continued in the next 6 month open-label phase. Two patients with baseline urinary free cortisol (UFC) 5.3-6.7 times the upper limit of normal had a rapid sustained response to pasireotide and entered the extension phase after 12 months. They remain in clinical and biochemical disease remission and 1 patient now only requires 300 μg daily of pasireotide. All 4 patients developed glucose intolerance; however, the two patients in the extension phase were eventually able to discontinue all diabetes pharmacotherapy. Adverse events included second degree atrioventicular block type 1 without QT prolongation in a patient with pre-existing sinus bradycardia, and symptomatic cholelithiasis requiring cholecystectomy in a second patient. Pasireotide therapy can provide normalization of UFC and of clinical symptoms and signs of CD during up to 5 years of follow-up. This study demonstrates the possible recuperation of normoglycemia after continued use of pasireotide and control of underlying hypercortisolemia. Longer-term monitoring for potential adverse events related to continued use of pasireotide is indicated.

High variability in baseline urinary free cortisol values in patients with Cushing's disease

ObjectiveTwenty-four-hour urinary free cortisol (UFC) sampling is commonly used to evaluate Cushing’s syndrome. Because there are few data on UFC variability in patients with active Cushing’s disease, we analysed baseline UFC in a large patient cohort with moderate-to-severe Cushing’s disease and assessed whether variability correlates with hypercortisolism severity. These data will help clinicians establish the minimum number of UFC samples required to obtain reliable data.DesignObservational study (enrolment phase of Phase III study).MethodsPatients (n = 152) with persistent/recurrent or de novo Cushing’s disease and mean UFC (mUFC) ≥1·5×ULN (normal: 30–145 nmol/24 h) were included. Mean UFC level was calculated from four 24-h urine samples collected over 2 weeks.ResultsOver 600 24-h UFC samples were analysed. The mUFC levels of samples 1 and 2 and samples 3 and 4 were 1000 nmol/24 h (SD 1872) and 940 nmol/24 h (SD 2148), respectively; intrapatient coefficient of variation (CV) was 38% for mUFC. The intrapatient CV using all four samples was 52% (95% CI: 48–56). The intrapatient CV was 51% (95% CI: 44–58) for samples 1 and 2, 49% (95% CI: 43–56) for samples 3 and 4 and 54% (95% CI: 49–59) for samples 1, 2 and 3. Variability in mUFC increased as UFC levels increased. There were no correlations between UFC and clinical features of hypercortisolism.ConclusionsThere is intrapatient variability of approximately 50% in 24-h UFC measurements, which is relevant to targets set to estimate any treatment effect. Analysing more than two 24-h collection periods in individual patients does not result in a relevant decrease in variability. Interestingly, UFC levels did not correlate with hypercortisolism severity.

The low-dose dexamethasone suppression test: a reevaluation in patients with Cushing's syndrome.

Low-dose dexamethasone suppression testing has been recommended for biochemical screening when Cushing's syndrome is suspected. The criterion for normal suppression of cortisol after dexamethasone is controversial. To assess diagnostic utility (sensitivity), we report the results of low-dose dexamethasone suppression testing in 103 patients with spontaneous Cushing's syndrome. There were 80 patients with Cushing's disease (78%), 13 with the ectopic ACTH syndrome (13%), and 10 with cortisol-producing adrenocortical adenomas (10%). Fourteen (18%) of 80 patients with Cushing's disease suppressed serum cortisol to less than 5 micro g/dl (<135 nmol/liter) after the overnight 1-mg test, whereas six patients (8%) actually showed suppression of serum cortisol to less than 2 micro g/dl (<54 nmol/liter). In addition, the 2-d, low-dose dexamethasone suppression test yielded false-negative results in 38% of patients when urine cortisol was used and 28% when urinary 17-hydroxycorticosteroids were used. Serum cortisol after the 1-mg test correlated with baseline urinary free cortisol (r = 0.705, P < 0.001), plasma ACTH level (r = 0.322, P = 0.001), and urinary free cortisol after the 2-d test (r = 0.709, P = 0.001). This study provides evidence that low-dose dexamethasone may suppress either plasma cortisol or urinary steroids to levels previously thought to exclude Cushing's syndrome and that these tests should not be used as the sole criterion to exclude the diagnosis of endogenous hypercortisolism.

The relation between cortisol excretion and fractures in healthy older people: results from the MacArthur studies-Mac.

In persons with depression, higher urinary cortisol is associated with lower bone mineral density. To examine the relation between urinary free cortisol (UFC) and fractures. Community-based samples from Durham, NC, East Boston, MA, and New Haven, CT. 684 men and women, aged 70 to 79 at baseline, who were part of the MacArthur Study of Successful Aging. Cohort study. Participants with previous history of fractures at baseline were excluded. The primary exposure variable was overnight (8:00 p.m. to 8:00 a.m.) UFC (microg/g creatinine) at baseline (1988). Outcomes were self-reported hip, arm, spine, wrist, or other fracture during the follow-up period (1988-1995). Covariates were baseline age, gender, race, body mass index, current physical activity, lower extremity strength, depression subscale of the Hopkins Symptom Checklist, and current use of cigarettes and alcohol. Logistic regression was used to predict the occurrence of incident fractures (1988-1995) as a function of quartiles of baseline UFC. Models were adjusted for age, gender, and race and were also multiply adjusted for the remaining covariates listed above. Gender-stratified models and models that excluded corticosteroid users were also run. In multiply adjusted models, higher baseline levels of UFC were significantly associated with incident fractures. Odds of fracture (95% Confidence Intervals) for increasing quartiles of baseline UFC, multiply adjusted, were: 2.28 (.91, 5.77); 3.40 (1.33, 8.69); 5.38 (1.68, 17.21). Results were not materially influenced by exclusion of persons using corticosteroids. Higher baseline UFC is an independent predictor of future fracture.