24-h Urinary Free Cortisol Excretion Research Articles

PS-C21-3: URINARY FREE CORTISOL EXCRETION AS A MARKER OF DECREASED BONE DENSITY IN PATIENTS WITH ADRENAL CUSHING'S SYNDROME

Objective: Patients with adrenal Cushing's syndrome (CS) have a poor prognosis due to the autonomous hypersecretion of endogenous cortisol from the adrenal gland. Although several clinical examinations have been developed to manifest the autonomous hypersecretion of endogenous cortisol in this syndrome, it is unknown which parameter of cortisol overproduction is best associated with adrenal cortisol content and the bone and vascular complications of this syndrome. Therefore, the present study was undertaken to evaluate the parameter(s) associated with adrenal cortisol content in patients with adrenal CS, as well as to assess the associations between these parameters and the vascular and bone complications of this syndrome. Design and method: Patients with CS who were over 18 years old and had undergone adrenalectomy for this syndrome were enrolled in this study. Patients who were pregnant, had an allergy to iodine, or who were receiving medications that may interfere with the evaluation of 131I-adosterol single-photon emission computed tomography (SPECT) /computed tomography (CT) were excluded. Those taking medications that may interfere with the evaluation for the diagnosis of CS were also excluded. Relationships between office blood pressure and pulse rate, urinary examinations, blood examinations, endocrinological examinations, CT and 131I-adosterol SPECT/CT data, bone density, physiological function tests, and adrenal cortisol concentration/content were examined. In addition, relationships between the parameter associated with adrenal cortisol concentration/content and complications of CS were investigated. Results: Cardiovascular factors, except for diastolic blood pressure, failed to show an association with adrenal cortisol content. 24-h urinary free cortisol excretion (ρ = 0.893, P = 0.007) and plasma cortisol levels after the 1 mg (ρ = 0.857, P = 0.014) or 8 mg (ρ = 0.900, P = 0.037) overnight dexamethasone suppression test, but not plasma cortisol levels in the morning or at late night or indices of 131I-adosterol SPECT/CT, were significantly and positively associated with adrenal cortisol content. 24-h urinary free cortisol excretion, and not plasma cortisol levels after the 1 or 8 mg overnight dexamethasone suppression test was significantly and negatively associated with lumbar spine bone density (lumbar spine T-score, ρ = -0.883, P = 0.009; lumbar spine Z-score, ρ = -0.883, P = 0.009). Conclusions: 24-h urinary free cortisol excretion is best associated with a decrease in bone density via increased adrenal cortisol overproduction and suggested that it could be used as a marker for osteoporosis in these patients.

OR12-1 Activity of Abiraterone Acetate in the management of Cushing syndrome associated to advanced adrenocortical carcinoma: results of the ABACUS trial.

Abstract Background More than 50% of adrenocortical carcinomas (ACC) in adults are associated with cortisol excess that makes tumor management challenging and has a negative impact on patient outcome. Abiraterone acetate (AA) is an irreversible inhibitor of the 17α-hydroxylase/C17, 20-lyase (CYP17 enzyme) that is used in patients with prostate cancer, in whom it leads to suppression of cortisol and androgens. Thus, the drug is potentially useful in the medical treatment of steroid-secreting tumors. The aim of this study was to assess the activity of AA to control cortisol excess in patients with advanced ACC and overt Cushing syndrome. Methods We designed the phase II trial ABACUS (NCT 03145285) whose primary endpoint was normalization of 24-h urinary free cortisol (UFC) excretion within 1 month from treatment start. Inclusion criteria were histologically proven ACC, locally advanced or metastatic disease, and Cushing syndrome confirmed by two 24-h UFC >1.5 times the upper normal limit with suppressed ACTH. No concomitant treatment with mitotane or chemotherapy was allowed for the first 4 weeks of the study. AA was given orally at the daily dose of 1000 mg. Results From 2017 to 2019, we included 17 patients with ACC (2 stage III, 15 stage IV), 13 women (76%), median age 51 years (18-76), of whom 8 have been heavily pretreated and 9 were treatment naïve. In 8 patients, multiple steroid secretion was found. Patients were treated with AA for a median of 17 days (7-163). Median 24-h UFC (measured by gas-mass spectrometry) was 368 μg/24h (121-7422) at baseline and 94 μg/24h (20-1793) at end of treatment (p=0.01). Normalization of 24-h UFC was attained in 8 patients (53%) and a >50% decrement in 11 patients (73%). The median time to effect was 21 days and median 24-h UFC reduction 81.8% (-97.7 - +25.9). Androgen and precursor steroids were also significantly reduced by AA treatment. The median Cushing Syndrome Score was 5.0 (2 - 8) at baseline and 3.5 (1 - 6) at the end of treatment, thus confirming clinical improvement. Blood pressure was significantly reduced and hypokalemia was not observed. In 2 patients, treatment was discontinued for toxicity. Seven patients died of ACC progression during follow-up with an overall survival of 5.4 months (0.5-39.3). Conclusions AA was able to control rapidly cortisol excess in most patients with a good safety profile. The results of this proof-of-concept study show that AA looks promising and may be viewed as an additional weapon to manage Cushing syndrome in patients with ACC. These findings pose the basis for power calculation and implementation of a prospective long-term study to establish AA efficacy in patients with a steroid-secreting ACC. Presentation: Sunday, June 12, 2022 11:00 a.m. - 11:15 a.m.

Urinary free cortisol excretion is associated with lumbar bone density in patients with adrenal Cushing's syndrome.

Patients with adrenal Cushing's syndrome have a poor prognosis due to the autonomous hypersecretion of endogenous cortisol from the adrenal gland. Although several clinical examinations have been developed to manifest the autonomous hypersecretion of endogenous cortisol in this syndrome, it is unknown which parameter of cortisol overproduction is best associated with the adrenal cortisol content and bone and vascular complications of this syndrome. Therefore, the present study was undertaken to evaluate the parameter(s) associated with the adrenal cortisol content in patients with adrenal Cushing's syndrome, as well as to assess the associations between these parameters and the vascular and bone complications of this syndrome. Cardiovascular factors such as blood pressure and pulse rate, glucose metabolism, lipid metabolism, renal function, and indices of arteriosclerosis, except for diastolic blood pressure, failed to show an association with the adrenal cortisol content. Twenty-four-hour urinary free cortisol excretion (ρ = 0.893, P = 0.007) and plasma cortisol levels after the 1-mg (ρ = 0.857, P = 0.014) or 8-mg (ρ = 0.900, P = 0.037) overnight dexamethasone suppression test, but not plasma cortisol levels in the morning or late at night or indices of 131I-adosterol single-photon emission computed tomography-computed tomography, were significantly and positively associated with the adrenal cortisol content. Twenty-four-hour urinary free cortisol excretion, and not plasma cortisol levels after the 1- or 8-mg overnight dexamethasone suppression test, was significantly and negatively associated with lumbar spine bone density (lumbar spine bone mineral density, ρ = -0.786, P = 0.036; lumbar spine T score, ρ = -0.883, P = 0.009; and lumbar spine Z score, ρ = -0.883, P = 0.009). These results indicate that 24-h urinary free cortisol excretion is best associated with a decrease in bone density via increased adrenal cortisol overproduction and suggest that it could be used as a marker for osteoporosis in these patients.

Cortisol and Phosphate Homeostasis: Cushing's Syndrome Is Associated With Reversible Hypophosphatemia.

ObjectivesThe influence of hypercortisolism on phosphate homeostasis is relatively unknown. A few previous studies have reported on patients with Cushing’s syndrome (CS) with hypophosphatemia in whom serum phosphate normalized after initiation of treatment for CS. We aimed to investigate the prevalence of hypophosphatemia in CS, the association between the degree of hypercortisolism and serum phosphate and the change in serum phosphate after remission of CS. We compared the prevalence of hypophosphatemia in CS with the prevalence in the population-based Rotterdam Study (RS).MethodsPatients diagnosed with CS and treated at the Department of Endocrinology of Erasmus MC in the period of 2002-2020 were included and data was collected on age at diagnosis, sex, serum phosphate, calcium and potassium levels, kidney function and BMI. Using multivariate linear regression, we analyzed the association between 24h urinary free cortisol excretion (UFC) and serum phosphate. Changes in serum phosphate and covariates were tested with a repeated measurement ANOVA, using mean levels of laboratory values for the periods before remission, and 0-14 days and 15-180 days after remission.ResultsHypophosphatemia before treatment was present in 16% of the 99 CS patients with data on serum phosphate, 24h UFC and covariates. In comparison, the prevalence of hypophosphatemia in RS was 2.0-4.2%. Linear regression showed a negative association between the level of UFC and serum phosphate at diagnosis, which remained significant after adjusting for covariates [β -0.002 (95%CI -0.004; -0.0004), p=0.021]. A subset of 24 patients had additional phosphate measurements at 0-14 days and 15-180 days after remission. In this subgroup, serum phosphate significantly increased from 1.03 ± 0.17 mmol/L prior to remission to 1.22 ± 0.25 mmol/L 15-180 days after remission (p = 0.008). BMI decreased after remission [-1.1 kg/m2, (95%CI -2.09 to -0.07), p=0.037]. Other covariates did not show an equivalent change over time.ConclusionIn this retrospective study, we found that 16% of patients with CS had hypophosphatemia. Moreover, serum phosphate was related to the level of cortisoluria and increased after remission of CS. Potential underlying mechanisms related to urinary phosphate excretion and possibly involving FGF23, BMI and parathyroid hormone levels should be further explored.

SUN-397 A Rare Case of Ectopic Adrenocorticotropic Hormone (ACTH) Syndrome Due to Thymic Large Cell Neuroendocrine Carcinoma Presenting as Severe Hypokalemia in a Taiwanese Man

Background Ectopic ACTH syndrome (EAS) represented 5% of Cushing syndrome. EAS is rapid onset, severe, associated with hypercortisolism related life-threatening infections and hypokalemia. In 60% of cases, the tumor is located in intrathoracic organ (lung, bronchus and thymus). Large cell neuroendocrine tumor of thymus secreting ACTH is a high grade, aggressive, poor prognosis and only few case reports in literature. Here we report a case of thymic LCNEC related EAS, which presented as severe hypokalemia, metabolic alkalosis and muscle weakness. Clinical Case A 71-year-old man presented with 12-kg weight loss, progressive generalized weakness and bilateral legs edema for two months.He has medical histories of hypertension and diabetes mellitus. Physical examination revealed generalized weakness without Cushingoid appearance. Laboratory examination showed metabolic alkalosis and severe hypokalemia (1.7 mmol/L, range 3.4-4.7).Hypokalemia work-up showed high morning ACTH 497 pg/mL (normal <46.0), cortisol 87.8 μg/dL (range 3.7-19.4), and normal limits of other pituitary hormones. Cushing syndrome survey showed lack of ACTH/cortisol circadian rhythm, markedly increased 24h urinary free cortisol excretion on two consecutive days ( 21429, 17061 μg). Low-dose and high-dose dexamethasone suppression tests showed non-suppressible. Ovine corticotrophin-releasing hormone stimulation test and desmopressin (DDAVP) test showed ectopic ACTH source. Pituitary MRI revealed negative findings. Bilateral inferior petrosal sinus sampling showed no central-to-peripheral ACTH gradient. Ectopic ACTH syndrome was impressed. Etomidate continuous infusion was prescribed.Fournier gangrene of left scrotum occurred during hospitalization and antibiotic and surgical treatment were given. Chest CT scan revealed tiny lobulated nodule in left lower lung field and soft tissue nodule in prevascular of mediastium. In-111 Octreoscan revealed several nodular lesions with increased In-111 uptake in the paraortic and prevascular region considering neuroendocrine tumor. Anterior mediastinal tumor excision was performed and histopathological report showed large cell neuroendocrine carcinoma of thymus with mitotic count 13/10 HPF and positive immunohistochemical stain for synaptophysin, chromogranin, DD-56, SSTR2 and ACTH. Sandostain LAR injection was administered afterward. Unfortunately, tumor progression with hypercortisolemia occurred after 6 months . External radiation and systemic chemotherapy were performed later. Clinical Lessons Although rare, Cushing syndrome must be considered in differential diagnosis of hypokalemia like our case, a challenging case of EAS. Early diagnosis and treatment was important to avoid life-threatening infections and metabolic complications. Moreover recurrence free survival with Sandostain LAR alone was only 6 months for LCNEC.

Chrousos syndrome: from molecular pathogenesis to therapeutic management.

Primary Generalized Glucocorticoid Resistance or Chrousos syndrome is a rare genetic condition characterized by end-organ insensitivity to glucocorticoids owing to inactivating mutations of the NR3C1 gene. We conducted a systematic review of the published, peer-reviewed medical literature using MEDLINE (1975 through November 2014) to identify original articles and reviews on this topic. The search terms included 'primary generalized glucocorticoid resistance', 'Chrousos syndrome', 'glucocorticoid receptor gene' and 'glucocorticoid receptor mutations'. Only a few cases of Chrousos syndrome have been described to date, ranging from asymptomatic to severe forms of mineralocorticoid and/or androgen excess. All reported cases have been associated with point mutations or deletions in the NR3C1 gene. The tremendous progress of molecular biology has enabled us to apply standard methods to investigate the molecular mechanisms of action of the mutant glucocorticoid receptors (GRs). We and others have identified and functionally characterized novel mutations causing Chrousos syndrome, while structural biology has enabled us to have a better understanding of how conformational changes of the receptor cause glucocorticoid resistance. In this review, we also present our results of the functional characterization of two recently described mutations, and we discuss the diagnostic approaches and therapeutic management of patients with Chrousos syndrome. Although Chrousos syndrome is a rare condition, many clinical cases remain unrecognized for a long time. We recommend determination of the 24-h urinary free cortisol excretion and sequencing of the NR3C1 gene in patients with hyperandrogenism and/or hypertension of unknown origin.

Effects of adverse life events on heart rate variability, cortisol, and C-reactive protein.

Our objective was to assess whether self-reported adverse life events during childhood or over the lifespan are associated with altered activity of the autonomic nervous system (ANS), the hypothalamic-pituitary-adrenal axis (HPA axis), and the immune system. This study was performed in a population-based cohort of 1094 adults aged 33-79years, 46.3% male, average age 53 (SD 11.4). Two waves of data were collected at a 2-year interval, enabling replication of the analyses. Cumulative exposure to adverse life events was assessed by means of the List of Threatening Experiences. ANS function was assessed by spectral analysis of heart rate variability in the high-frequency band (HRV-HF). HPA axis function was assessed by 24-h urinary free cortisol (24-h UFC) excretion. Inflammation was assessed by high-sensitive C-reactive protein (hsCRP). Multiple linear regression analyses did not reveal any significant associations, with the exception of one significant negative association between the lifetime score of adverse life events and HRV-HF β=-0.028; P=0.037 at baseline, but not at follow up 2years later. In a large population-based cohort, adverse life events were not consistently associated with HRV-HF, 24-h UFC or (hsCRP).

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.

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.

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.

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.

Stress‐related Development of Obesity and Cortisol in Women

Chronic exposure to environmental stress may play a role in the development of obesity, through hyperactivation of the hypothalamic-pituitary-adrenocortical (HPA) axis. This study investigated the dynamics of weight gain and the activity of the HPA axis in women who developed weight gain after a stressful event. This is a case-control retrospective study. Two groups of age-matched premenopausal women were selected. One (n = 14) included women characterized by a rapid weight gain following a stressful event, defined as the "stress-related obesity " (SRO) group, and the other (n = 21) women with nonstress-related development of obesity, defined as the "nonstress-related obesity " (NSRO) group. Twenty-one healthy premenopausal women served as normal-weight controls. Baseline hormonal and metabolic parameters, and 24-h urinary free cortisol (UFC/24 h) excretion rate (as a measure of HPA-axis activity) were measured in all women. Anthropometry, diet, and physical activity were similar in both obese groups. Both obese groups showed similar metabolic and hormonal profiles, but the SRO group had UFC/24 h values (41.1 +/- 14.3 microg) significantly higher (P < 0.001) with respect to the NSRO (26.6 +/- 17.6 microg) or the normal-weight control groups (21.1 +/- 9.8 microg). Moreover, time (years) to achieve maximum Deltaweight gain (kg) and the Deltaweight gain/time ratio were significantly shorter (P < 0.001) and higher (P < 0.001) in the SRO group with respect to the NSRO group, respectively. In the SRO group, there was a tendency to a significant correlation between UFC/24 h and the Deltaweight gain/time ratio. These findings support the concept that SRO has distinct pathophysiological mechanisms, including hyperactivity of the HPA axis.

Dysfunction of the hypothalamic-pituitary-adrenal axis and functional somatic symptoms: A longitudinal cohort study in the general population

In persons with functional somatic symptoms (FSS), no conventionally defined organic pathology is apparent. It has been suggested that complex interactions of psychological, physiological, and social factors are involved in the etiology of FSS. One of the physiological mechanisms that may contribute to FSS is the function of the hypothalamic-pituitary-adrenal (HPA)-axis. This study investigates the association of HPA-axis function with cross-sectional presence and prospective development of FSS in the general population. This study was performed in a population-based cohort of 741 male and female adults (mean age 53.1, S.D. 10.9). Participants completed the somatization section of the Composite International Diagnostic Interview (CIDI) in which the presence of 43 FSS is surveyed. In addition to the total number of FSS, bodily system FSS clusters with musculoskeletal, gastrointestinal, cardiorespiratory, and general symptoms were constructed. HPA-axis function was assessed by measuring 24-h urinary free cortisol (24-h UFC) excretion. Follow-up measurements were performed approximately 2 years later. All analyses were adjusted for age, gender, body mass index, smoking, alcohol use, depression, exercise frequency, and urinary volume. Regression analysis detected no cross-sectional association between 24-h UFC excretion and the number of FSS (beta=-0.021, t=-0.521, p=0.603). In addition, 24-h UFC excretion was not associated with any of the bodily system FSS clusters (all p>0.050). Furthermore, 24-h UFC excretion did not predict new-onset FSS in the 2-year follow-up period (beta=0.021, t=0.566, p=0.572). We conclude that this study does not provide evidence for an association between altered HPA-axis function, as indexed by 24-h UFC, and FSS in the general population. We conclude that this study does not provide evidence for an association between altered HPA-axis function, as indexed by 24-h UFC, and FSS in the general population.

Relationship of non‐alcoholic hepatic steatosis to cortisol secretion in diet‐controlled Type 2 diabetic patients

To examine the association of non-alcoholic hepatic steatosis (HS) with the activity of the hypothalamo-pituitary-adrenal (HPA) axis in Type 2 diabetic individuals. The activity of the HPA axis, as measured by 24-h urinary free cortisol (UFC) excretion and serum cortisol levels after 1.0 mg dexamethasone, was measured in 40 diet-controlled, predominantly overweight, Type 2 diabetic patients with non-alcoholic HS and in 40 diabetic patients without HS who were comparable for age, sex and body mass index (BMI). Subjects with non-alcoholic HS had significantly higher 24-h UFC excretion (191 +/- 4 vs. 102 +/- 3 nmol/24 h; P < 0.001) and post-dexamethasone cortisol concentrations (29.1 +/- 2 vs. 14.4 +/- 1 nmol/l; P < 0.001) than those without HS. Patients with HS had significantly higher values for HOMA insulin resistance score, plasma triglycerides and liver enzymes. Age, sex, BMI, waist-hip ratio (WHR), diabetes duration, HbA1c, LDL-cholesterol and blood pressure values were not different between the groups. The differences in urinary and serum cortisol concentrations between the groups remained significant after adjustment for age, sex, BMI, WHR, HOMA insulin resistance score, plasma triglycerides, HbA1c and liver enzymes. In multiple logistic regression analyses, 24-h UFC or serum cortisol concentrations (P < 0.05 and P = 0.02, respectively), along with age and HOMA insulin resistance, predicted the presence of HS, independently of potential confounders. These results demonstrate that non-alcoholic HS is closely associated with a subtle, chronic overactivity of the HPA axis in diet-controlled Type 2 diabetic individuals.

Effects of Mometasone Furoate Dry Powder Inhaler and Beclomethasone Dipropionate Hydrofluoroalkane and Chlorofluorocarbon on the Hypothalamic-Pituitary-Adrenal Axis in Asthmatic Subjects

Mometasone furoate dry powder inhaler (MF-DPI) [400 mug] is an inhaled corticosteroid (ICS) that is effective in the treatment of asthma. MF-DPI has a low potential for suppression of the hypothalamic-pituitary-adrenal (HPA) axis at its clinical dose. The effect of MF-DPI, 400 microg qd, on the HPA axis was compared to that of beclomethasone dipropionate (BDP) using hydrofluoroalkane (HFA) and chlorofluorocarbon (CFC) propellants via metered-dose inhalers (MDIs) twice daily. This randomized, third-party blind, parallel-group study compared the effects of MF-DPI 400 mug one puff qd in the morning (n = 18), HFA-BDP 200 microg two puffs MDI bid (n = 18), and CFC-BDP 400 microg two puffs MDI bid (n = 17) for 14 days on the area under the 24-h serum cortisol concentrations curve (AUC(0-24)) and on total 24-h urinary free cortisol excretion in mild asthmatic subjects. Effects on morning/evening peak expiratory flow (PEF) and on inhaled albuterol use were also assessed. Adverse events that occurred during or > or = 30 days after the study were recorded. The mean decrease from baseline in the serum cortisol concentrations AUC(0-24) in the MF-DPI group was significantly less than in either the HFA-BDP (p = 0.024) or the CFC-BDP (p = 0.011) groups. Decreases in serum cortisol concentrations AUC(0-24) in the two BDP groups did not differ from one another. The MF-DPI group trended toward higher morning and evening PEF than either BDP group. Treatment-associated adverse events were reported by seven subjects in the MF-DPI group, vs one subject in the HFA-BDP and three subjects in the CFC-BDP groups; these were mild, and no subject discontinued treatment due to an adverse event. Fourteen days of treatment with MF-DPI 400 microg qd was associated with a significantly lesser decrease in the serum cortisol concentrations AUC(0-24) compared with HFA-BDP 200 microg MDI or CFC-BDP 400 microg MDI bid.

Endocrinologic and psychologic evaluation of 21-hydroxylase deficiency carriers and matched normal subjects: evidence for physical and/or psychologic vulnerability to stress.

Carriers of congenital adrenal hyperplasia due to 21-hydroxylase (21-OH) deficiency demonstrate increased secretion of cortisol precursors after ACTH stimulation, suggestive of impaired cortisol production and compensatory increases in hypothalamic CRH secretion. Because both cortisol and CRH have behavioral effects, and hypothalamic CRH hypersecretion has been associated with chronic states of anxiety and depression, we performed endocrine and psychologic studies in consecutively admitted parents of patients with classic congenital adrenal hyperplasia due to 21-OH deficiency and parents of children with other chronic endocrine disorders. The number of excluded carriers because of pathologic reasons was higher than that of controls (P = 0.05). Carriers of 21-OH deficiency had a lower mean 24-h urinary free cortisol excretion (26.4 +/- 3.4 vs. 42.7 +/- 6.4 microg/d, P = 0.03) and higher peak ACTH (75.7 +/- 8.1 vs. 54.2 +/- 5.9 pg/ml, P = 0.04) and 17-hydroxyprogesterone (224.2 +/- 28.1 vs. 107.1 +/- 12.5 ng/dl, P < 0.001) concentrations post CRH stimulation than control subjects. Cortisol and androstenedione responses were similar in the two groups. Psychometric assessment performed by administering the State-Anxiety Inventory, Beck Depression Inventory, Profile of Mood States, Symptom Checklist-90R, and Temperament and Character Inventory revealed no differences between the two subject groups. Interestingly, a stepwise multiple linear regression model analysis in each population sample revealed that in carriers of 21-OH deficiency but not in the control subjects, a lower mean 24-h urinary free cortisol excretion and a higher ACTH response to ovine CRH stimulation predicted predisposition to obsessive-compulsive behavior, novelty seeking, reward dependence, and harm avoidance. We conclude that carriers of 21-OH deficiency appear to have mild hypocortisolism and compensatory changes of CRH secretion secondary to lower cortisol concentrations. These changes might predict mild predisposition of these subjects to physical and psychologic pathology, suggesting that larger studies are necessary.

Diminished urinary free cortisol excretion in patients with moderate and severe renal impairment.

The diagnosis of Cushing syndrome remains a challenge for most general clinicians and even endocrinologists. Because the clinical features of Cushing syndrome overlap with those in some healthy obese individuals, biochemical investigations play an important role. The 24-h urinary free cortisol excretion is widely used because of its relatively good sensitivity and specificity (1)(2). Although salivary cortisol has been recommended for screening of Cushing syndrome (3), this assay has not been widely available. Because plasma free cortisol is filtered through the glomeruli with partial tubular reabsorption, the amount of free cortisol appearing in the urine is theoretically dependent on the glomerular filtration rate. However, the high reliability of using 24-h urinary cortisol excretion for the diagnosis of Cushing syndrome implies that urinary excretion of cortisol is relatively unaffected by renal function. In patients with confirmed Cushing disease and severe renal impairment, the urinary free cortisol excretion rate reportedly is normal despite markedly increased plasma cortisol (4)(5)(6). The relationship between glomerular filtration rate and urinary cortisol excretion has not been documented in patients with different degrees of renal impairment. We selected 100 leftover portions of urine samples that had been sent for the measurement of creatinine clearance (CrCl) in the Prince of Wales Hospital of Hong Kong during September, October, and November 2002. All patients were given clear instructions by an experienced nurse to ensure the completeness of 24-h urine collection. Simultaneous serum samples were also received for the …

Steroids in Adult Men With Type 1 Diabetes

To compare steroids and their associations in men with type 1 diabetes and healthy control subjects. We studied 52 adult men with type 1 diabetes without microvascular complications, compared with 53 control subjects matched for age and BMI. Steroids and their binding globulins were assessed in a single venous blood sample and a 24-h urine sample. In adult men with type 1 diabetes, total testosterone did not differ from healthy control subjects, but sex hormone-binding globulin (SHBG) (42 [14-83] vs. 26 [9-117] nmol/l, P < 0.001), cortisol-binding globulin (CBG; 0.87 +/- 0.17 vs. 0.73 +/- 0.10 nmol/l, P < 0.001), and cortisol levels (0.46 +/- 0.16 vs. 0.39 +/- 0.14 nmol/l, P < 0.01) were higher. The free testosterone index was lower (60 [17-139] vs. 82 [24-200], P < 0.001), and the calculated free testosterone was slightly lower (497 [115] vs. 542 [130], P < 0.064), but the pituitary-gonadal axis was not obviously affected in type 1 diabetes. The calculated free serum cortisol was not different, and 24-h urinary free cortisol excretion was lower in type 1 diabetes (121 [42-365] vs. 161 [55-284] nmol/24 h, P < 0.009). Testosterone was mainly associated with SHBG. Estimated portal insulin was a contributor to SHBG in control subjects but not in type 1 diabetes. Cortisol was associated with CBG. HbA(1c) contributed to CBG in men with diabetes but not in control subjects, whereas estimated portal insulin did not contribute. Adult men with fairly controlled type 1 diabetes without complications who are treated with subcutaneous insulin have a tendency to hypogonadism, as reflected by lower free testosterone levels in the presence of similar total testosterone levels and higher SHBG levels.

Altered hypothalamic–pituitary–adrenocortical function in rhesus monkeys ( Macaca mulatta) with self-injurious behavior

Individually housed rhesus monkeys sometimes spontaneously develop self-injurious behavior (SIB) in the form of self-directed biting that, on occasion, results in severe tissue damage and mutilation. We previously demonstrated lower levels of plasma cortisol in rhesus monkeys with a history of self-wounding (SW) when compared to non-wounders (NW). Furthermore, cortisol levels were negatively correlated with rates of self-directed biting. The present study was designed to further characterize the relationships between hypothalamic–pituitary–adrenocortical (HPA) activity, self-wounding, and self-directed biting. Basal 24-h urinary free cortisol excretion, the urinary free cortisol response to a low dose of dexamethasone, and the plasma cortisol response to ACTH were examined in 24 individually housed rhesus monkeys, based on wounding history, i.e. the presence/absence of a veterinary record of self-wounding, and current rates of self-directed biting, i.e. the median split of self-directed biting frequency (independent of wounding status). There were no reliable group differences on any of the physiological measures when analyzed by wounding history. However, the plasma cortisol response 30 min post-ACTH stimulation was significantly correlated with wounding recency, such that lower responsivity was associated with more recent wounding episodes. When the results were analyzed on the basis of biting frequency, high frequency biters (HFB) compared to low frequency biters (LFB) showed decreased HPA negative feedback sensitivity to dexamethasone and a trend towards an attenuated plasma cortisol response to ACTH stimulation. These findings suggest that SIB in socially reared monkeys is associated with complex changes in HPA axis function that are related to the expression of the pathology, i.e. self-directed biting, and to the recency of a wounding episode. It remains to be determined whether humans who exhibit SIB show similar alterations in HPA function.