Urinary Cortisol Excretion Rate Research Articles

Low Impact of Urinary Cortisol in the Assessment of Hydrocortisone Replacement Therapy.

Hydrocortisone replacement therapy is a cornerstone in the treatment of adrenal insufficiency (AI). While urinary cortisol has been used as a diagnostic tool for AI, it remains unclear whether it is a useful parameter to monitor hydrocortisone replacement therapy. Aim of this study was to evaluate possible differences in cortisol metabolism between adrenal insufficient patients and healthy subjects and to assess the value of urinary cortisol in AI management. In a case-control study, urinary cortisol excretion was determined in 14 patients with primary and secondary AI receiving hydrocortisone infusions from midnight to 8:00 AM. Results were correlated with serum cortisol levels and compared to urinary values obtained from 53 healthy volunteers. Urinary cortisol excretion in healthy subjects was 14.0±7.8 μg/8 h (range: 0.24-35.4), levels did not differ between 3 groups aged 20-34 years, 35-49 years, and ≥50 years. Patients with AI receiving hydrocortisone infusions demonstrated significantly higher rates of urinary cortisol excretion (51.6±37.8 μg/8 h; range 17.1-120.0, p<0.001); the values correlated with serum cortisol levels (r(2)=0.98). Of interest, patients with secondary AI showed significantly higher serum cortisol levels after hydrocortisone infusion than those with primary AI, conceivably due to residual adrenal function. In conclusion, we showed that: (i) there is a wide inter-individual variability in urinary cortisol excretion rates; (ii) cortisol metabolism in adrenal insufficient patients differs when compared to controls; (iii) there is a strong correlation between urinary and serum cortisol levels; and (iv) urinary cortisol levels despite their variability may help to discriminate between secondary and primary adrenal insufficiency.

An Unusual Presentation of Pediatric Cushing Disease: Diabetic Ketoacidosis

<h3>ABSTRACT</h3> <b>Objective:</b> Cushing syndrome (CS) is very rare in pediatric patients. The major cause of endogenous CS is Cushing disease (CD), which is due to excessive adreno-corticotropic hormone (ACTH) secretion from pituitary cells. CS that presented with diabetic ketoacidosis (DKA) has rarely been reported in adults. However, to our knowledge, there is no report of a pediatric case of CD presenting with DKA. <b>Methods:</b> A case report and literature review. <b>Results:</b> A 16-year-old female suffering from polyuria and polydipsia for 2 weeks was admitted with amenorrhea and oral moniliasis. Due to her hyperglycemia, ketonuria, glucosuria, and metabolic acidosis on arterial blood gas, she was diagnosed with DKA. Oral moniliasis, acanthosis nigricans, moon face, central obesity, and striae were detected on physical examination. Based on the results of overnight and low-dose dexamethasone suppression tests, the patient was diagnosed with CS. In a high-dose dexa-methasone suppression test (HDDST), her urinary free cortisol (UFC) excretion rate was suppressed by 73.3%. Brain magnetic resonance imaging (MRI) revealed a 4-mm pituitary microadenoma. Because serum cortisol and 24-hour UFC levels were not sufficiently suppressed by the HDDST and the diameter of adenoma in the MRI was <5 mm, bilateral inferior petrosal sinus (BIPS) sampling was performed. A diagnosis of CD was confirmed by determining a high central/peripheral ACTH ratio (12.88, normal <3) <b>Conclusion:</b> Although very rare in childhood, CS should be considered in pediatric patients with obesity, acanthosis nigricans, moniliasis, and striae. DKA may be the presenting clinical feature in patients with impaired glucose metabolism. <b>Abbreviations: ACTH</b> adrenocorticotropic hormone <b>BIPS</b> bilateral inferior petrosal sinus <b>C</b> cholesterol <b>CD</b> Cushing disease <b>CS</b> Cushing syndrome <b>DKA</b> diabetic ketoacidosis <b>DM</b> diabetes mellitus <b>HDDST</b> high-dose dexamethasone suppression test <b>MRI</b> magnetic resonance imaging <b>TSS</b> transsphenoidal surgery <b>UFC</b> urinary free cortisol

Combined food intake and exercise unmask different hormonal responses in lean and obese children

Our purpose was to investigate the effect of obesity in prepubertal children on the hormonal response to exercise performed under different conditions of nutrient availability. Prepubertal obese (age, 10.3 ± 1.8 years; %body fat, 36.1 ± 6.1; n = 9) and lean (age, 9.2 ± 1.6 years; %body fat, 22.2 ± 4.1; n = 7) children completed 2 experimental sessions in which they performed a 30 min of cycling exercise at 50% of their maximal aerobic power either 1 h (T1h) or 3 h (T3h) after a standardized breakfast. Plasma insulin-like growth factor 1 (IGF-1), IGF binding protein 1 (IGFBP-1), and IGFBP-3 levels were assessed at baseline and after exercise. Urine was collected during the sessions, and catecholamine and glucocorticoid excretions were analyzed. A significant time effect was observed for IGFBP-1; postexercise levels decreased in lean and obese children (p ≤ 0.001). IGF-1 and IGFBP-3 were not affected by obesity or food intake combined with exercise. In lean children, urinary excretion rates of epinephrine, norepinephrine, cortisol, and cortisone were significantly higher during the sessions than during the overnight resting period; in obese children, only epinephrine in T1h was significantly increased (p ≤ 0.05 for all). Our study indicates that the activity of the hypothalamic-pituitary-adrenal axis and sympathetic adrenal medullary axis was similar in lean and obese children, based on measurement under resting conditions, but response to exercise performed in postprandial conditions was altered in obese children for both axes. In addition, exercise in the postprandial state elicited a decrease in IGFBP-1 plasma levels, whereas IGF-1 and IGFBP-3 levels were not significantly altered.

Luteinizing hormone correlates with adrenal function in postmenopausal women

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

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

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

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

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

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.

Administration of glycyrrhetinic acid: significant correlation between serum levels and the cortisol/cortisone-ratio in serum and urine.

In vitro, cortisol and aldosterone have a similar affinity to the mineralocorticoid receptor. The 11beta-hydroxysteroid dehydrogenase catalyzes the interconversion of cortisol to its inactive 11-oxo-metabolite cortisone. This interconversion is responsible for the in vivo specificity of the mineralocorticoid receptor. A defect of this enzyme leads to a pseudohyperaldosteronism with hypertension and hypokalemia, the so-called apparent mineralocorticoid excess syndrome. Glycyrrhetinic acid, a compound of licorice, also leads to pseudohyperaldosteronism by an inhibition of the 11beta-hydroxysteroid dehydrogenase. We studied the pharmacokinetics of glycyrrhetinic acid and its effect on the 11beta-hydroxysteroid dehydrogenase. Ten healthy students, aged 24 to 38 years, were included in the study. On the first day 500 mg glycyrrhetinic acid were given orally at 08.00 h. Blood and urine samples were taken prior to and 2, 4, 7, 10 and 24 hours after ingestion of glycyrrhetinic acid. We measured the serum level of cortisol, cortisone and glycyrrhetinic acid and the urinary excretion rates of cortisol, cortisone and their 20-dihydrometabolites. For determination of glycyrrhetinic acid and steroid levels we used a fully automated liquid chromatographic analyzer which allows the highly specific and simultaneous determination of steroid profiles even in the matrix of urine. Ratios of the 11-hydroxy- and 11-oxo-metabolites were calculated and correlated to the serum level of glycyrrhetinic acid. We found a significant correlation of the steroid-ratios to the serum levels of glycyrrhetinic acid. Coefficients of correlation were 0.9873, 0.7812, 0.7396 and 0.5844 between the serum level of glycyrrhetinic acid and the cortisol/cortisone-ratio in serum (p < 0.0001), the cortisol/cortisone-ratio in urine (p = 0.0279), the 20alpha-dihydrocortisol/20alpha-dihydrocortisone-ratio in urine (p = 0.0119) and the 20beta-dihydrocortisol/20beta-dihydrocortisone-ratio in urine (p = 0.0419), respectively. We conclude that the ratios of cortisol to cortisone and of the 20-dihydrometabolites of cortisol to the 20-dihydrometabolites of cortisone provide a simple noninvasive tool for monitoring the in-vivo activity of the 11beta-hydroxysteroid dehydrogenase.

Urinary free cortisone, but not cortisol, is associated with urine volume in severe obesity

Background High urine volume enhances urinary free cortisol (UFF) and cortisone (UFE) excretion rates in normal-weight adults and children. Renal excretion rates of glucocorticoids (GC) and their metabolites are frequently altered in obesity. The aim of the present study was to investigate whether UFF and UFE excretion is also affected by urine volume in severely obese subjects. Experimental In 24-h urine samples of 59 extremely obese subjects (mean BMI 45.3 ± 8.9 kg/m 2) and 20 healthy lean subjects (BMI 22.1 ± 1.8 kg/m 2), UFF and UFE, tetrahydrocortisol (THF), 5α-tetrahydrocortisol (5α-THF), and tetrahydrocortisone (THE) were quantified by RIA. The sum of THF, 5α-THF, and THE (GC3), the three major GC metabolites, reflects daily cortisol secretion. 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity was assessed by the ratio UFE/UFF. Daily GC excretion rates were corrected for urine creatinine and adjusted for gender and body weight. Results In extremely obese subjects, urine volume was significantly associated with creatinine-corrected UFE and 11β-HSD2 activity after adjustment for gender and BMI ( r = 0.47, p = 0.0002 and r = 0.31, p = 0.02, respectively). However, urine volume was not associated with creatinine-corrected UFF and GC3 ( p = 0.4 and p = 0.6, respectively). In lean controls, urine volume was significantly associated with creatinine-corrected UFE and UFF ( r = 0.58, p = 0.01 and r = 0.55, p = 0.02, respectively), whereas urine volume was not associated with 11β-HSD2 activity after appropriate adjustment ( p = 0.3). Conclusions In severe obesity, in contrast to normal weight, renal excretion of UFE, but not of UFF is affected by fluid intake. This discrepancy may be due to the increased renal 11β-HSD2 activity in obesity.

Breast Cancer-Specific Intrusions are Associated with Increased Cortisol Responses to Daily Life Stressors in Healthy Women Without Personal or Family Histories of Breast Cancer

Studies indicate that women fear breast cancer more than any other disease and that women's levels of breast cancer-specific intrusions are related to their perceived risk of breast cancer. Here, we explore possible biological consequences of higher breast cancer risk perceptions and intrusions in healthy women without personal or family histories of the disease. We hypothesized that women with higher perceived risk would have more intrusions about breast cancer, which would constitute a background stressor sufficient to increase hypothalamus-pituitary-adrenal axis (HPA) responsivity to daily stress. HPA responses to an ordinary life stressor (work) were assessed in 141 employed women (age = 37.2+/-9.2) without personal or family histories of breast cancer. Urinary cortisol excretion rates were assessed with timed sample collections at work, home, and during sleep. Repeated measures ANOVA revealed a significant Group by Time interaction with higher work cortisol levels in women with breast cancer-specific intrusions compared to women without intrusions (p < 0.02). Regression analyses revealed a significant association between risk perceptions and intrusions (p < 0.001). Regression analysis with intrusions and risk perceptions predicting work cortisol indicated a significant contribution of intrusions (p < 0.04), but not risk perceptions (p = 0.53). Overestimation of breast cancer risk is associated with higher levels of breast cancer-specific intrusions that can result in increased cortisol responsivity to daily stressors. This heightened responsivity could have long-term negative health implications.

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.

Urinary Steroid Excretion Rates in Acromegaly

Using gas chromatography/mass spectrometry, urinary excretion rates of cortisol, cortisone and of various steroid metabolites were determined in 35 acromegalic patients (18 men, 17 women) and in 45 age- and weight-matched controls. The ratio of excreted cortisol/cortisone was similar in acromegalics (0.75 ± 0.20) and in controls (0.75 ± 0.24). Hence, the preponderance of the main cortisone-derived metabolite, tetrahydrocortisone, over the main metabolites of cortisol (tetrahydrocortisol and allotetrahydrocortisol; p

Studies on the origin of circulating 18-hydroxycortisol and 18-oxocortisol in normal human subjects.

18-Hydroxycortisol (18-OHF) and 18-oxocortisol (18-oxoF) are derivatives of cortisol found in primary aldosteronism but whose origin and regulation in normal subjects are uncertain. 18-OHF can be synthesized by zona fasciculata 11-beta hydroxylase; 18-oxoF can only be produced by zona glomerulosa aldosterone synthase (AS). Stably transfected cell lines expressing either CYP11B1 (11beta-hydroxylase) or CYP11B2 (AS) were incubated with cortisol and other substrates over a range of concentrations. Both enzymes could synthesize 18-OHF from cortisol, but only AS could synthesize 18-oxoF. AS was more efficient than 11beta-hydroxylase at 18-hydroxylation. The apparent Michaelis-Menten constant (K(m)) of AS for cortisol was estimated to be 2.6 microm. In five patients with adrenal insufficiency maintained on hydrocortisone, urinary free cortisol and cortisone levels were high; 18-oxoF was detectable in all patients and 18-OHF in three. It is likely that the 18-oxygenated steroids were synthesized from circulating cortisol, either in the zona glomerulosa or at extraadrenal sites. In eight male volunteers, dexamethasone treatment decreased urinary excretion rates of free cortisol, cortisone, 18-OHF, and 18-oxoF, confirming dependence of 18-oxygenated steroid levels on cortisol availability. In both groups, hydrocortisone administration resulted in detectable levels of 18-OHF and raised levels of 18-oxoF. There was close correlation between 18-oxoF and cortisol excretion during hydrocortisone administration in normal subjects (r = 0.86; P < 0.001). These data show, for the first time, that 18-OHF and 18-oxoF can be synthesized from circulating cortisol. The close correlation between 18-oxoF and cortisol suggests that 18-oxoF is normally produced by the action of AS using circulating cortisol as a substrate. Although 18OHF can be synthesized using circulating cortisol as substrate, our data suggest this is normally produced in the zona fasciculata by 11beta-hydroxylase from locally available cortisol.

Response of the hypothalamic-pituitary-adrenal axis to small dose arginine-vasopressin and daily urinary free cortisol before and after alprazolam pre-treatment differs in obesity

Arginine vasopressin (AVP) has a central role in the response of the hypothalamic-pituitary-adrenal (HPA) axis to stress conditions. A low dose of AVP has been shown to have a modest, but significant effect on ACTH response in normal weight subjects. The aim of this study was to test the response of the HPA axis in obese subjects in order to assess eventual primary neuroendocrine alterations, previously demonstrated by using AVP combined with corticotropin releasing hormone (CRH). In addition, given its central inhibitory action on the HPA axis, we investigated whether the suppressive capacity of alprazolam (APZ) pretreatment on the hormone response to low-dose AVP challenge and daily urinary free cortisol (UFC) excretion rate may be altered in the presence of obesity. Fifteen overweight or obese women and eight normal-weight controls randomly underwent two low-dose AVP tests (0.3 UI iv bolus), one without (AVP test) and the other preceded by APZ administration (0.5 mg at midnight and 0.5 mg 90 min before the test in the morning at 08:30 h) (APZ/AVP test). Blood samples for ACTH and cortisol assay were obtained at baseline and throughout each test. The day before each test, 24h-UFC/ creatinine was also mea-sured. Basal ACTH levels were similar in the two groups, whereas cortisol concentrations were significantly lower in the overweight/obese group. Overweight/obese women had higher ACTH and cortisol responses to the AVP tests and significantly greater hormone inhibition after APZ than controls. In both groups, AVP-induced delta-peak cortisol values before and after APZ pre-treatment were significantly correlated. Body fat distribution had no effect on the HPA axis response to AVP either before or after APZ. Moreover, APZ decreased 24h-UFC/creatinine values unsignificantly in controls and by approximately 50% in the overweight/obese subjects. These changes were unrelated to the cortisol response to the AVP test before and after APZ pretreatment. On the other hand, percent changes of 24h-UFC/creatinine after APZ were negatively related to the body mass index (BMI) but positively with waist circumference values, which indicates that the abdominal obesity phenotype may counteract the 24 h-UFC/creatinine that would be expected on the basis of BMI values. Our data further support the concept that in women obesity may represent a condition of hyperresponsiveness or hypersensitivity of the HPA axis to neuroendocrine stimuli, which appear to be independent of feedback control. In addition, the data on the inhibiting capacity of APZ on UFC excretion confirm that the alterations of the HPA axis in obesity is particularly evident in the abdominal phenotype.

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 …

Synergy between angiotensin and aldosterone in evoking sodium appetite in baboons.

The synergy between ANG II and aldosterone (Aldo) in the induction of salt appetite, extensively studied in rats, has been tested in baboons. ANG II was infused intracerebroventricularly at 0.5 or 1.0 microg/h; Aldo was infused subcutaneously at 20 microg/h. Separate infusions over 7 days had no significant effect on the daily intake of 300 mM NaCl. Concurrent infusions, however, increased daily NaCl intake approximately 10-fold and daily water intake approximately 2.5-fold. In addition, the combined infusions caused 1) a reduction in daily food intake, 2) changes in blood composition indicative of increased vasopressin release, and 3) changes of urinary excretion rates of cortisol and Aldo indicative of increased ACTH release. Arterial blood pressure, measured in two baboons, rose during concurrent ANG II and Aldo treatment. These results indicate a potent synergy between central ANG II and peripheral Aldo in stimulating salt appetite in baboons. At the same time, other ANG II-specific brain mechanisms concerned with water intake, food intake, vasopressin release, ACTH release, and blood pressure regulation appear to have been activated by the same type of synergy. These central enhancement processes have never been previously demonstrated in primates.

Impaired urinary cortisol excretion and early cardiopulmonary dysfunction in immature baboons.

Early adrenal insufficiency is associated with cardiopulmonary dysfunction in immature infants. Isolated cortisol levels and ACTH stimulation testing may not adequately show ontogeny of postnatal cortisol secretion nor identify at risk infants. Our objectives were 1) to determine postnatal urinary cortisol excretion rate (UCER) from birth to 14 d in immature baboons and 2) to evaluate the relation between UCER and cardiac performance. UCER was assessed via 6-h blocked urine collections from birth to 336 h of age in twenty-one 125-d gestation (term = 185 d) baboons. Urinary cortisol was measured by RIA. Cardiopulmonary parameters were averaged over the same time periods as urine collection. Serial two-dimensional echocardiograms were performed. After 24-h age, a subgroup (n = 8) received up to four doses (0.5-1.0 mg/kg each) of hydrocortisone for refractory hypotension. UCER significantly increased from 0 to 6 h through 66 to 72 h age for non-cortisol-treated infants. Significantly reduced UCER patterns between birth and 24 h were found for animals subsequently requiring cortisol treatment. Cortisol-treated infants had lower mean blood pressure, worse metabolic acidosis, increased fluid needs, and impaired left ventricular function between 12 and 48 h of age. No group differences were found in gas exchange or ventilator support. We conclude that adrenal cortisol secretion significantly improves over the initial 72 h of life in the 125-d immature baboon. Failure to increase UCER after 12-24 h of life correlated with poor cardiovascular function that improved with hydrocortisone therapy. Adrenal hypofunction in the immature baboon is similar to the very preterm human and could serve as a model for future postnatal investigations.

Parathyroid hormone suppression in spinal cord injury patients is associated with the degree of neurologic impairment and not the level of injury

Objective: To demonstrate that after spinal cord injury (SCI) suppression of the parathyroid-vitamin D axis is associated with the degree of neurologic impairment and not the level of injury. Design: A retrospective analysis of clinical and biochemical data obtained from hospital records of patients with SCI compared to a control group of patients with traumatic brain injury (TBI). Setting: The inpatient rehabilitation unit of a tertiary care hospital. Subjects: The medical records of 82 consecutive admissions to the rehabilitation unit with a diagnosis of SCI or TBI were reviewed. Patients with SCI were classified by the American Spinal Injury Association (ASIA) impairment scale and then grouped based on the completeness and level of injury. Main Outcome Measure: Comparisons of serum parathyroid hormone (PTH), 25-hydroxyvitamin D, and 1,25-dihydroxy-vitamin D (1,25-D) were planned. Multiple comparisons were performed for total and ionized serum calcium levels, serum phosphorus levels, and 24-hour urinary calcium excretion rates to reflect changes in mineral homeostasis. Multiple comparisons were also performed for serum albumin, prolactin, thyroid function tests, and AM cortisol levels, as well as 24-hour urinary urea nitrogen and cortisol excretion rates to reflect metabolic responses to stress. Results: Patients with SCI had significant suppression in PTH ( p < .000009) and 1,25-D ( p < .02) levels with elevated phosphorus ( p < 0.03) and prolactin ( p < .03) levels compared to patients with TBI. Also, more patients with SCI were hypoalbuminemic ( p < .003) than patients with TBI. Patients with complete SCI (ASIA A) had more suppressed PTH ( p < .03) and higher urinary urea nitrogen ( p < .05) levels than SCI patients with incomplete injuries (ASIA B-D). Patients with complete, but not incomplete, SCI had lower albumin levels than patients with TBI ( p < .05). These differences were not found between patients with tetraplegic and paraplegic SCI. ASIA motor scores did not correlate with any of the measured parameters but when used as a covariate did abolish differences in PTH and 1,25-D among the study groups by ANOVA. Conclusion: In patients with SCI, the degree of neurologic impairment, and not the level of injury, is associated with PTH suppression and markers of metabolic stress.

Primary Pigmented Nodular Adrenocortical Disease: Reevaluation of a Patient with Carney Complex 27 Years after Unilateral Adrenalectomy

A 45-yr-old man with primary pigmented nodular adrenocortical disease (PPNAD) is described. This patient underwent unilateral adrenalectomy for ACTH-independent Cushing’s syndrome (CS) in 1969. Although his daily urinary free cortisol (UFC) excretion rate normalized, and the major clinical manifestations of CS subsided, loss of a circadian cortisol rhythm persisted after surgery. Twenty-seven years later, the patient presented again with short stature, severe osteopenia, skeletal deformities, thinning of the skin, and myopathy(Cline Endocrinol Metab 82: 1274–1278, 1997).

Epinephrine and cortisol responses to work: A test of the models of Frankenhaeuser and Karasek

Both Frankenhaeuser and Karasek have put forward models describing how job demand and control influence epinephrine and cortisol levels. These models were tested in a sample of 53 women and 51 men in a variety of occupations. They were studied over one rest day and two working days. Subjects reported their perceived demand and control and their mood on each day, as well as providing urine for assessment of urinary excretion rates of epinephrine and cortisol. In men, but not women, epinephrine levels were higher on the working days than on the rest day, and demand was found to covary positively with epinephrine, supporting Frankenhaeuser's model with respect to epinephrine variation in men. However, cortisol levels were not elevated on working days compared to the rest day, and no relationship between job control and cortisol was seen which is in contradiction of Frankenhaeuser's model with respect to cortisol variation. There was some suggestion that demand was most strongly associated with elevated epinephrine in men when job control was low in accordance with Karasek's model, but there was no evidence for such an effect with respect to cortisol.