Circadian cortisol secretory rhythms in Cushing's disease.

Plasma cortisol was measured at 20-min intervals for 24 h in eight patients with Cushing's disease and ACTH-secreting pituitary tumors. The 24-h mean (+/- SD) cortisol level was 25.6 +/- 11.3 microgram/dl (range, 15.5--40.6), which was significantly higher than the level of normal control subjects (P less than 0.01). The 24-h mean ACTH level varied between 22--107 pg/ml, with a mean +/- SD of 63.4 +/- 27.2. The mean ACTH level was higher than that of the control subjects but the difference was not statistically significant. The 24-h cortisol secretory pattern was characterized by an absence of the normal circadian variation and a failure of the plasma cortisol level to fall to less than 2 microgram/dl between 2300--0300 h. The coefficient of variation, an expression of the amplitude of cortisol secretory episodes, was significantly decreased in patients with Cushing's disease compared to normal control subjects; there was no significant difference in the number of cortisol secretory episodes in the patients vs. control subjects. Three of the patients were restudied after successful resection of their ACTH-secreting pituitary tumors. Two showed normalization of their 24-h circadian cortisol patterns and normal metyrapone responses. In the third, the 24-h mean cortisol level was normal, but the circadian cortisol rhythm remained abnormal. This patient had diminished ACTH reserve, demonstrated by a subnormal response to metyrapone. Additional studies will be required to determine if normalization of the circadian cortisol rhythm occurs in all patients with Cushing's disease who are cured after transsphenoidal microsurgery and who also show normal ACTH reserve.     

Cushing's syndrome due to adrenal adenoma with persistent diurnal cortisol secretory rhythm.

A 41-yr-old female with presumed Cushing's syndrome was found to have a diurnal cortisol rhythm characterized by low values of 8:00 a.m. and consistently high values at 4:00 p.m. and midnight. Hourly sampling of plasma cortisol over 24 hr confirmed this rhythm, as did measurement of urinary free cortisols in samples collected every 6 hr over 24 hr. Hypercortisolemia was not suppressed by 2 mg of dexamethasone given every 6 hr for 24 hr. The adrenal tissue was responsive to ACTH. Iodocholesterol scanning revealed unilateral activity, and the patient's syndrome was cured by resection of an adrenal adenoma. In this patient a diurnal cortisol secretory pattern was present due to the secretory activity of the adenoma. The cause of the abnormal but persistent diurnal pattern is unknown.     

Size at birth, the metabolic syndrome and 24-h salivary cortisol profile

OBJECTIVE: Individual variation in hypothalamic-pituitary-adrenal axis (HPAA) function has been suggested to be important in linking small size at birth with adult cardiovascular disease and its risk factors, in particular the metabolic syndrome. Human studies have, however, so far only been performed in clinic settings, and their results have not been consistent. Our aim was to assess whether HPAA activity in everyday living circumstances is related to the metabolic syndrome and size at birth. DESIGN: Clinical birth cohort study. SUBJECTS: A total of 151 women born between 1924 and 1933 in Helsinki, Finland, with measurements at birth recorded. The subjects had previously undergone detailed clinical examinations including fasting cortisol measurement and 1 micro g ACTH1-24 and overnight 0.25 mg dexamethasone tests. MEASUREMENTS: Salivary cortisol concentration was measured during a normal 24-h period: at awakening, 15 and 30 min thereafter, at 12.00 h, 17.00 h and 22.00 h and the following morning. In addition, the following summary variables were calculated: awakening response (mean of the three awakening measurements), mean of all individual measurements, and mean, SD and contrast (a measure of blunted diurnal variability, calculated as mean of morning minus mean of 1200, 1700 and 2200) of all individual z scores. RESULTS: Salivary cortisol awakening response was correlated with serum fasting (r = 0.17; P = 0.04), ACTH1-24-stimulated (r = 0.32; P < 0.0001), and dexamethasone-suppressed (r = 0.29; P = 0.0004) cortisol concentrations. However, no salivary cortisol measurement was associated with any component of the metabolic syndrome (waist circumference, serum triglyceride, HDL cholesterol or glucose concentration, or blood pressure). Moreover, no correlation was observed between salivary cortisol and weight, length, ponderal index, or gestational age at birth. CONCLUSIONS: In elderly women, cortisol concentrations in an everyday environment do not appear to be associated with the metabolic syndrome or size at birth. We propose that detecting relationships between HPAA function, prenatal events and adult disease might require a test involving HPAA stimulation.     

The effect of dexamethasone on the 24-hour profiles of adrenocorticotropin and cortisol in Cushing's syndrome

ACTH and cortisol are normally secreted episodically rather than continuously. This characteristic of episodic secretion is preserved in patients with Cushing's syndrome. To determine whether exogenous glucocorticoids modulate this pulsatility and to study its possible etiological implications, we obtained 24-h plasma cortisol profiles in seven patients with Cushing's syndrome (five Cushing's disease, one adrenal adenoma, and one bilateral adrenal cortical macronodular hyperplasia) before and during suppression with various doses of dexamethasone [low (0.5 mg, every 6 h), high (2 mg, every 6 h), and very high (4 mg, every 6 h)]. Simultaneous 24-h plasma ACTH profiles were obtained in two patients with Cushing's disease. Blood was drawn at 30-min intervals for 25 h. Individual profiles were analyzed to determine the 24-h mean level, the presence of a circadian component and its amplitude, and the number and magnitude of significant secretory pulses over the 24-h span. The concordance between significant ACTH and cortisol pulses also was quantified. Baseline values in patients were compared to those in seven normal subjects. Under basal conditions, the 24-h mean cortisol level was 3- to 4-fold higher than normal in all patients with Cushing's syndrome. In contrast, the basal 24-h mean ACTH level was normal in one, and slightly elevated in the other of the two patients with Cushing's disease in whom plasma ACTH concentrations were measured. However, in contrast to the normal subjects, all ACTH values were above 10 pg/ml even during the period of minimal secretion. Basal circadian variation in adrenocortical activity, albeit of reduced amplitude, was found in four of five patients with Cushing's disease; it was absent in the patient with adrenal adenoma. Low dose dexamethasone reduced the 24-h mean cortisol level and increased the amplitude of the circadian rhythm, unmasking a diurnal rhythm in the single patient with Cushing's disease in whom no significant circadian periodicity was present in the basal condition. This effect was further increased with the high dose of dexamethasone, which concomitantly reduced the number and increments of the secretory pulses. A lesser effect was found in the patient with bilateral nodular hyperplasia, and no effect was seen in the patient with adrenal adenoma. ACTH pulsatility, but not diurnal rhythm, also was dampened by dexamethasone. Reduction in the magnitude, but not the number, of ACTH secretory pulses by dexamethasone produced a reduced concordance ratio of ACTH with cortisol pulses of 0.39, compared to 0.64 in the basal state.(ABSTRACT TRUNCATED AT 400 WORDS)     

Irregular and frequent cortisol secretory episodes with preserved diurnal rhythmicity in primary adrenal Cushing's syndrome

To evaluate the pathophysiology of altered cortisol secretion in patients with primary adrenal hypercortisolism, cortisol secretion was investigated in 12 patients, seven with a unilateral adenoma and five with ACTH-independent macronodular adrenal hyperplasia compared with age- and gender-matched controls and with patients with pituitary-dependent hypercortisolism. Pulsatile secretion was increased 2-fold (P = 0.04), attributable to increased event frequency (P = 0.002). All patients showed a significant diurnal rhythm with a delay in phase shift of 3 h (P = 0.01). Approximate entropy ratio, a feedback-sensitive measure, was increased compared with controls (P = 0.00003) but similar to that of pituitary-dependent hypercortisolism (P = 0.77), denoting loss of autoregulation. Cortisol burst-mass tended to be smaller in patients with ACTH-independent macronodular adrenal hyperplasia than in unilateral adenoma (P = 0.06). In conclusion, increased cortisol secretion in patients with primary adrenal Cushing's syndrome is caused by amplified pulsatile secretion via event frequency modulation. We speculate that partial preservation of secretory regularity and diurnal rhythmicity point to incomplete autonomy of these tumors.     

Plasma cortisol profiles in Cushing's syndrome.

Plasma cortisol profiles were studied by the frequent sampling method in 5 patients with Cushing's disease (CD), 7 patients with Cushing's syndrome due to adrenocortical adenoma (AA), and one patient with bronchogenic carcinoma. Plasma ACTH was measured by radioimmunoassay at 10 min intervals in 2 of the subjects. In CD, there was distinct episodic secretion of cortisol and ACTH; the coefficients of variation about the mean plasma cortisol concentration ranged from 24 to 27%; plasma ACTH ranged from zero to 455 pg/ml with a mean of 94 pg/ml. In AA, the tumour secreted cortisol at a constant rate with little fluctuation; the coefficients of variation of plasma cortisol concentration ranged from 8 to 14%; plasma concentrations of ACTH were always near zero. In the patient with bronchogenic carcinoma, the coefficient of variation of cortisol was 14%. These results were apparent even in profiles of plasma cortisol concentrations measured over only a 6 h period. It is concluded that characteristics of plasma cortisol and ACTH secretory patterns are helpful in differentiating Cushing's syndrome of differing aetiology.     

唾液皮质醇诊断库欣综合征的临床意义

近年来多项研究显示唾液皮质醇对于诊断库欣综合征是一个敏感和方便的筛查指标。午夜唾液皮质醇的测定可明确诊断大部分的库欣综合征,排除假性库欣综合征;结合小剂量地塞米松唾液皮质醇抑制试验能提高诊断敏感性。唾液皮质醇的稳定性尤其适用于周期性库欣综合征的诊断和随访。     

Dissociation of adrenal androgen and cortisol secretion in Cushing's syndrome

OBJECTIVES While ACTH may modulate adrenal androgen production, there is evidence that other factors are required. Cushing's disease and ectopic ACTH secretion provide a little utilized opportunity to examine adrenal androgen levels in conditions of ACTH excess. We have compared plasma cortisol values with plasma levels of androstenedione, dehydroeplandrosterone (DHEA), DHEA-sulphate (DHEAS), testosterone and an Index of free testosterone, the testosterone/sex hormone binding globulin ratio, prior to treatment in patients with Cushing's syndrome. PATIENTS AND MEASUREMENTS Plasma from 15 adult patients with Cushing's disease and three adults with the ectopic ACTH syndrome was obtained prior to treatment and submitted to specific immunoassays for the measurement of the above steroids. RESULTS Plasma cortisol values of 15 patients with Cushing's disease (range 326–1140 nmol/l, normal range 190–690 nmol/l) were elevated in 9; In contrast, plasma androstenedione (4·1–11·3 nmol/l, normal range, men 2·1–7·7, women 3·3–9·9 nmol/l) was elevated in only two patients, plasma DHEAS (3·3–17·8 μmol/l, normal range, men 4·5–18·4, women 3·5–11·8 μmol/l) was elevated in only 4 patients and plasma DHEA (4·8–45·2 nmol/l, normal range 11–48 nmol/l) was normal or low in all 15 patients. Plasma androstenedione was markedly elevated (74 nmol/l) in one of three patients with ectopic ACTH syndrome, moderately elevated in another, and normal in the third patient. In contrast, plasma DHEA and DHEAS levels were suppressed in the patient with the highest androstenedione level and low or normal in the other two patients. CONCLUSIONS These data suggest that ACTH alone does not control adrenal androgen Secretion. The data also suggest that variability in the processing of proopiomelanocortin (the precursor of ACTH and related peptides) occurring in Cushing's disease and ectopic ACTH syndrome may account for differences in the relation of cortisol to androgens observed between the disorders and when compared to that in normal subjects.     

Late-night salivary cortisol measurement in the diagnosis of Cushing's syndrome

Making a definite diagnosis of Cushing's syndrome is a challenging problem. Unsuspected Cushing's syndrome occurs in 2-3% of patients with poorly controlled diabetes, 0.5-1% with hypertension, 6-9% with incidental adrenal masses, and 11% with unexplained osteoporosis and vertebral fractures. The increasing recognition of this syndrome highlights the need for a simple, sensitive, and specific diagnostic test. Patients with Cushing's syndrome consistently do not reach a normal nadir of cortisol secretion at night. The measurement of late-night salivary cortisol levels might, therefore, provide a new diagnostic approach for this disorder. Salivary cortisol concentrations reflect those of active free cortisol in plasma and saliva samples can easily be obtained in a nonstressful environment (e.g. at home). Late-night salivary cortisol measurement yields excellent overall diagnostic accuracy for Cushing's syndrome, with a sensitivity of 92-100% and a specificity of 93-100%. Several factors can, however, make interpretation of results difficult; these factors include disturbed sleep-wake cycles, contamination of samples (particularly by topical corticosteroids), and illnesses known to cause physiologic activation of the pituitary-adrenal axis. In this Review, we discuss the methods and value of measuring salivary cortisol for the diagnosis of Cushing's syndrome, and put forward some recommendations to maximize accuracy of results.     

24-hour thyroid-stimulating hormone secretory pattern in elderly men

A chronobiological study was carried out in 10 elderly male subjects (78-83 years) to evaluate the 24-hour thyroid-stimulating hormone (TSH) secretory pattern. 10 young adult males (26-35 years) made up the control group. Hourly blood samples were drawn from each subject for a 24-hour period. TSH levels in elderly subjects showed blunted circadian fluctuations compared to those seen in young adult subjects. Mean 24-hour TSH values in elderly (3.1 +/- 0.3 microU/ml) and young adult subjects (3.5 +/- 0.1 microU/ml) did not differ statistically, but nighttime TSH values observed in elderly subjects (3.2 +/- 0.3 microU/ml) were lower (p less than 0.05) than those recorded in young adults (4.1 +/- 0.1 microU/ml).     

Spontaneous 24-h ghrelin secretion pattern in fasting subjects: maintenance of a meal-related pattern

OBJECTIVE: Ghrelin stimulates GH release and causes weight gain through increased food intake and reduced fat utilization. Ghrelin levels were shown to rise in the preprandial period and decrease shortly after meal consumption, suggesting a role as a possible meal initiator. However, ghrelin secretion in fasting subjects has not yet been studied in detail. DESIGN: 24-h ghrelin profiles were studied in six healthy volunteers (three females; 25.5 years; body mass index 22.8 kg/m(2)) and compared with GH, insulin and glucose levels. METHODS: Blood samples were taken every 20 min during a 24-h fasting period and total ghrelin levels were measured by RIA using a polyclonal rabbit antibody. The circadian pattern of ghrelin secretion and pulsatility (Cluster analysis) were evaluated. RESULTS: An increase and spontaneous decrease in ghrelin were seen at the timepoints of customary meals. Ghrelin was secreted in a pulsatile manner with approximately 8 peaks/24 h. An overall decrease in ghrelin levels was observed during the study period. There was no correlation of ghrelin with GH, insulin or blood glucose levels. CONCLUSIONS: This pilot study indicates that fasting ghrelin profiles display a circadian pattern similar to that described in people eating three times per day. In a fasting condition, GH, insulin and glucose do not appear to be involved in ghrelin regulation. In addition, we found that ghrelin is secreted in a pulsatile pattern. The variation in ghrelin independently of meals in fasting subjects supports previous observations that it is the brain that is primarily involved in the regulation of meal initiation.     

Diagnostic value of salivary cortisol in Cushing's syndrome (CS)

Objective The diagnosis of Cushing's syndrome (CS) remains a challenge in clinical endocrinology. The aim of this study was to determine the reproducibility and diagnostic value of late‐night salivary cortisol (SAF₂₃) for CS and its utility along the follow‐up of treated patients. In addition, using the same radioimmunoassay reactives, the cut‐off values for saliva and serum cortisol, assessed synchronically after the overnight 1 mg dexamethasone suppression test (DST), were defined. Design Twenty‐one patients with confirmed CS and 121 volunteers were studied. All the subjects collected 24‐h urine for cortisol (UFC). On the same day whole saliva was obtained from the subjects at 23 h for SAF₂₃. The intraclass coefficient of correlation (ICC) of SAF₂₃ was estimated in 47 subjects (21 CS and 26 C). At 8 h, after DST, simultaneous saliva and serum samples for cortisol (SAF_dex and F_dex, respectively) were obtained in 51 subjects (17 CS and 34 C). After specific therapy, 18 patients with CS were followed with SAF₂₃ measurements. SAF and F were expressed as nm . Results The intraclass coefficient of correlation of SAF₂₃ was 0·89 in CS and 0·83 in C. SAF₂₃ > 3·8 nm showed a sensitivity and specificity of 100% and 97·5%, respectively, for diagnosing CS. SAF₂₃ correlated positively with UFC (r = 0·685; P = 0·0001). After DST, SAF_dex significantly correlated with F_dex (r = 0·61, P < 0·0001). A cut‐off value of SAF_dex > 2·0 nm and F_dex > 50·0 nm detected CS with 100% sensitivity and specificity. After successful surgical therapy, 13 patients with CS had SAF₂₃ levels < 3·8 nm (1·4 ± 0·8 nm ). Conclusions SAF₂₃ and SAF_dex seem to be good screening tools based on their noninvasive nature, remarkable reproducibility and diagnostic performances.     

Diurnal changes of plasma and cerebrospinal fluid somatostatin and 24-h growth hormone secretory pattern in man. A study in hydrocephalic patients

Somatostatin concentration was determined in plasma and in cerebrospinal fluid during a 24-h period in 7 male patients suffering from hydrocephalus of differing aetiologies. Blood and ventricular cerebrospinal fluid samples were taken every 2 h during the day (08.00-22.00 h) and every hour during the night (24.00-07.00 h). Simultaneously, plasma growth hormone levels were also evaluated. Plasma SRIH levels showed significant circadian variations with highest values in the daytime and lowest values during the night. Cerebrospinal fluid SRIH did not show any significant time-related circadian changes. Plasma GH levels showed the well-known circadian pattern in the majority of patients. No significant correlation was found between the plasma GH and plasma or cerebrospinal fluid SRIH values recorded during the 24-h period. Results suggest that peripheral SRIH does not play any major role in the control of the 24-h GH secretory pattern in man.