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Objective: Serum free cortisol, rather than serum total cortisol (TC), determines glucocorticoid activity in vivo, but how the considerable inter-subject variation in ambient serum free cortisol affects the outcome of dynamic hypothalamic-pituitary-adrenal (HPA) assessment in noncritically ill subjects is unknown., Design, Patients and Measurements: We performed the low-dose 1-μg ACTH test in 75 subjects referred for HPA evaluation. Serum TC was determined by a chemiluminescence method, and serum free cortisol was measured by the same method following equilibrium dialysis. In a subset of these patients, salivary cortisol was also measured., Results: Mean fraction of free cortisol was 5·07 ± 4·08% (±SD; range 1·77-10·1%). Although no correlation was seen between TC and the fraction (%) of free serum cortisol, a positive correlation existed between baseline total and free cortisol (R = 0·539 P = 0·01), as well as between peak ACTH-stimulated total and free cortisol (R = 0·619; P = 0·01). There was no correlation between baseline salivary cortisol and serum free cortisol and between peak ACTH-stimulated salivary and serum free cortisol. Using the lowest attained peak serum free cortisol in subjects whose TC response to ACTH was normal (≥ 500 nM), the minimal 'pass' level for normal serum free cortisol response to 1 μg ACTH was set at 25·0 nM. Five of the 19 subjects showing subnormal TC response to 1 μg ACTH had normal serum free cortisol response., Conclusions: Discrepancies between the peak free and TC were noted mostly for subjects whose ACTH-stimulated TC peaked between 440 and 580 nm. At this range, the measurement of serum free cortisol allows further refinement of the assessment of borderline responses to 1-μg ACTH., (© 2011 Blackwell Publishing Ltd.)

Background: The rapid re-accumulation of fluid following aspiration of thyroid cystic lesions suggests that active transport of sodium and water may be involved in volume regulation of these lesions. In this study we address the possibility that aldosterone may take part in this process., Subjects and Methods: Thirty-one patients (29 women and two men), with a mean age of 52.7 +/- 13.2 years (range: 27-77 years) underwent evaluation for thyroid nodules that had a sonographic cystic component. Cystic fluid obtained by FNA biopsy was sent for cytological examination and biochemical measurements. In 10 patients, material was collected for RNA extraction and determination of aldosterone synthase expression by RT-PCR amplification., Results: All lesions were benign, cystic, colloid nodules. Cyst fluid aldosterone levels as measured by routine radioimmunoassay (RIA) were elevated above the normal plasma levels in all but five patients. Mean aldosterone levels were 27.1 +/- 22.9 ng/dl (SD) (range: 5.9-117.5 ng/dl). In contrast, cyst cortisol values were in the low, low normal serum range (6.2 +/- 2.9 microg/dl, range: 0.2-10.2 microg/dl). Sodium, chloride and potassium levels were 137 +/- 4.7 mEq/l, 98 +/- 5 mEq/l and 4.9 +/- 1.4 mEq/l, respectively. Plasma aldosterone levels were normal in all patients tested. To confirm these results, 12 samples were assayed after extraction and chromatography using a highly specific antibody. Cyst aldosterone levels in this group were elevated above the normal serum range in all but one patient (mean concentration: 24.5 +/- 14.6 ng/dl, range: 8.72-40.1 ng/dl). In this group, 18(OH)B levels were within the normal plasma range (12-55 ng/dl) in all but one patient (34.9 +/- 17 ng/dl). Furthermore, aldosterone synthase mRNA expression was found in aspirates of four of 10 patients., Conclusions: The increased aldosterone concentration and the presence of aldosterone synthase expression suggest that aldosterone may be locally produced and secreted in thyroid tissue. The pathophysiological implications of this finding remain to be established.

Objectives: Salivary cortisol is unaffected by cortisol binding globulin (CBG) and hence allows CBG-related variations in serum total cortisol to be bypassed. We assessed whether or not salivary cortisol can be used for the low-dose (1 microg) ACTH test in subjects with presumed normal and elevated levels of CBG., Patients/methods: We measured serum and salivary cortisol responses to intravenous administration of 1 microg ACTH in 14 healthy volunteers, 14 'hyperoestrogenic' women [in their first or early second trimester of pregnancy, using oral contraceptives (OC) or on hormone replacement therapy (HRT)] and 10 patients with secondary hypoadrenalism. Cortisol levels were recorded before as well as 30 and 60 min (+30; +60 min) after ACTH administration., Results: Baseline salivary cortisol did not differ significantly between the hypoadrenal and healthy patients (7.11+/-1.4 and 12.13+/-1.59 nmol/l; P=0.48) but there was a significant difference between hypoadrenal and hyperoestrogenic patients (18.94+/- 3.44 nmol/l; P=0.01). The largest difference between hypoadrenal patients and healthy individuals was observed at+30 min (9.16+/-2.8, 52.65+/-8.78 and 48.81+/- 6.9 nmol/l, in the hypoadrenal, healthy and hyperoestrogenic patients, respectively; P< 0.05). At this time-point values< 24.28 nmol/l were found in all hypoadrenal patients and cortisol levels >or= 27.6 nmol/l were found in 26 out of 28 healthy volunteers. ACTH-stimulated serum cortisol but not salivary cortisol was significantly higher in hyperoestrogenic women than in the healthy volunteers at either+30 or+60 min., Conclusions: The salivary low-dose ACTH test yields results that parallel the response of circulating cortisol to ACTH and may provide an alternative to the blood test, particularly in situations where increased CBG levels complicate the changes in serum cortisol levels.

Background: Ghrelin is a potent GH secretagogue that also plays an important role in appetite and weight regulation. Ghrelin increases hunger and food intake, and its levels decrease after a standard meal or glucose., Objective: To examine the effects of standard oral glucose, lipid and protein loads on ghrelin levels, investigating the possibility that these responses may be modulated by several anthropometric and metabolic factors., Subjects and Methods: There were 24 adult nondiabetic subjects (13 men/11 women; mean age 55.3 +/- 2.9 years, range 26-74 years). Each participant underwent one or more of the following nutrient loads: (i) a standard oral glucose (75 g) load (n = 18); (ii) an oral lipid load (40 g, with 24 g saturated fat; n = 13); (iii) an oral protein load (40 g; n = 11)., Results: Fasting ghrelin levels were negatively related to body mass index (BMI; r =-0.47; P = 0.02), waist circumference (r = -0.58; P = 0.0028), waist/hip ratio (r = -0.56; P = 0.0046), fasting insulin (r = -0.44, P = 0.03), and homeostasis model assessment insulin resistance index (HOMA-R; r = -0.43, P = 0.034). Glucose load induced a decrease in ghrelin levels (P < 0.0001), and this response was modulated by sex (P < 0.0001), in that levels were significantly higher in females. The presence of obesity affected ghrelin response to glucose (< 0.0217), in that log-transformed ghrelin levels started to increase back to baseline after its initial decline earlier in obese than in lean subjects. Ghrelin levels after a glucose load were lower over time in subjects with more pronounced insulin resistance (P < 0.0001). Similarly, ghrelin levels decreased significantly following the lipid meal (P = 0.035), and were modulated by HOMA-R (P = 0.027) and gender (P = 0.029). Protein did not affect ghrelin levels., Conclusions: This study demonstrates that ghrelin levels respond in a different manner to glucose, lipid and protein loads, and are subject to modulation according to gender, obesity and insulin sensitivity.

Objective: We have shown previously that in contrast to the standard high-dose 250-microgram ACTH test, a low-dose 1-microgram ACTH stimulation test correctly identified all patients with pituitary disease who had impaired hypothalamo-pituitary-adrenal (HPA) function. In this study we further compared the performances of these two tests as screening procedures for possible HPA impairment., Design: A comparison of the 1-microgram and the 250-microgram ACTH stimulation tests in healthy controls and in patients with pituitary disease whose HPA axis status was characterized formally by a gold standard test., Subjects: A total of 89 subjects were investigated: 27 healthy normal controls, 43 patients with pituitary disease and normal HPA function, and 19 patients with various pituitary diseases and impaired HPA function., Measures: All 89 subjects underwent stimulation with 1 microgram ACTH; 80 also underwent the high-dose 250-microgram ACTH test. A receiver operating characteristic analysis (ROC) was performed to compare the tests., Results: Using a stimulated cortisol > 500 nmol/l as the criterion for a normal response, the 1-microgram ACTH stimulation identified 18 of the 19 subjects with impaired HPA function (94.7% sensitivity with a likelihood ratio of 0.0588 for a negative test). In contrast, 15/16 passed the high-dose test (a 6.2% sensitivity with a likelihood ratio of 0.875 for a negative test). All normal controls, and 36/43 patients with preserved HPA function, passed the 1-microgram ACTH test (90% specificity). This degree of accuracy was unrivalled by the high dose test at all the cut-off levels considered., Conclusions: More sensitive and accurate, the low-dose 1-microgram ACTH test is as simple and safe as the standard 250-microgram test. We suggest it should replace it in screening for adrenal insufficiency.