Comparison of different regimens of glucocorticoid replacement therapy in patients with hypoadrenalism

Since the optimal glucocorticoid replacement needs to avoid over and under treatment, the adequacy of different daily cortisone acetate (CA) doses was assessed in 34 patients with primary and central hypoadrenalism. The conventional twice CA 37.5 mg/day dose was administered to all patients (A regimen: 25 mg at 07:00 h, 12.5 mg at 15:00 h), while in 2 subgroups of 12 patients the dose was shifted on 2 thrice daily regimens (B: 25 mg at 07:00, 6.25 mg at 12: 00, 6.25 mg at 17:00; C: 12.5 mg, 12.5 mg, 12.5 mg). In other 12 patients the conventional dose was reduced to a thrice 25 mg/day administration (D regimen: 12.5 mg, 6.25 mg, 6.25 mg). In all patients, urinary free cortisol (UFC) excretion and cortisol day curves were evaluated. During the CA 37.5 mg administration, nadir cortisol levels were significantly higher with the thrice daily regimens (143 +/- 31 on B and 151 +/- 34 nmol/l on C) than with the conventional twice (85 +/- 16 nmol/l). Moreover, UFC, morning cortisol levels and mean cortisol day curves were similar in each group. Finally, during D regimen nadir cortisol levels were higher than in A and similar to B and C regimens. No difference in UFC and in cortisol day curves by reducing the CA dose was found. In conclusion, the thrice daily cortisone regimens, in which more physiological cortisol levels are achieved, perform better as replacement therapy. The administration of 25 mg/day CA confirms that replacement therapy is more adequate with a lower dose, particularly in patients with central hypoadrenalism.     

Screening for Cushing's syndrome in obese women with and without polycystic ovary syndrome

Obesity and insulin resistance, menstrual abnormalities and clinical and biochemical signs of hyperandrogenism are common features in women with polycystic ovary syndrome (PCOS) and Cushing's syndrome (CS). Further, an overdrive of the pituitary-adrenal axis has been documented in PCOS and this condition is often present in women with CS. For this reason, screening for hypercortisolism is often needed in obese women with polycystic ovaries. The aim of this study was to compare the diagnostic value of different screening tests for CS in a population of obese premenopausal women with PCOS and without PCOS (OB) and in a group of patients with CS. We reviewed retrospectively the case records of 117 obese women of reproductive age (60 PCOS and 57 OB, BMI 25.1-70.1, 13-45 yr) who were screened for CS at our Institution in the years 1995-2001 and turned out to be free of the disease. Data were compared with those of 58 premenopausal obese women with active CS (BMI 25.1-50.2 kg/m2, 18-45 yr). Screening for CS was performed by urinary free cortisol (UFC) (three consecutive 24-h urine collections), cortisol circadian rhythm (blood samples taken at 08:00-17:00-24:00 h), and 1 mg overnight dexamethasone suppression test (DST). A 24:00 h plasma cortisol (MNC) of 207 nmol/l, a UFC of 221 nmol/day and plasma cortisol after DST of 50 nmol/l and 138 nmol/l were taken as cut-off values for the diagnosis of CS. As expected, patients with CS showed elevated basal and post-dexamethasone plasma cortisol and UFC levels (p < 0.001 vs OB and PCOS). PCOS had higher UFC (p < 0.005) but not MNC and post-DST plasma cortisol levels compared to OB. DST showed the greatest specificity and diagnostic accuracy in differentiating CS from PCOS and OB (both p < 0.05 vs MNC and UFC, according to the 138 nmol/l criterion) while MNC and UFC displayed a similar discriminatory value. However, by using a lower threshold (50 nmol/l) as response criterion, there were no diagnostic differences between DST and the other tests. Specificity and diagnostic accuracy of UFC measurement was lower in PCOS than in OB (both p < 0.05) whilst there were no differences between groups for DST and MNC. Similarly, the area under the ROC curve relative to DST, giving an estimate of the inherent diagnostic accuracy of the test, was slightly greater than those of MNC and UFC (z = 0.694 and z = 0.833 for DST vs MNC and UFC, respectively, both p = NS). These results indicate that the 1-mg DST and MNC are unaffected by the presence of PCOS and can be safely used to screen for CS premenopausal obese women with PCOS, while caution should be exercised in interpreting mildly elevated UFC levels in these patients.     

An Assessment of Optimal Hydrocortisone Replacement Therapy

OBJECTIVE To assess the management of hydrocortisone replacement therapy in one institution, and derive recommendations for optimum starting and maintenance replacement therapy with hydrocortisone. DESIGN Retrospective survey of clinical management using a clinical information system and the patient case notes. PATIENTS Using the department’s clinical information system, 210 patients were identified who had been treated with hydrocortisone. Case notes were reviewed and 130 patients were identified whose records contained the results of at least one valid hydrocortisone day curve. Data on 174 day curves performed on these patients (65 on twice daily and 109 on thrice daily hydrocortisone regimes) formed the basis of this analysis. METHODS Hydrocortisone day curves had been performed as part of routine clinical management: patients collected a 24 h urine for free cortisol on the day prior to the test and took their morning hydrocortisone at the normal time, at home, on wakening. During a day-case attendance serum cortisol was then measured at 0900 h, 1230 h (prior to any lunchtime dose) and 1730 h (prior to the evening dose). ‘Optimal replacement’ was arbitrarily defined as that dose which achieved a UFC and 09:00h cortisol within the reference range for the normal population (to avoid over-replacement) combined with 1230 h and 1730 h cortisol above 50 nmol/l, and ideally above 100 nmol/l (to avoid under-replacement). Raw data from all hydrocortisone day curves was analysed in an Excel spreadsheet to determine the effect of different dose regimens on the percentage of patients achieving each and all of these 4 criteria, and on an overall ‘quality score’ (comprising 1 point for each of the 4 criteria attained). RESULTS Patients on twice daily hydrocortisone regimes achieved optimal replacement in 15% of cases compared to 60% on thrice daily regimes (P < 0.001 by χ²); mean overall ‘quality scores’ for these regimens were 2.72 and 3.49 respectively (P < 0.001 by t-test). Of individual dose regimens with sufficient cases for valid comparison, a dose of 10 mg/5 mg/5 mg (rising/lunch/evening) achieved optimal replacement in 66% and mean ‘quality score’ of 3.62 (n = 53), compared to 50% and 3.32 for 10 mg/10 mg/5 mg (n = 28) and 10% and 2.48 for 20 mg/–/10 mg (n =29). CONCLUSIONS The use of arbitrary, but logical, criteria to assess the quality of hydrocortisone replacement regimens indicates that optimal replacement is achieved with thrice daily hydrocortisone regimens, and that the traditional twice daily regime results in a 0900 h cortisol above normal in one-third, and late afternoon cortisol below 50 nmol/l in one-half of patients thus treated. An appropriate starting dose of hydrocortisone of 10 mg/5 mg/5 mg (rising/lunch/evening) is suggested, with subsequent individual adjustment based on simple hydrocortisone day curves.     

Evaluation of two replacement regimens in primary adrenal insufficiency patients. effect on clinical symptoms, health-related quality of life and biochemical parameters

OBJECTIVE: To evaluate clinical symptoms, health-related quality of life (HRQL) and biochemical parameters in patients with primary adrenal insufficiency under treatment with two different hydrocortisone regimens (20 mg-0 mg-10 mg/day and 10 mg-5 mg-5 mg/day), each maintained for 3 months and compare results obtained with those in healthy controls. Design, PATIENTS AND METHODS: Twelve patients with primary adrenal insufficiency were studied. Clinical symptoms and HRQL with the Nottingham Health Profile (NHP) were evaluated and Na, K and serum cortisol determined at 09:00 h, 12:30 h and 17:30 h and urinary free cortisol (UFC) throughout the day. Control group comprised 19 healthy subjects. RESULTS: No differences in specific adrenal insufficiency symptoms were detected between the two regimens. HRQL was worse in energy dimension assessed by the NHP compared to the general population, regardless of 20 mg-0 mg-10 mg/day or 10 mg-5 mg-5 mg/day treatment (p=0.03 and p=0.013). The total NHP score was only adversely affected when patients were on the 10 mg-5 mg-5 mg/day hydrocortisone replacement regimen (p=0.008). Serum cortisol concentrations were higher than controls at 09:00 h, and lower at 17:30 h with both regimens, whereas serum cortisol at 12:30 h and UFC were within the 5th-95th percentile normal range only with the 10 mg-5 mg-5 mg/day regimen. CONCLUSIONS: Patients with primary adrenal insufficiency had worse HRQL in the NHP energy dimension compared with the general population, regardless of the hydrocortisone regimen although total score for HRQL was worse only with the 10 mg-5 mg-5 mg/day regimen. Patients on the thrice-daily hydrocortisone regimen showed a more physiological cortisol profile, leading us to recommend initially treating patients with this dose and increasing it in the case of impaired HRQL.     

Associations between liver histology and cortisol secretion in subjects with nonalcoholic fatty liver disease

OBJECTIVES: To assess associations between the activity of hypothalamo-pituitary-adrenal (HPA) axis and liver histology in patients with nonalcoholic fatty liver disease (NAFLD). DESIGN AND PATIENTS: In a cross-sectional study, we enrolled 50 consecutive, overweight, NAFLD patients and 40 control subjects who were comparable for age, sex and body mass index (BMI). MEASUREMENTS: NAFLD (by liver biopsy), HPA axis activity (by 24-hour urinary free cortisol [UFC] excretion and serum cortisol levels after 1 mg dexamethasone), insulin resistance (by homeostasis model assessment: HOMA-IR), and metabolic syndrome (MetS) features. RESULTS: NAFLD patients had markedly higher (P < 0.001) 24-h UFC (149 +/- 24 vs. 90 +/- 16 nmol/day) and postdex suppression cortisol concentrations (32 +/- 10 vs. 16 +/- 7 nmol/l) than controls. The MetS and its individual components were more frequent among NAFLD patients. The marked differences in urinary/serum cortisol concentrations that were observed between the groups were little affected by adjustment for age, sex, BMI, waist circumference, systolic blood pressure, triglycerides, homeostasis model assessment for insulin resistance score and presence of diabetes. Importantly, 24-h UFC and postdex cortisol concentrations strongly correlated to hepatic necroinflammatory grade (P < 0.01) and fibrosis stage (P < 0.001) among NAFLD patients. By logistic regression analysis, 24-h UFC (odds ratio (OR) 1.80, 95%CI 1.3-2.8) or postdex cortisol concentrations (OR 1.95, 95%CI 1.4-3.1) independently predicted the severity of hepatic fibrosis, but not necroinflammation, after adjustment for potential confounders. CONCLUSIONS: These results suggest that NAFLD patients have a subtle, chronic overactivity in the HPA axis (that is closely associated with the severity of liver histopathology) leading to subclinical hypercortisolism that might be implicated in the development of NAFLD.     

Circadian hydrocortisone infusions in patients with adrenal insufficiency and congenital adrenal hyperplasia

OBJECTIVE: Conventional hydrocortisone therapy in adrenal insufficiency cannot provide physiological replacement. We have explored the potential of circadian delivery of hydrocortisone as proof of concept for such therapy delivered in modified-release tablet formulation. METHODS: We investigated whether the circadian intravenous infusion of hydrocortisone could improve control of ACTH and androgen levels. Two healthy subjects, two patients with Addison's disease and two patients with congenital adrenal hyperplasia (CAH) were studied. RESULTS: In patients on thrice daily oral hydrocortisone, peak serum cortisol levels were higher than in normal subjects and overnight levels were very low. Patients had very high plasma ACTH levels before their morning dose of hydrocortisone, both at the beginning and at the end of their conventional oral therapy: mean +/- SEM 311.8 +/- 123.2 and 311.2 +/- 85.4 ng/l, respectively. In the patients with CAH, serum 17-hydroxyprogesterone levels were also elevated: 550 and 642 nmol/l at the beginning and 550 and 777 nmol/l at the end of conventional treatment, respectively. The overall 24-h mean cortisol levels were similar for conventional oral hydrocortisone and the circadian infusion. At 0700 h, ACTH levels were much higher on conventional treatment than after circadian infusion: mean +/- SEM 311.2 +/- 85.4 vs. 70.5 +/- 45.0 ng/l, respectively (P < 0.05). The same pattern was observed in 17-hydroxyprogesterone levels, which were 550 and 777 nmol/l after conventional treatment and 3 and 64 nmol/l after circadian infusion. CONCLUSIONS: In patients with poor biochemical control of Addison's disease and CAH, a 24-h circadian infusion of hydrocortisone can decrease morning ACTH and 17-hydroxyprogesterone levels to near normal.     

The influence of hydrocortisone substitution on the quality of life and parameters of bone metabolism in patients with secondary hypocortisolism

OBJECTIVE: Hydrocortisone replacement regimes remain rather empirical and produce serum cortisol profiles very different from normal physiology. We have analysed the effects of different dosages of hydrocortisone (HC) replacement therapy on the health perception and general well-being of patients with secondary hypocortisolism. We also evaluated the effects of these regimens on bone metabolism. DESIGN: In a prospective randomized double-blind study, 3 groups of 3 patients were treated with 3 different dosages of HC (15, 20 and 30 mg/day), in different sequences, each sequence for two weeks. PATIENTS: Nine adult patients with complete secondary hypocortisolism. MEASUREMENTS: Serum cortisol, ACTH, aldosterone, renin, alkaline phosphatase, bone specific alkaline phosphatase, osteocalcin, PTH, C-telopeptides of type-I collagen, sodium, potassium, phosphate; urinary free cortisol, pyridinium cross-links, urine sodium, potassium and phosphate were measured at the beginning and after each week of the study. For quality of life assessment the patients completed three different questionnaires, the Basler Befindlichkeits-Skala (BBS), the Befindlichkeits-Skala (Bf-S), the Beschwerde-Liste (BL) each week. RESULTS: With increasing doses of 15, 20 and 30 mg hydrocortisone a significant increase of free urinary cortisol was achieved (298 +/- 26 nmol/day, 454 +/- 43, 819 +/- 59, respectively; P < 0.01). The mean scores of the psychological questionnaires did not change significantly during the whole study (BBS 81.8 +/- 3.9; 82.8 +/- 3.9, 83.6 +/- 3.9; Bf-S 15.9 +/- 3.4, 11.3 +/- 2.6, 12.5 +/- 2.8; BL 15.7 +/- 2.3, 14.4 +/- 2.5, 14.8 +/- 2.6, respectively). Osteocalcin decreased significantly (2. 3 +/- 0.49, 2.1 +/- 0.42, 1.8 +/- 0.38, P < 0.01) with increasing HC doses but remained within the normal range. The other investigated parameters were within or nearly within the normal range in all patients at the beginning and did not change during the study. CONCLUSION: Dosages of 15, 20 or 30 mg hydrocortisone/day have equivalent effects on quality of life in patients with secondary hypocortisolism. With 15 or 20 mg hydrocortisone/day the patients feel nearly as well and content as normal healthy individuals. Since long-term treatment with a high replacement dose of glucocorticoids (hydrocortisone 30 mg/day) induces bone loss, this risk can be avoided with a substitution dosage of 20 mg or even 15 mg hydrocortisone/day, without influencing the well-being of the patient.     

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

AIMS: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.     

Diagnosis of Cushing's syndrome: re-evaluation of midnight plasma cortisol vs urinary free cortisol and low-dose dexamethasone suppression test in a large patient group.

We studied plasma cortisol levels at 00:00 h and 08:00 h in 103 patients with Cushing's syndrome and 144 patients in whom this diagnosis had been excluded. These patients were hospitalized in our department from 1975 to 1996. Additionally, we measured these parameters in 20 healthy volunteers and in 5 patients with nonendocrine disease. Corresponding data of urinary free cortisol and low-dose dexamethasone suppression testing were included in the evaluation. Values (mean+/-SD) from patients with Cushing's syndrome: 510+/-232 nmol/l (range 165-1488) for plasma cortisol 00:00 h, 574+/-242 nmol/l (range 236-1612) for plasma cortisol 08:00 h, 991+/-885 nmol/24 h (range 154-4866) for urinary free cortisol and 479+/-304 nmol/l (range 34 - 1,393) for plasma cortisol after 1.5 mg dexamethasone. Values from the patients excluded from Cushing's syndrome: 99+/-76 nmol/l (range 5-371) for plasma cortisol 00:00 h, 393+/-136 nmol/l (range 119-812) for plasma cortisol 08:00 h, 126+/-84 nmol/24 h (range 30-485) for urinary free cortisol, and 64+/-82 nmol/l (range 5-395) for plasma cortisol after 1.5 mg dexamethasone. Values of the healthy volunteers respectively patients with non-endocrine disease: 59+/-30 nmol/l (range 25-130) respectively 127+/-80 nmol/l (range 62-265) for plasma cortisol 00:00 h and 388+/-144 nmol/l (range 157-651) respectively 498+/-113 nmol/l (range 302-581) for plasma cortisol 08:00 h. None of the Cushing patients exhibited a 00:00 h plasma cortisol below 140 nmol/l and only one had a urinary free cortisol below 200 nmol/24 h, whereas 4 were complete dexamethasone suppressors. The diagnostic value of these parameters was examined based on various cutoffs. We recommend determination of midnight plasma cortisol as an efficient and simple additional procedure for the diagnosis of Cushing's syndrome. The sensitivity and specificity of this procedure is similar to urinary free cortisol and slightly above the low-dose dexamethasone suppression testing in our hospitalized patients.     

Adrenal gland volume and dexamethasone-suppressed cortisol correlate with total daily salivary cortisol in African-American women

CONTEXT: Population-based studies of associations between subclinical hypercortisolism and risk for disease states, such as type 2 diabetes mellitus, have been difficult to assess because of imprecise measures of glucocorticoid exposure. Alternative measures (salivary cortisol and adrenal gland volume) have not been systematically compared with 24-h urine free cortisol (UFC) in a healthy population. OBJECTIVE: Our objectives were: 1) to determine whether 24-h UFC and total daily salivary cortisol correlated with each other, adrenal gland volume, and salivary cortisol after dexamethasone suppression and 2) to evaluate the association of adrenal gland volume with salivary cortisol after dexamethasone suppression. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study of 20 healthy, premenopausal African-American women aged 18-45 yr. MAIN OUTCOME MEASURES: Salivary cortisol was assessed at six time points throughout the day simultaneous with 24-h UFC collection. Adrenal gland volume was measured by computed tomography scan. Dexamethasone-suppressed salivary cortisol was measured at 0800 h after administration of 0.5 mg dexamethasone at 2300 h the prior evening. RESULTS: Dexamethasone-suppressed salivary cortisol levels correlated strongly with individual, timed salivary cortisol measurements, total daily salivary cortisol (rs=0.75; P=0.0001; n=20), and adrenal gland volume (rs=0.66; P=0.004; n=17). Total daily salivary cortisol and adrenal gland volume also correlated (rs=0.46; P=0.04; n=19). In contrast, 24-h UFC levels did not correlate with any of the other hypothalamic-pituitary-adrenal axis measures. CONCLUSION: A dexamethasone suppression test or adrenal gland volume may be alternative measures for characterizing subtle subclinical hypercortisolism in healthy adults.     

Conventional glucocorticoid replacement overtreats adult hypopituitary patients with partial ACTH deficiency

BACKGROUND: Glucocorticoid therapy is associated with potentially serious side-effects, but there is no information available regarding glucocorticoid requirement in adult hypopituitary patients with partial ACTH deficiency. SUBJECTS: Ten male adult hypopituitary patients with partial ACTH deficiency, baseline plasma cortisol > 200 nmol/l but a peak stimulated cortisol < 500 nmol/l and 10 matched healthy male control volunteers participated. DESIGN: Patients were assigned, in a random order, to a cross-over protocol of treatment for 1 week with full dose hydrocortisone (10 mg twice daily), half-dose hydrocortisone (5 mg twice daily), or no treatment. All patients completed all three of the treatment limbs. MEASUREMENTS: Following each treatment schedule, patients underwent an 11-h cortisol day curve (CDC), and the results were compared with those from the 10 control volunteers on no glucocorticoid treatment. RESULTS: The integrated CDC values were significantly higher in patients taking a full dose of hydrocortisone compared to controls (P < 0.001). There was no significant difference in the integrated CDC between patients on half-dose (P = 0.37) or no hydrocortisone treatment (P = 0.13), compared to control subjects. Peak postabsorption cortisol values were higher in patients receiving full-dose hydrocortisone treatment compared to controls (P < 0.001). There was no significant difference in plasma sodium concentration, blood pressure or corticosteroid-binding globulin between patients on any treatment schedule and controls. CONCLUSION: Adult patients with pituitary disease and partial ACTH deficiency have a cortisol secretory pattern comparable to that of healthy controls. Conventional full-dose replacement with 10 mg twice daily of hydrocortisone produces hypercortisolaemia, whereas half-dose produces a CDC that is not statistically different from that of healthy controls. The results suggest that current conventional glucocorticoid replacement overtreats patients with partial ACTH deficiency under normal unstressed physiological conditions.     

Effects of chronic administration of PPAR-gamma ligand rosiglitazone in Cushing's disease

OBJECTIVE: Rosiglitazone, a thiazolidinedione compound with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-binding affinity, is able to suppress adrenocorticotropic hormone (ACTH) secretion in treated mice and in AtT20 pituitary tumor cells. These observations suggested that thiazolidinediones may be effective as therapy for Cushing's disease (CD). PATIENTS AND METHODS: Rosiglitazone (8 mg/day) was administered to 14 patients with active CD (13 women, one man, 18-68 years). Plasma ACTH, serum cortisol (F) and urinary free cortisol (UFC) levels were measured before and then monthly during rosiglitazone administration. RESULTS: In six patients a reduction of ACTH and F levels and a normalization of UFC were observed 30-60 days after the beginning of rosiglitazone administration: there was a significant difference between basal and post-treatment values for UFC (1238+/-211 vs 154+/-40 nmol/24 h, P<0.03), but not for ACTH (15.9+/-3.7 vs 7.9+/-0.9 pmol/l) and F levels (531+/-73 vs 344+/-58 nmol/l). Two of six cases, followed up for 7 months, showed a mild clinical improvement. Eight patients were nonresponders after 30-60 days of rosiglitazone treatment: their ACTH, F and UFC levels did not differ before and during drug administration. Immunohistochemical analysis of pituitary tumors removed from two responder and two nonresponder patients showed a similar intense immunoreactivity for PPAR-gamma in about 50% of cells. CONCLUSIONS: The administration of rosiglitazone seems able to normalize cortisol secretion in some patients with CD, at least for short periods. Whether the activation of PPAR-gamma by rosiglitazone might be effective as chronic pharmacologic treatment of CD needs a more extensive investigation through a randomized and controlled study.     

Urinary free cortisol increases in adolescent caucasian females during perimenarche

Urinary free cortisol (UFC) excretion has been thought to be constant during female reproductive maturation when normalized for body surface area. We sought to determine whether there are longitudinal changes in urinary free cortisol excretion during perimenarche in adolescent females. We performed a longitudinal study of 24-h UFC excretion obtained at 6-month intervals over a 4-yr period in a cohort of 112 adolescent non-Hispanic white perimenarchal females from south central Pennsylvania. The overall mean values (mean +/- SD) for UFC/24 h for all measurements between ages 12 and 17 yr was 67.4 +/- 43.8 micro g/24 h (to convert to nanomoles per day, multiply by 2.759). In our model, we found a significant positive association between UFC excretion with both gynecological age (P = 0.002) and chronological age (P = 0.0001). For every incremental increase in Tanner stage, the UFC/BSA increased by 3.0 microg/24 h per square meter. Correcting the UFC values by both creatinine and BSA creates a fairly constant number (6.3 +/- 3.1 microg/mg per square meter per 24 h) over the age range 12-17 yr represented in this study. An increase in cortisol excretion may be part of normal reproductive maturation.     

Reproducibility of nighttime salivary cortisol and its use in the diagnosis of hypercortisolism compared with urinary free cortisol and overnight dexamethasone suppression test

BACKGROUND/METHODS: Nighttime salivary cortisol (NSC) has been suggested to be a useful diagnostic test for Cushing's syndrome (CS). In the absence of published data on its day-to-day variability, we assessed the reproducibility of NSC by repeated measurements in healthy volunteers. Its diagnostic performance was compared with 24-h urinary free cortisol (UFC) and 1 mg overnight dexamethasone suppression test in 12 patients with CS, 20 healthy volunteers, 14 referred patients in which CS was excluded or not firmly established, 16 obese patients, and 20 women in late pregnancy. RESULTS: NSC showed a superior reproducibility in healthy volunteers with a low day-to-day variability as reflected by an intraclass correlation coefficient of 0.78. The receiver operating characteristic curve-estimated cutoff of 6.1 nmol/liter (0.22 microg/dl) demonstrated a sensitivity and specificity of 100% (area under the receiver operating characteristic curve, 1.0; 95% confidence interval, 0.94-1.0) in the diagnosis of CS. NSC, 24-h UFC [after adjusting the local laboratory cutoff to 504 nmol/d (183 microg/d)], and the urinary cortisol/creatinine ratio showed a tendency to be superior to 1 mg dexamethasone suppression test in correctly identifying CS. In late pregnancy, the preserved diurnal variation at a higher level of salivary cortisol reduced the specificity of NSC to 75%. CONCLUSION: Based on its remarkable reproducibility, easy noninvasive nature, and at least similar diagnostic performance, NSC appears to be a preferable alternative to 24-h UFC as a first-line screening test for CS. The cutoff values of NSC, 24-h UFC, and urinary cortisol/creatinine ratio have to be carefully adjusted using assay and center-specific reference ranges of sufficiently large populations.     

Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

The management of congenital adrenal hyperplasia due to 21-hydroxylase (CYP21) deficiency requires glucocorticoid substitution with oral hydrocortisone given twice or thrice daily. In paediatric practice little is known of the bioavailability of oral hydrocortisone tablets used in these patients. The aim of this study was to assess the bioavailability of oral hydrocortisone and to evaluate current replacement therapy in the light of cortisol pharmacokinetic properties. We determined the bioavailability of hydrocortisone following oral and intravenous administration in sixteen (median age: 10.9 years, range: 6.0-18.4 years) adequately controlled CYP21 deficient patients. Serum total cortisol concentrations were measured at 20-min intervals for 24 h while patients were on oral substitution therapy, and at 10-min intervals for 6 h following an intravenous bolus of hydrocortisone in a dose of 15 mg/m(2) body surface area. The area under the serum total cortisol concentration versus time curve (AUC) following oral and intravenous administration of hydrocortisone was calculated using the trapezoid method. The bioavailability was estimated by dividing the corrected for dose AUC after oral hydrocortisone administration by the corrected for dose AUC after the intravenous hydrocortisone administration and was exemplified as a percentage. After oral administration of hydrocortisone in the morning, median serum total cortisol concentrations reached a peak of 729.5 nmol/l (range: 492-2520 nmol/l) at 1.2 h (range: 0.3-3.3 h) and declined monoexponentially thereafter to reach undetectable concentrations 7 h (range: 5-12 h) after administration. Following administration of the evening hydrocortisone dose, median peak cortisol concentration of 499 nmol/l (range: 333-736 nmol/l) was attained also at 1.2 h (range: 0.3-3.0 h) and subsequently declined gradually, reaching undetectable concentrations at 9 h (5-12 h) after administration of the oral dose. After the intravenous hydrocortisone bolus a median peak serum total cortisol concentration of 1930 nmol/l (range: 1124-2700 nmol/l) was observed at 10 min (range: 10-20 min). Serum cortisol concentrations fell rapidly and reached undetectable levels 6 h after the hydrocortisone bolus. The absolute bioavailability of oral hydrocortisone in the morning was 94.2% (90% confidence interval (CI): 82.8-105.5%) whereas the apparent bioavailability in the evening was estimated to be 128.0% (90% CI: 119.0-138.0%). We conclude that the bioavailability of oral hydrocortisone is high and may result in supraphysiological cortisol concentrations within 1-2 h after administration of high doses. The even higher bioavailability in the evening, estimated using as reference the data derived from the intravenous administration of hydrocortisone bolus in the morning, is likely to reflect a decrease in the hydrocortisone clearance in the evening. Decisions on the schedule and frequency of administration in patients with congenital adrenal hyperplasia should be based on the knowledge of the bioavailability and other pharmacokinetic parameters of the hydrocortisone formulations currently available.     

TRILOSTANE AND THE NORMAL HYPOTHALAMIC-PITUITARY-ADRENOCORTICAL AXIS

Trilostane has been used to treat Cushing's syndrome and other adrenocortical disorders. To investigate its effect on the normal adrenal gland, trilostane (initially 240 mg/day) was given to ten healthy men, the dose increasing at weekly intervals by 240 mg/day up to a final dose of 960 mg/day. The drug was well tolerated although one subject withdrew after the first week because of gastrointestinal side effects. Trilostane had no significant effect on aldosterone levels or blood pressure. The mean 24-h urinary free cortisol excretion rose from 14.2 to 22.0 mumol/mol creatinine (P less than 0.01) before and after trilostane 240 mg/day but did not rise thereafter. Early morning serum cortisol and plasma ACTH levels did not change on trilostane. The mean increment in serum cortisol after the i.v. injection of 0.25 mg of ACTH was reduced from 398 nmol/l before trilostane to 287 nmol/l on 240 mg/day and to 291 nmol/l on 960 mg/day (P less than 0.01). Insulin-induced hypoglycaemia while on 960 mg/day produced a maximum increment in serum cortisol of 361 +/- 118 nmol/l (mean +/- SD) although one subject had a subnormal increment of 180 nmol/l (normal greater than 200 nmol/l). Plasma ACTH rose with hypoglycaemia in all cases. We conclude that trilostane has only a minor effect on the normal hypothalamic-pituitary-adrenocortical axis.     

Comparison of one week 0900 h serum cortisol, low and standard dose synacthen tests with a 4 to 6 week insulin hypoglycaemia test after pituitary surgery in assessing HPA axis

OBJECTIVE: To compare the use of 0900 h serum cortisol and both low and standard dose Synacthen tests, one week after pituitary surgery with an insulin hypoglycaemia test performed 4-6 weeks after surgery in assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis. DESIGN: 0900 h basal serum cortisol was measured on days 6 and 7 after pituitary surgery (24 h off replacement hydrocortisone) followed by a low dose Synacthen test (1 microg intravenously) on day 6 and a standard dose Synacthen test (250 microg intramuscularly) on day 7. Three to 5 weeks later an insulin hypoglycaemia test was performed on all patients. Both low and standard dose Synacthen tests were performed on control subjects using an identical protocol. SUBJECTS: Forty-two patients (21 male, 21 female), median age 49 years (range 23-73) who had pituitary surgery (Cushing's disease excluded). One patient had undergone repeat surgery for residual tumour and was studied following each operation. Sixteen healthy normal volunteers, median age 37 years (range 21-55). MEASUREMENTS: Serum cortisol measured by radioimmunoassay. RESULTS: Two standard deviations below the mean serum cortisol (logarithmic transformation) in the normal volunteers 30 minutes after low dose Synacthen (1 microg) was 496 nmol/l and after standard dose Synacthen (250 microg) was 504 nmol/l. A normal response was therefore taken as serum cortisol > 500 nmol/l at 30 minutes in both tests (using 496 and 504 nmol/l did not alter results). 0900 h serum cortisols 1 week after surgery were > 250 nmol/l in 31 patients and 29 of these had a normal response to hypoglycaemia (peak serum cortisol > 550 nmol/l). Of the remaining two patients, one had 0900 h serum cortisol on day 6 and 7 after surgery of 405 and 441 nmol/l with a peak serum cortisol response to hypoglycaemia of 451 nmol/l; the other patient had 0900 h serum cortisols of 416 and 251 nmol/l and a peak cortisol response to hypoglycaemia of 498 nmol/l. All eight patients who had a 0900 h serum cortisol < 100 nmol/l failed a subsequent insulin hypoglycaemia test. Seven discrepancies were noted between the low dose Synacthen test and the insulin hypoglycaemia test in the 41 patients who had both tests. In six of these, a subnormal response to low dose Synacthen was followed by a normal response to hypoglycaemia. Three discrepancies were noted between the standard dose Synacthen test and the insulin hypoglycaemia test in the 40 patients who had both tests. In all three cases a normal response to Synacthen was followed by a subnormal response to hypoglycaemia. CONCLUSIONS: A 0900 h serum cortisol < 100 nmol/l (24 h off replacement hydrocortisone) indicated ACTH deficiency and need for lifelong steroid replacement. A 0900 h serum cortisol > 450 nmol/l one week after pituitary surgery is highly suggestive of a normal cortisol response to hypoglycaemia. A 0900 h serum cortisol between 250 and 450 nmol/l one week after pituitary surgery permits safe withdrawal of steroid therapy pending an insulin hypoglycaemia test 1 month after surgery. Patients with 0900 h serum cortisol between 100 and 250 nmol/l should continue replacement steroids until definitive testing. Low dose and standard dose Synacthen tests 1 week after pituitary surgery are unreliable and should not be used.     

Short term effects of ketoconazole in Cushing's syndrome

The effects of Ketoconazole (600 mg/day) were evaluated in 10 patients with Cushing's syndrome during a mean period of 4.5 weeks (range 1-12). The urinary free cortisol excretion (UFC) decreased by 21 +/- 15% (mean +/- SEM) (p less than 0.01) on day 1; 54 +/- 8% (p less than 0.0001) on day 2; 60 +/- 15% (p less than 0.0001) on day 3 and 87 +/- 3% (p less than 0.0001) on day 8 compared to baseline. Salivary cortisol at 0800 h decreased similarly. On day 3, 7 patients showed normal UFC values and on day 8, only 1 patient, with the ectopic ACTH syndrome, had persistent hypercortisolism. The cortisol decrease was associated with an increase in desoxycorticosterone values (p less than 0.01) and a decrease in dehydroepiandrosterone sulfate (p less than 0.001), delta 4 androstenedione (p less than 0.05) and testosterone (p less than 0.05). No significant variations were observed in ACTH, 11 desoxycortisol, aldosterone, plasma renin activity, corticosteroid-binding globulin and sex hormone-binding globulin. Side effects were few: mild clinical adrenal insufficiency (n = 5), oedema (n = 3) and reversible hepatic toxicity (n = 1). We conclude that Ketoconazole is an effective inhibitor of cortisol and androgens synthesis. It is well tolerated, rapidly effective and its efficacy persists unchanged for at least one month in all forms of Cushing's syndromes. For these reasons Ketoconazole may be a valuable drug for preoperative treatment of Cushing's syndrome.     

Effects of low-dose oral hydrocortisone replacement versus short-term reproduction of physiological serum cortisol concentrations on insulin action in adult-onset hypopituitarism

OBJECTIVE: Hypercortisolism is associated with impaired glucose tolerance and insulin resistance. For many years hydrocortisone 30 mg was the standard total daily replacement dose in adult hypopituitarism. The use of this conventional dose has now been shown to result in mild biochemical hypercortisolism and might contribute to the increased cardiovascular risk reported in hypopituitarism. The use of lower doses of hydrocortisone replacement therapy might prevent some of the adverse metabolic effects seen with conventional doses. PATIENTS: In a randomized crossover study we assessed peripheral and hepatic insulin action in 15 ACTH-deficient patients with normal glucose tolerance on two occasions while receiving either a low-dose oral hydrocortisone replacement (LOR) therapy (15 mg at 0800, 5 mg at 1700) or a physiological hydrocortisone infusion (PHI), which achieved physiological serum cortisol concentrations. RESULTS: Exogenous glucose infusion rates required to maintain euglycaemia were similar for the LOR and the PHI protocols (26.2 +/- 0.4 vs. 23.8 +/- 0.6 micromol/kg/min, respectively). Endogenous glucose production was also similar (12.0 +/- 2.5 vs. 11.6 +/- 2.4 micromol/kg/min, respectively) and in the post-absorptive state suppressed to a similar extent following insulin (4.5 +/- 2.0 vs. 5.1 +/- 3.1 micromol/kg/min). CONCLUSION: Hydrocortisone replacement therapy at a dose of 15 mg with breakfast, 5 mg with evening meal does not increase peripheral or hepatic insulin resistance when compared to a hydrocortisone infusion designed to simulate physiological serum cortisol concentrations.     

Comparison of adrenocorticotropin (ACTH) stimulation tests and insulin hypoglycemia in normal humans: low dose, standard high dose, and 8-hour ACTH-(1-24) infusion tests.

The efficacy of the standard high dose ACTH stimulation test (HDT), using a pharmacological 250-microg dose of synthetic ACTH-(1-24), in the diagnosis of central hypoadrenalism is controversial. The insulin hypoglycemia test is widely regarded as the gold standard dynamic stimulation test of the hypothalamo-pituitary-adrenal (HPA) axis that provides the most reliable assessment of HPA axis integrity and reserve. Alternatively, a prolonged infusion of ACTH causes a continuing rise in plasma cortisol levels that may predict the adrenals' capacity to respond to severe ongoing stress. In nine normal subjects, we compared plasma ACTH and cortisol levels produced by three i.v. bolus low doses of ACTH-(1-24) (0.1, 0.5, and 1.0 microg/1.73 m2; LDTs) with those stimulated by hypoglycemia (0.15 U/kg insulin) and with the cortisol response to a standard 250-microg dose of ACTH-(1-24). The normal cortisol response to an 8-h ACTH-(1-24) infusion (250 microg at a constant rate over 8 h) was determined using three modern cortisol assays: a high pressure liquid chromatography method (HPLC), a fluorescence polarization immunoassay (FPIA), and a standard RIA. In the LDTs, stepwise increases in mean peak plasma ACTH were observed (12.4 +/- 2.0, 48.2 +/- 7.2, 120.2 +/- 15.5 pmol/L for the 0.1-, 0.5-, and 1.0-microg LDTs, respectively; P values all <0.0022 when comparing peak values between tests). The peak plasma ACTH level after insulin-induced hypoglycemia was significantly lower than that produced in the 1.0-microg LDT (69.6 +/- 9.3 vs. 120.2 +/- 15.5 pmol/L; P < 0.0002), but was higher than that obtained during the 0.5-microg LDT (69.6 +/- 9.3 vs. 48.2 +/- 7.2 pmol/L; P < 0.02). In the LDTs, statistically different, dose-dependent increases in peak cortisol concentration occurred (355 +/- 16, 432 +/- 13, and 482 +/- 23 nmol/L; greatest P value is 0.0283 for comparisons between all tests). The peak cortisol levels achieved during the LDTs were very different from those during the HDT (mean peak cortisol, 580 +/- 27 nmol/L; all P values <0.00009. However, the mean 30 min response in the 1.0-microg LDT did not differ from that in the HDT (471 +/- 22 vs. 492 +/- 22 nmol/L; P = 0.2). In the 8-h ACTH infusion test, plasma cortisol concentrations progressively increased, reaching peak levels much higher than those in the HDT [995 +/- 50 vs. 580 +/- 27 nmol/L (HPLC) and 1326 +/- 100 vs 759 +/- 31 nmol/L (FPIA)]. Significant differences in the basal, 1 h, and peak cortisol levels as determined by the three different assay methods (HPLC, FPIA, and RIA) were observed in the 8-h infusion tests. Similarly, in the HDTs there were significant differences in the mean 30 and 60 min cortisol levels as measured by HPLC compared with those determined by FPIA. We conclude that up to 30 min postinjection, 1.0 microg/1.73 m2 ACTH-(1-24) stimulates maximal adrenocortical secretion. Similar lower normal limits at 30 min may be applied in the 1.0-microg LDT and the HDT, but not when lower doses of ACTH-(1-24) are administered. The peak plasma ACTH level produced in the 1.0-microg LDT is higher than in the insulin hypoglycemia test, but is of the same order of magnitude. The peak cortisol concentration obtained during an 8-h synthetic ACTH-(1-24) infusion is considerably higher than that stimulated by a standard bolus 250-microg dose, potentially providing a means of evaluating the adrenocortical capacity to maintain maximal cortisol secretion. Appropriate interpretation of any of these tests of HPA axis function relies on the accurate determination of normal response ranges, which may vary significantly depending on the cortisol assay used.