Development, repeatability and validity regarding energy and macronutrient intake of a semi-quantitative food frequency questionnaire: methodological considerations.

BACKGROUND AND AIM: The aim of this work was to evaluate the repeatability and the validity of a food frequency questionnaire (FFQ), and to discuss the methodological framework of such procedures. METHODS AND RESULTS: The semi-quantitative FFQ included 69 questions regarding the frequency of consumption of all main food groups and beverages usually consumed and 7 questions regarding eating behaviors. Five hundred individuals (37 ± 15 yrs, 38% males) were recruited for the repeatability process, while another 432 (46 ± 16 yrs, 40% males) also completed 3-Day Diaries (3DD) for the validation process. The repeatability of the FFQ was adequate for all food items tested (Kendall's tau-b: 0.26-0.67, p < 0.05), energy and macronutrients intake (energy adjusted correlation coefficients ranged between 0.56-0.69, p < 0.05). Moderate validity of the FFQ was observed for "dairy products", "fruit", "alcohol" and "stimulants" (tau-b: 0.31-0.60, p < 0.05), whereas low agreement was shown for "starchy products", "legumes", "vegetables", "meat", "fish", "sweets", "eggs", "fats and oils" (tau-b < 0.30, p < 0.05). The FFQ was also valid regarding energy and macronutrients intake. Sensitivity analyses by sex and BMI category (< or ≥25 kg/m(2)) showed similar validity of the FFQ for all food groups (apart from "fats and oils" intake), as well as energy and nutrient intake. CONCLUSION: The proposed FFQ has proven repeatable and relatively valid for foods' intake, and could therefore be used for nutritional assessment purposes.

Association between serum cystatin C, monocytes and other inflammatory markers.

BACKGROUND: Cystatin C is a marker of renal function that appears to be associated with inflammation. The aim of the present study was to investigate whether there is any relationship between cystatin C, total and differential leukocyte count and other inflammatory markers. METHODS: Cystatin C, creatinine, high sensitivity C-reactive protein (hs-CRP), haptoglobin, ferritin, serum albumin, glucose, total cholesterol, HDL and triglycerides together with total and differential leukocyte count were determined in 490 adults (46 ± 16 years, 40% men) who underwent a typical health examination. Glomerular filtration rate was estimated by the simplified Modification of Diet in Renal Disease formula. Anthropometric and lifestyle characteristics were also recorded. RESULTS: After adjustment for demographic risk factors, comorbid health conditions and renal function, a positive and independent relationship of serum cystatin C levels with peripheral monocyte blood count (regression coefficient ± SE: 12 ± 3.38, P < 0.001) and white blood count (0.616 ± 0.278, P= 0.027) was evident. In this multiple linear regression analysis, other inflammatory markers (i.e. hs-CRP, haptoglobin, ferritin, albumin) did not seem to affect cystatin C blood levels. CONCLUSION: The results of this study demonstrated that monocytes, which play an important role in chronic inflammation and atherosclerosis, were independently related with cystatin C concentrations. This finding may provide a plausible link for the usefulness of cystatin C in predicting increased cardiovascular risk.

The hypothalamic-pituitary-adrenal axis in partial (late-onset) 21-hydroxylase deficiency.

Patients with late-onset congenital adrenal hyperplasia (LOCAH) due to partial 21-hydroxylase deficiency have no clinical or biochemical evidence of hypocortisolism. In contrast, patients with the classical forms of CAH frequently develop adrenal insufficiency, characterized by elevated plasma ACTH and low serum cortisol levels. To examine the various components of the hypothalamic-pituitary-adrenal axis in patients with LOCAH, we studied 12 patients with this disorder (10 females and 2 males; age range, 51/2-36 yr). Plasma ACTH and serum cortisol, 17-hydroxyprogesterone (17-OHP), and androstenedione (Adione) concentrations were measured after administration of ovine CRH (oCRH); 1 micrograms/kg at 2000 h) and in the unstimulated state (every 30-60 min for 24 h). The patients' oCRH-stimulated ACTH, cortisol, and Adione responses did not differ from those of normal subjects, whereas their serum 17-OHP concentrations were elevated both basally and after oCRH (P less than 0.05). The patients' unstimulated 24-h ACTH and cortisol levels were normal and exhibited normal diurnal variability. Cortisol pulse frequency was normal. The patients' unstimulated serum 17-OHP levels exceeded those in the normal subjects at all times (P less than 0.01) and exhibited diurnal variability paralleling that of ACTH and cortisol. Unstimulated serum Adione levels in 4 adult women were in the normal or low normal range, except between 0200-0730 h when they were moderately elevated (P less than 0.05). We conclude that the ACTH-cortisol component of the hypothalamic-pituitary-adrenal axis is in normal equilibrium in this group of patients with LOCAH. Because serum Adione levels were elevated only briefly, we suggest that peripheral tissue conversion of 17-OHP to androgens may be the primary cause of the hirsutism and acne in these patients.

Pulsatile administration of human corticotropin-releasing hormone in patients with secondary adrenal insufficiency: restoration of the normal cortisol secretory pattern.

Human corticotropin-releasing hormone (hCRH) was administered in a pulsatile fashion to eight patients with secondary adrenal insufficiency. These patients were selected on the basis of a normal or exaggerated plasma ACTH response to exogenous ovine CRH, suggesting sparing of the corticotrophs. A continuous 48-h iv infusion of ACTH to restore the adrenal glands to an ACTH-responsive state preceded hCRH administration. Eight 1 microgram/kg bolus injections of hCRH were administered in a 24-h period. The time intervals between hCRH injections were selected to resemble the frequency of spontaneously occurring secretory episodes of plasma ACTH and cortisol. Four of the patients underwent a second study, of identical design, in which normal saline injections were administered instead of hCRH. Pulsatile hCRH treatment resulted in a secretory pattern of ACTH and cortisol similar to that in normal subjects. ACTH and cortisol levels during saline administration were low and had no circadian variation. These findings indicate that exogenous CRH is able to restore normal basal ACTH and cortisol secretory patterns when given in an appropriate manner. It is possible that the pulsatile administration of hCRH may prove to be a more physiological technique for restoring adrenal function of patients with corticotroph-sparing secondary adrenal insufficiency and may avoid some of the complications of glucocorticoid administration.

Human corticotropin-releasing factor in man: pharmacokinetic properties and dose-response of plasma adrenocorticotropin and cortisol secretion.

The responses of plasma immunoreactive ACTH (IR-ACTH), cortisol, GH, PRL, and LH to a single iv injection of 0.01-5 micrograms/kg human corticotropin-releasing factor (hCRF) were investigated in healthy volunteers. The lowest effective dose of hCRF was 0.5 micrograms/kg. hCRF caused brief pulse-like elevations of plasma IR-ACTH and cortisol without any effect on the plasma concentrations of GH, PRL, and LH. By contrast, ovine CRF (oCRF), given for comparison, produced long-lasting stimulation of the human pituitary-adrenal axis. The difference in duration of effect between hCRF and oCRF may be attributed to an approximately 3-4 times higher MCR of hCRF [7.9 +/- 1.2 (+/- SE) ml/kg min; n = 14] than oCRF (1.9 +/- 0.1 ml/kg min; n = 9) in man. No serious side effects occurred at any of the doses of hCRF tested. The highest dose (5 micrograms/kg) caused a slight increase of heart rate that was not associated with significant changes in arterial blood pressure. All subjects receiving 5 micrograms/kg and one third of the subjects receiving 1 micrograms/kg hCRF experienced a transient facial flush. We conclude that hCRF causes brief plasma ACTH and cortisol secretory episodes in man, similar to the physiological plasma ACTH and cortisol secretory episodes. This is in contrast to oCRF, which causes prolonged ACTH and cortisol secretion. These differences between the two peptides may be explained by the higher MCR of hCRF than oCRF.

Pituitary-adrenal responsiveness to corticotropin-releasing hormone in patients receiving chronic, alternate day glucocorticoid therapy.

We examined the responsiveness of the pituitary-adrenal axis to ovine corticotropin-releasing hormone (oCRH) in 14 women with systemic lupus erythematosus receiving chronic, alternate day glucocorticoid therapy with prednisone. Testing was done twice and in a random order (at 2000 h) on the day when the steroid was taken (12 h after the last dose) and on the day when no glucocorticoid was administered (36 h after the last dose). Plasma ACTH and cortisol responses were markedly blunted on the day of treatment and mildly blunted on the day off treatment compared to those in normal subjects. Altered metabolic clearance of exogenous oCRF was not responsible for this difference, since the plasma disappearance curves of immunoreactive oCRH were similar on both days. The degree of suppression was dependent on the dose of prednisone, and the amount of cortisol secreted during the oCRH test was directly proportional to the logarithm of the concurrent plasma ACTH level. Thus, the cortisol response to ACTH was normal in all patients. These data suggest that the blunting of responsiveness to oCRH on both days of testing represents prednisolone suppression of the corticotroph cell. Despite this, the adrenal glands retain normal responsiveness to ACTH, suggesting that moderate decreases in daily ACTH secretion are compatible with sustaining normal adrenal function. Hence, the site of the mild suppression of the hypothalamic-pituitary-adrenal axis during chronic, alternate day treatment with glucocorticoids is central, whereas the adrenal glands appear to remain functionally unaffected.

Pulsatile human corticotropin-releasing hormone prevents dexamethasone-induced suppression of the plasma cortisol response to hypoglycemia in normal men.

Insulin-induced hypoglycemia causes a sequential stimulation of all three components of the hypothalamic-pituitary-adrenal axis. States of acute glucocorticoid excess, such as the overnight (1 mg) dexamethasone suppression test (DST), inhibit both the basal cortisol level and the response to an insulin tolerance test (ITT). However, whether this negative feedback effect is exerted primarily at the hypothalamic or the pituitary level is not clear. To explore this question further we have examined the cortisol response to insulin-induced hypoglycemia in three experimental settings, in the following order: 1) a control ITT performed at 0900 h after an overnight hospital stay (cITT); 2) an ITT at 0900 h after oral dexamethasone, 1 mg, at 2300 h on the previous evening (DST + ITT); and 3) an ITT at 0900 h after dexamethasone, 1 mg, at 2300 h and hCRH, 1 microgram/kg iv, at 90 min intervals from 0100-0700 h (DST+hCRH + ITT). The response to ITT was defined as the peak cortisol increment (peak minus baseline). Since the study objective was to test whether overnight pulsatile hCRH could prevent dexamethasone-induced suppression of the response to a morning ITT, only subjects that demonstrated a greater than 25% decrease in the cortisol response to DST + ITT vs. cITT received the full protocol (five of nine normal men). Basal ACTH and cortisol secretion remained suppressed throughout the night during both the Dex + ITT and Dex + hCRH + ITT studies when compared to the control study (cITT, P < 0.05). However, the cortisol response to hypoglycemia during DST + hCRH + ITT was significantly greater than during DST+ITT (P < 0.05) and was similar to the cITT response. Thus, pulsatile hCRH, administered during the 10 h between dexamethasone and the subsequent hypoglycemic stimulus, prevented acute suppression by dexamethasone of the cortisol response to hypoglycemia. We conclude that the dexamethasone-induced inhibition of the cortisol response to hypoglycemia results primarily from suppression by dexamethasone of basal hypothalamic corticotropin-releasing factor and the consequent impairment of corticotroph responsiveness to exogenous and endogenous corticotropin-releasing factor.

The effect of pulsatile human corticotropin-releasing hormone administration on the adrenal insufficiency that follows cure of Cushing's disease.

Successful transsphenoidal surgery for Cushing's disease leads to secondary adrenal insufficiency in most patients. This form of transient adrenal insufficiency is thought to result from hypothalamic and pituitary suppression due to the preceding hypercortisolism. Whether the rate-limiting step in the recovery of adrenal function in this setting is the hypothalamic CRH neuron or the pituitary corticotroph cell, however, is not known. We studied this question by examining the response to ovine CRH (oCRH) before, during, and after prolonged pulsatile administration of human CRH (hCRH) beginning 1-2 weeks after curative microadenomectomy for Cushing's disease. Five patients cured of Cushing's disease received eight hCRH injections (1 microgram/kg) daily for 7 days. This CRH regimen was found previously to normalize plasma ACTH and cortisol patterns in patients with secondary adrenal insufficiency who had normal ACTH responses to a single injection of oCRH (hypothalamic adrenal insufficiency). The plasma ACTH and cortisol responses to oCRH (1 microgram/kg at 2000 h) were assessed immediately before, 2.5 h after, and 7 days after the end of pulsatile hCRH administration. To control for time-related improvement in the hormonal response to ovine CRH, an additional five patients cured of Cushing's disease underwent oCRH tests 1-2 and 3-4 weeks after transsphenoidal surgery, but did not receive hCRH. There was no significant difference in basal or oCRH-stimulated plasma ACTH and cortisol levels among any of the three oCRH tests in the patients who received hCRH. The baseline and oCRH-stimulated plasma ACTH and cortisol levels 1-2 and 3-4 weeks after surgery in the patients who did not receive pulsatile hCRH were similar to the values at those times in the patients who received pulsatile hCRH. Compared to normal subjects, however, both the hCRH-treated and non-hCRH-treated patients had significantly decreased peak and time-integrated plasma ACTH and cortisol responses to oCRH. We conclude that an impaired pituitary response to CRH contributes to the postoperative hypocortisolism of patients recently cured of Cushing's disease, and that this impaired pituitary response to CRH is not reversible by 1 week of pulsatile hCRH administration.

Dissociation between cortisol and adrenal androgen secretion in patients receiving alternate day prednisone therapy.

To evaluate the hypothesis that chronic, low dose, alternate day prednisone treatment may suppress adrenal androgen secretion without causing long term suppression of the hypothalamic-pituitary-adrenal axis we studied seven patients with systemic lupus erythematosus who had been taking low dose (5-20 mg), alternate day prednisone therapy for at least 1 yr. Basal and ovine CRH (oCRH)-stimulated plasma ACTH, cortisol, and adrenal androgen levels were measured 12 h (day on) and 36 h (day off) after the most recent dose of prednisone, and the results were compared to those in seven age- and sex-matched normal subjects. The patients' basal ACTH and cortisol levels did not differ significantly from those in the normal subjects on either the day on or the day off prednisone treatment. By contrast, their basal adrenal androgen levels were significantly decreased compared to those in normal subjects on both the day on and the day off prednisone (P less than 0.05). The patients' oCRH-stimulated ACTH and cortisol levels on the day off prednisone did not differ from normal levels, but were significantly blunted during the day on prednisone (P less than 0.05). In contrast, the patient's oCRH-stimulated adrenal androgen levels were significantly decreased during both the day off and the day on prednisone (P less than 0.05). These findings are consistent with the hypothesis that chronic alternate day prednisone therapy, at doses close to or below replacement, suppresses adrenal androgen levels without long term suppression of the hypothalamic-pituitary-adrenal axis. Based upon these findings, we postulate that an alternate day regimen of prednisone might maintain the benefits while reducing the risks of glucocorticoid therapy of adrenal hyperandrogenism.

The corticotropin-releasing hormone test in the postoperative evaluation of patients with cushing's syndrome.

After surgical cure of Cushing's syndrome most patients develop transient secondary adrenal insufficiency that lasts for approximately 1 yr. Since ACTH-secreting pituitary adenomas generally respond to ovine CRH (oCRH), we tested the hypothesis that an early postoperative response to oCRH may indicate the presence of residual pituitary tumor and, therefore, predict recurrence. We also assessed the usefulness of oCRH for monitoring the recovery of the hypothalamic-pituitary-adrenal axis and for clarifying the pathophysiology of this condition. Thirty-four patients cured of Cushing's syndrome (29 with Cushing's disease, 3 with adrenal adenomas, and 2 with the ectopic ACTH syndrome) had an evening oCRH test 1-2 weeks after surgery. Nine patients (6 with Cushing's disease, 2 with adrenal adenomas, and 1 with the ectopic ACTH syndrome) participated in a longitudinal evaluation and had repeated oCRH and 1-h ACTH tests at 2-month intervals for a year after surgery. Patients were considered to be cured on the basis of at least 3 subnormal urinary [less than 20 micrograms/24 h (less than 55 nmol/day)] or morning plasma cortisol levels [0600-0900 h; less than 6 micrograms/dL (less than 170 nmol/L)] in the first 2 weeks after surgery. The plasma ACTH and cortisol responses to oCRH in the early postoperative period were subnormal in 23 and normal in 6 patients with Cushing's disease. Three patients developed recurrent Cushing's disease (3, 3, and 23 months after transphenoidal surgery). All 3 were among the 6 who had a normal early postoperative response to oCRH. All of the 23 patients who had a subnormal response to oCRH in the early postoperative period have remained in remission for an average follow-up period of 14 months (6-42 months). Thus, the recurrence rate was significantly greater in patients with normal oCRH tests in the early postoperative period (P less than 0.001, by chi 2 analysis). Surgically cured patients with adrenal adenomas or ectopic ACTH secretion also had subnormal plasma ACTH and cortisol responses to oCRH during the early postoperative period. During longitudinal evaluation for 12 months after surgery, the ACTH and cortisol responses to oCRH increased progressively (regardless of the cause of Cushing's syndrome). Cortisol responses to oCRH correlated significantly with the cortisol responses to exogenous ACTH (r = 0.89; P less than 0.00001). We conclude that most patients with Cushing's syndrome have suppressed responses to oCRH during the early postoperative period.(ABSTRACT TRUNCATED AT 400 WORDS)

High C-reactive protein response in lupus polyarthritis.

Five out of 6 patients with systemic lupus erythematosus (SLE) and chronic polyarthritis were found to have significantly raised (greater than 20 mg/l.) C-reactive protein (CRP) levels. In contrast, slight elevations in CRP levels were present in only 5 of 16 SLE patients without chronic polyarthritis. Thus, an elevated CRP level might be a distinctive feature of SLE patients with chronic polyarthritis.

Selective renal angiography in Wegener's granulomatosis.

Two patients whose illnesses meet the criteria of Wegener's granulomatosis are presented. Selective renal angiography performed in both revealed multiple arterial aneurysms similar to those classically found in polyarteritis nodosa.

A comparison of the overnight and the standard metyrapone test for the differential diagnosis of adrenocorticotrophin-dependent Cushing's syndrome.

OBJECTIVE: We wished to develop optimal criteria for interpreting the single-dose overnight metyrapone test and to compare the diagnostic efficiency of the overnight and the standard 6-dose metyrapone tests for the differential diagnosis of ACTH-dependent Cushing's syndrome. DESIGN: Retrospective pilot study based on all patients who completed both metyrapone tests and whose diagnoses were subsequently confirmed surgically. PATIENTS: Sixty-three patients, 57 with pituitary tumours and 6 with ectopic ACTH syndrome, were studied. MEASUREMENTS: The sensitivity and specificity were determined using stimulation of plasma 11-deoxycortisol and suppression of plasma cortisol as endpoints for the overnight test and stimulation of urine 17-hydroxysteroid and plasma 11-deoxycortisol as endpoints for the standard test. The lest response that gave the highest sensitivity for the diagnosis of Cushing's disease, with 100% specificity, was determined for each test endpoint. RESULTS: Both the stimulation of plasma 11-deoxycortisol and the suppression of plasma cortisol were expressed as the ratio of the post-metyrapone value to baseline. A plasma 11-deoxycortisol ratio > than 220 or a plasma cortisol ratio > 0.6 was associated with 100% specificity for diagnosis of Cushing's disease by the overnight test. When these two criteria were combined, the sensitivity was 65%, which was significantly higher than that obtained using either steroid alone: 42% for both plasma 11-deoxycortisol and plasma cortisol. The sensitivity of 65% for the overnight test, at 100% specificity, was nearly identical to that of the standard test in the same patients: 67% for the combined criterion of > 70% stimulation of urine 17-hydroxysteroid or > 480-fold increase of plasma 11-deoxycortisol. When the criteria for both the overnight and standard tests were combined, the sensitivity increased to 84%, which was higher than that obtained using the criteria for either test alone (P < 0.02). CONCLUSION: The single-dose overnight metyrapone test, which can be performed in 24 hours and which avoids the disadvantages associated with timed urine collections, has a nearly identical sensitivity (for a specificity of 100%) as the 6-dose standard metyrapone test for the diagnosis of Cushing's disease. Furthermore, the diagnostic performance of a criterion that combines the results of both tests is significantly better than the best criterion for either test alone.

Regulation of corticotropin releasing hormone receptor type 1 messenger RNA level in Y-79 retinoblastoma cells: potential implications for human stress response and immune/inflammatory reaction.

We report the regulation of type 1 receptor mRNA in Y-79 human retinoblastoma cells, grown in the absence or presence of pharmacological levels of phorbol esters, forskolin, glucocorticoids and their combinations. To control for inducibility and for assessing the sensitivity of the Y-79 system to glucocorticoids, corticotropin releasing hormone mRNA levels were measured in parallel. All treatments stimulated corticotropin releasing hormone receptor type 1 gene expression relative to baseline. A weak suppression of corticotropin releasing hormone mRNA level was observed during dexamethasone treatment. The cell line expressed ten-fold excess of receptor to ligand mRNA under basal conditions. The findings predict the presence of functional phorbol ester, cyclic AMP and glucocorticoid response elements in the promoter region of corticotropin releasing hormone receptor type 1 gene and support a potential role for its product during chronic stress and immune/inflammatory reaction.

Asymptomatic diffuse fasciitis with eosinophilia.

The case of a 70-year-old woman with asymptomatic diffuse fasciitis with eosinophilia, confirmed by biopsy, is presented.

The ovine corticotropin-releasing hormone stimulation test and the dexamethasone suppression test in the differential diagnosis of Cushing's syndrome.

We gave a standard dexamethasone suppression test and an ovine corticotropin-releasing hormone (CRH) stimulation test to 41 patients with adrenocorticotrophic hormone (ACTH)-dependent hypercortisolism to determine the efficacy of each test in the differential diagnosis of Cushing's syndrome. Twenty-nine of thirty-three patients with Cushing's disease and 0 of 8 patients with ectopic secretion of ACTH responded to the ovine CRH test with increased levels of cortisol. When a cortisol response was judged as positive for Cushing's disease, the CRH test had a diagnostic sensitivity, specificity, and accuracy of 88%, 100%, and 90%, respectively. Twenty-nine patients with Cushing's disease and 1 patient with ectopic secretion of ACTH responded to the dexamethasone suppression test. A combined-test strategy requiring negative results from both tests to exclude a diagnosis of Cushing's disease yielded superior sensitivity (100%) and diagnostic accuracy (98%). Thus, the ovine CRH test works as well as the standard dexamethasone suppression test in discriminating between Cushing's disease and ectopic ACTH secretion. The diagnostic power of each test is enhanced when the two tests are combined.

The metyrapone and dexamethasone suppression tests for the differential diagnosis of the adrenocorticotropin-dependent Cushing syndrome: a comparison.

OBJECTIVE: To develop criteria for interpreting results of the metyrapone test for the differential diagnosis of the adrenocorticotropin (ACTH)-dependent Cushing syndrome and to compare its diagnostic accuracy with that of the high-dose dexamethasone suppression test. DESIGN: Retrospective cohort study. SETTING: Inpatient research ward. PATIENTS: 186 patients believed to have the ACTH-dependent Cushing syndrome who had the metyrapone test, the dexamethasone test, and a surgical procedure to remove the source of excessive ACTH. MEASUREMENTS: The sensitivity, specificity, and diagnostic accuracy were determined for the metyrapone test using urine excretion of hydroxysteroid and plasma levels of 11-deoxycortisol. For the dexamethasone suppression test, urine excretions of 17-hydroxysteroid (17-OHS) and free cortisol were used. MAIN RESULTS: 156 patients had pituitary disease, 15 had ectopic ACTH secretion, and 15 had no diagnosis after pituitary surgery. Of those 15 patients, 14 were ultimately classified as having pituitary disease on the basis of follow-up, and 1 was found to have ACTH-independent Cushing syndrome. After administration of metyrapone, stimulation of 17-OHS excretion greater than 70% or of a plasma 11-deoxycortisol level greater than 400-fold did not result in the misclassification of any of the patients with surgically confirmed cases of ectopic ACTH secretion. When these criteria were combined, the percentage of correct predictions (122 of 186 [71%; 95% CI, 62% to 79%]) was higher than that for either steroid alone (116 of 186 [62%; CI, 52% to 71%]) for excretion of 17-OHS and that for plasma 11-deoxycortisol (82 of 186 [44%; CI, 34% to 54%]). When the criteria for both the metyrapone test and the dexamethasone test were combined, the percentage of correct predictions (153 of 186 [82%; CI, 75% to 87%]) was higher than that obtained when the criteria for either test alone were used (P = 0.001). Similar results were found when the 15 patients with indeterminate surgery were assigned to the appropriate group on the basis of follow-up. When the criteria for both the metyrapone and dexamethasone tests were combined to identify patients with the pituitary Cushing syndrome, the sensitivity and diagnostic accuracy improved to 88% and 89%, respectively. CONCLUSIONS: The metyrapone test, which can be done in 48 hours, has a sensitivity and specificity for the diagnosis of the Cushing syndrome identical to that of the standard 6-day high-dose dexamethasone suppression test. Combining both tests results in greater accuracy than that obtained with either test alone.

Abnormal hypothalamic-pituitary-adrenal function in anorexia nervosa. Pathophysiologic mechanisms in underweight and weight-corrected patients.

To study the pathophysiology of hypercortisolism in patients with anorexia nervosa, we examined plasma ACTH and cortisol responses to ovine corticotropin-releasing hormone before and after correction of weight loss. We also studied patients with bulimia whose weight was normal, since this disorder has been suspected to be a variant of anorexia nervosa. Before their weight loss was corrected, the anorexic patients had marked hypercortisolism but normal basal plasma ACTH. The hypercortisolism was associated with a marked reduction in the plasma ACTH response to corticotropin-releasing hormone. When these patients were studied three to four weeks after their body weight had been restored to normal, the hypercortisolism had resolved but the abnormal response to corticotropin-releasing hormone remained unchanged. On the other hand, at least six months after correction of weight loss their responses were normal. The bulimic patients whose weight was normal also had a normal response to corticotropin-releasing hormone. We conclude that in underweight anorexics, the pituitary responds appropriately to corticotropin-releasing hormone, being restrained in its response by the elevated levels of cortisol. This suggests that hypercortisolism in anorexics reflects a defect at or above the hypothalamus. The return to eucortisolism soon after correction of the weight loss indicates resolution of this central defect despite persistence of abnormalities in adrenal function.

Pharmacology of ovine and human CRH.

In primates, ovine and human CRH cause ACTH- and cortisol secretion in a dose-dependent fashion. Ovine CRH has a half-life, which is about three times longer than that of human CRH and results in long lasting ACTH- and cortisol responses. Plasma ACTH- and cortisol rises after administration of human CRH mimic the spontaneously occurring secretory episodes of these hormones in man. Pulsatile administration of human CRH restores the diurnal secretory pattern of ACTH and cortisol to normal in patients with apparent CRH deficiency. Facial and upper body flush occur in about 20% of patients receiving intravenously a 1 microgram/kg dose of CRH. Higher doses result in hypotension due to a decrease in peripheral vascular resistance. The latter is primarily due to dilatation of the superior mesenteric vessels. In in vitro models desensitization of the pituitary corticotroph by continuous, high-dose CRH administration occurs. No down-regulation of ACTH- and cortisol secretion has been shown in vivo, however. Pituitary-adrenal responsiveness to CRH can be modulated by many factors. These factors are involved in the basal regulation of the hypothalamic-pituitary-adrenal axis and in its activation during the stress response. Such factors include AVP, morphine, DAMME, and drugs modulating the endogenous serotoninergic and GABA/benzodiazepine system. Glucocorticoid feedback inhibition of the pituitary is one of the most important factors modulating ACTH- and cortisol responses to CRH. A negative correlation exists between the net ACTH- and cortisol response to exogenous CRH and the basal cortisol plasma concentration. Replacement doses of glucocorticoid result in a drastic decrease of basal plasma concentrations of cortisol and adrenal androgens.(ABSTRACT TRUNCATED AT 250 WORDS)