A new less-invasive and more informative low-dose ACTH test: salivary steroids in response to intramuscular corticotrophin

OBJECTIVE: The intravenous low-dose ACTH test has been proposed as a sensitive tool to assess adrenal function through circulating steroids. The aims of this study were to: (a) find the minimal intramuscular ACTH dose that induced serum and salivary cortisol and aldosterone responses equivalent to those obtained after a pharmacological dose of ACTH; and (b) define the minimum normal salivary cortisol and aldosterone responses in healthy subjects to that dose of ACTH. We also compared the performances of the standard- and low-dose ACTH intramuscular tests to screen patients with known hypothalamo-pituitary-adrenal impairments. DESIGN: Rapid ACTH tests were performed in individuals using various intramuscular doses (12.5, 25 and 250 microg) at 2-week intervals. SUBJECTS: Twenty-one healthy volunteers and 19 patients with primary (nine cases) and secondary (10 cases) adrenal insufficiency. MEASUREMENT: Serum and salivary cortisol and aldosterone concentrations were measured at baseline and after ACTH. Serum cortisol > or = 552.0 nmol/l and aldosterone > or = 555.0 pmol/l concentrations at 30 min after 250 microg of ACTH were defined as normal responses. RESULTS: In healthy volunteers cortisol and aldosterone responded to ACTH in a dose-dependent manner. The time to peak in saliva for each steroid was delayed as the dose of ACTH increased. The minimum ACTH dose that produced equivalent steroid responses at 30 min to 250 microg of ACTH (standard-dose test; SDT) was 25 microg (low-dose test; LDT). Saliva collection 30 min after LDT and SDT showed cortisol and aldosterone concentrations of at least 20.0 nmol/l and 100.0 pmol/l, respectively. These values were defined as normal steroid responses. Blunted salivary steroid responses to LDT and SDT were found in all patients with primary adrenal insufficiency. Subnormal salivary cortisol levels in response to LDT and SDT were found in all patients with secondary adrenal insufficiency. In five patients full recovery of adrenal function was demonstrated by both tests after steroid withdrawal. In the follow-up of four patients studied during the recovery period, subnormal SAF response after LDT and normal after SDT was demonstrated. Preservation of the adrenal glomerulosa was found in all the patients with secondary adrenal insufficiency through the normal rise in salivary aldosterone after both LDT and SDT. CONCLUSIONS: Adrenal function can be accurately investigated with simultaneous measurements of salivary cortisol and aldosterone in response to 25 microg of corticotrophin injected into the deltoid muscle. Our data suggest that this may become a useful and relatively noninvasive clinical tool to detect subclinical hypoadrenal states.     

The corticotropin-releasing hormone stimulation test: a possible aid in the evaluation of patients with adrenal insufficiency

Ten patients with adrenal insufficiency receiving chronic glucocorticoid therapy were studied. All had subnormal plasma cortisol responses to ovine corticotropin-releasing hormone ( CRH ) (1 microgram/kg as an iv bolus) 12-60 h after discontinuation of steroid treatment. Plasma ACTH responses to CRH fell into three different patterns. The first three patients with primary adrenal insufficiency had high basal ACTH levels and augmented ACTH responses to CRH . A fourth such patient, however, treated with pharmacologic doses of prednisone, had a low normal ACTH response. Patients with secondary adrenal insufficiency had either low basal ACTH levels and diminished responses to CRH or low basal ACTH values but prolonged and augmented plasma ACTH responses to CRH with a delayed peak. We postulate that the group of patients with the former pattern have pituitary gland destruction whereas the patients with the latter pattern have hypothalamic CRH deficiency. Thus, CRH may be useful in differentiating between hypothalamic and pituitary causes of adrenal insufficiency.     

Assessment of adrenal function in cirrhotic patients using concentration of serum‐free and salivary cortisol

Objective: Because over 90% of serum cortisol is bound to albumin and corticosteroid‐binding globulin (CBG), changes in these proteins can affect measures of serum total cortisol levels in cirrhotics without altering serum‐free and salivary cortisol concentrations. Methods: We assessed basal (T₀) and post‐synacthen (T₆₀) serum total cortisol, serum‐free and salivary cortisol in 125 consecutive cirrhotics (95 non‐septic and 30 septic patients with a Child>8). Results: Serum total cortisol levels significantly decreased from the Child A–C non‐septic group, as did albumin and CBG levels, with a non‐significant rise in serum‐free cortisol concentrations. Non‐septic patients with low albumin (≤25 g/L) or CBG levels (≤35 mg/L) had lower T₀ serum total cortisol levels than patients with near‐normal albumin (303.4 vs. 382.6 nmol/L; P=0.0035) or with normal CBG levels (289.9 vs. 441.4 nmol/L; P<0.0001), respectively, despite similar serum‐free cortisol or salivary cortisol concentrations. Subnormal T₆₀ serum total cortisol concentrations (<510.4 nmol/L) were measured in 7.2% of all patients (Child C: 14.5% vs. Child A and B: 0%; P=0.0013) but no patients exhibited symptoms suggesting adrenal insufficiency. Patients with or without subnormal T₆₀ total cortisol had similar T₀ salivary cortisol and serum‐free cortisol concentrations. A trend was observed towards high serum‐free cortisol concentrations and mortality in multivariate analysis. Conclusions: Serum total cortisol levels overestimated the prevalence of adrenal dysfunction in cirrhotics with end‐stage liver disease. Since serum‐free cortisol cannot be measured routinely, salivary cortisol testing could represent a useful approach but needs to be standardized.     

Reproducibility of the cortisol response to stimulation with the low dose (1 microg) of ACTH.

OBJECTIVE: Previous studies have shown that the rapid ACTH stimulation test using a low dose of 1 microg is more sensitive than that using 250 microg ACTH for detecting subtle cases of adrenal insufficiency. However, there are controversies for the reproducibility of the 1 microg-test. To evaluate the reproducibility of the 1 microg-test, we assessed both day-to-day and diurnal variations of cortisol responses to 1 microg ACTH injection. In addition, optimum sampling time for the 1 microg-test was also determined. SUBJECTS: AND DESIGN Eight healthy volunteers and five patients with secondary adrenal insufficiency were recruited. Healthy subjects were given 1 microg ACTH 3 times in the morning (0800 h) and 2 times in the afternoon (1600 h). Patients with adrenal insufficiency had 2-tests in the morning and 2 in the afternoon. Serum cortisol levels were measured every 10 minutes for 1 h after the injection. RESULTS: In healthy subjects, basal and peak serum cortisol levels were significantly higher in the morning (P < 0.05), whereas maximum cortisol increments were higher in the afternoon (P < 0.001). In patients with adrenal insufficiency, basal and peak serum cortisol levels in the morning were not different from corresponding values in the afternoon. Intra-individual coefficient of variation (CV) of peak serum cortisol response to 1 microg ACTH ranged from 3.0 to 16.4% in healthy subjects and 10.0-34. 4% in patients. Also, there was a significant correlation between peak morning or afternoon cortisol levels after 1 microg ACTH injection given in different days in both healthy subjects and patients. Twenty-six of the 40 studies in healthy subjects showed peak response at 20 minutes, while nine showed it at 30 minutes Using the data acquired at 20 and 30 minutes, all 40 studies in healthy subjects showed normal results while none of 20 studies in patients was normal. CONCLUSIONS: We conclude that the cortisol response to 1 microg ACTH stimulation was reproducible in both healthy subjects and patients with secondary adrenal insufficiency. In order to assess adrenal function more accurately with the 1 microg ACTH stimulation test, serum cortisol should be measured before and 20 and 30 minutes after ACTH injection.     

Reduced serum levels of dehydroepiandrosterone sulphate in adrenal incidentalomas: a marker of adrenocortical tumour

BACKGROUND AND OBJECTIVE Reduced serum levels of dehydroeplandrosterone sulphate (DHEAS) have been shown In patients with Cushing's syndrome resulting from adrenocortical adenoma, In contrast with normal DHEAS levels In patients with Cushing's disease. The elm of this study was to verify whether patients with incidentally discovered adrenocortical adenomas also have reduced levels of DHEAS. DESIGN Evaluation of serum DHEAS, serum and urinary cortisol, plasma ACTH and low dose dexamethasone suppression test In patients with adrenal Incidentaloma and Cushing's syndrome. PATIENTS Thirty-two patients with adrenal Incidentaloma and, as controls, 17 patients with overt Cushing's syndrome, were studied. RESULTS Serum DHEAS levels lower than normal were found In 21/24 (81.5 %) patients with adrenocortical Incidentaloma, but In only 1/8 patients with a mass of non-adrenocortical origin. This patient had massive bilateral metastatic infiltration of both adrenal glands and primary adrenal failure. The prevalence of low DHEAS levels in the two groups was significantly different (P= 00001). In patients with adrenocortical Incidentaloma, the prevalence of low DHEAS levels was significantly higher (P= 00001) than that found for some hormonal alterations Indicating pre-clinical hypercortlsoilsm (high urinary cortisol, unsuppressed serum cortisol after low dose dexamethasone administration and low plasma ACTH). Low DHEAS levels were found in all patients with Cushing's syndrome due to adrenocortical adenoma but in none of those with Cushing's disease. CONCLUSIONS Our results Indicate that the finding of low DHEAS levels can be considered a marker of the adrenocortical origin of an adrenal Incidentaloma, provided adrenal failure has been excluded.     

Hypothalamic pituitary adrenal function during critical illness: limitations of current assessment methods

CONTEXT: Activation of the hypothalamic-pituitary-adrenal (HPA) axis represents one of several important responses to stressful events and critical illnesses. Despite a large volume of published data, several controversies continue to be debated, such as the definition of normal adrenal response, the concept of relative adrenal insufficiency, and the use of glucocorticoids in the setting of critical illness. OBJECTIVES: The primary objective was to review some of the modulating factors and limitations of currently used methods of assessing HPA function during critical illness and provide alternative approaches in that setting. DESIGN: This was a critical review of relevant data from the literature with inclusion of previously published as well as unpublished observations by the author. Data on HPA function during three different forms of critical illnesses were reviewed: experimental endotoxemia in healthy volunteers, the response to major surgical procedures in patients with normal HPA, and the spontaneous acute to subacute critical illnesses observed in patients treated in intensive care units. SETTING: The study was conducted at an academic medical center. PATIENTS/PARTICIPANTS: Participants were critically ill subjects. Intervention: There was no intervention. MAIN OUTCOME MEASURE: The main measure was to provide data on the superiority of measuring serum free cortisol during critical illness as contrasted to those of total cortisol measurements. RESULTS: Serum free cortisol measurement is the most reliable method to assess adrenal function in critically ill, hypoproteinemic patients. A random serum free cortisol is expected to be 1.8 microg/dl or more in most critically ill patients, irrespective of their serum binding proteins. Because the free cortisol assay is not currently available for routine clinical use, alternative approaches to estimate serum free cortisol can be used. These include calculated free cortisol (Coolens' method) and determining the free cortisol index (ratio of serum cortisol to transcortin concentrations). Preliminary data suggest that salivary cortisol measurements might be another alternative approach to estimating the free cortisol in the circulation. When serum binding proteins (albumin, transcortin) are near normal, measurements of total serum cortisol continue to provide reliable assessment of adrenal function in critically ill patients, in whom a random serum total cortisol would be expected to be 15 microg/dl or more in most patients. In hypoproteinemic critically ill subjects, a random serum total cortisol level is expected to be 9.5 microg/dl or more in most patients. Data on Cosyntropin-stimulated serum total and free cortisol levels should be interpreted with the understanding that the responses in critically ill subjects are higher than those of healthy ambulatory volunteers. The Cosyntropin-induced increment in serum total cortisol should not be used as a criterion for defining adrenal function, especially in critically ill patients. CONCLUSIONS: The routine use of glucocorticoids during critical illness is not justified except in patients in whom adrenal insufficiency was properly diagnosed or others who are hypotensive, septic, and unresponsive to standard therapy. When glucocorticoids are used, hydrocortisone should be the drug of choice and should be given at the lowest dose and for the shortest duration possible. The hydrocortisone dose (50 mg every 6 h) that is mistakenly labeled as low-dose hydrocortisone leads to excessive elevation in serum cortisol to values severalfold greater than those achieved in patients with documented normal adrenal function. The latter data should call into question the current practice of using such doses of hydrocortisone even in the adrenally insufficient subjects.     

Hypothalamic-pituitary adrenal function in end-stage non-alcoholic liver disease

Abstract Patients with end-stage liver disease have significant mortality often associated with intercurrent episodes of bleeding or sepsis. Intact adrenal function is essential in such situations. In order to test the hypothesis that adrenal insufficiency might be present in severe liver disease, hypothalamic-pituitary adrenal function was evaluated in patients with end-stage liver disease awaiting transplantation. The study had a prospective, open comparative design with patients restricted to those having non-alcoholic liver disease in order to avoid the confounding direct effects of alcohol on adrenocortical function. Fifty-one consecutive patients with end-stage, non-alcoholic liver disease undergoing evaluation for liver transplantation and 40 healthy controls were studied. Patients who had used corticosteroids (n= 8) or who were unable to complete the investigations (n= 5) were excluded leaving 38 patients eligible for analysis. Adrenal function was evaluated under basal conditions by single morning measurements of plasma total and free cortisol, corticosteroid-binding globulin, dehydroepiandrosterone sulfate and by adrenal stimulation indirectly using insulin-induced (0.1 U/kg, i.v.) hypoglycaemia and/or directly by adrenocorticotrophic hormone (ACTH); 250 μg tetracosactrin, i.v.) stimulation. Compared with healthy controls, patients with liver disease had a 64% reduction in maximal increments of plasma cortisol to indirect adrenal stimulation via insulin-induced hypoglycaemia and a 39% reduction to direct adrenal stimulation by ACTH (all P < 0.001). There was a significant negative correlation between the severity of underlying liver disease as assessed by Child-Pugh scores and peak control responses to ACTH (r= -0.647, P < 0.0001) and insulin-induced hypoglycaemia (r= -0.597, P < 0.0001). Patients with liver disease also exhibited significantly blunted and delayed hypoglycaemic responses to insulin (0.1 U/kg), brisker growth hormone responses of reduced magnitude and decreased corticosteroid-binding globulin levels. Baseline morning cortisol, free cortisol and dehydroepiandrosterone sulfate levels were unchanged compared with healthy controls. Patients on spironolactone had lower basal and peak cortisol responses to ACTH and hypoglycaemia, but the reductions were unrelated to spironolactone dose. Although insulin resistance and spironolactone therapy are confounding factors, it can be concluded that hypothalamic-pituitary regulation of adrenal function is defective in end-stage non-alcoholic liver disease. It is therefore possible that functional central adrenal insufficiency might contribute to the mortality of patients with end-stage liver disease and raises the question of the need for controlled studies of adrenocortical replacement therapy during acute deteriorations (sepsis and haemorrhage) in severe hepatic disease.     

High prevalence of adrenal suppression during acute illness in hospitalized patients receiving megestrol acetate

INTRODUCTION: Megestrol acetate (MA) is a progestational agent used for palliation of breast and endometrial cancer. The drug promotes weight gain via appetite stimulation. This property has led to widespread use in patients with wasting illnesses. Increasing numbers of reports suggest glucocorticoid activity. OBJECTIVE: Unrecognized adrenal suppression may result from MA use. This is the first study to examine the prevalence of adrenal suppression in hospitalized patients treated with MA. SUBJECTS AND DESIGN: This is a cross-sectional study of hospitalized patients receiving MA compared to control subjects. Morning cortisol levels, endocrine signs and symptoms, and duration of MA therapy were evaluated in 28 hospitalized medical patients treated with MA, and 21 control patients admitted to the same hospital service during the study period. RESULTS: Median cortisol levels were significantly lower in patients using MA vs controls (160 vs 386 nmol/l, p=0.003). Forty-three percent of subjects on MA demonstrated morning cortisol levels below the normal range (138-690 nmol/l), compared with 10% of controls (p=0.013). Ninety-three percent of subjects taking MA had morning cortisol levels below the level that excludes adrenal insufficiency in hospitalized patients (497 nmol/l) vs 71% of controls (p=0.06). CONCLUSIONS: MA use is associated with significant adrenal suppression in acutely ill individuals. This should alert physicians to the possibility of adrenal insufficiency and the need to assess for signs or symptoms of adrenal insufficiency, and mandates a low threshold for testing adrenal function in hospitalized patients taking MA.     

Salivary cortisol measurement: a practical approach to assess pituitary-adrenal function

The salivary cortisol concentration is an excellent indicator of the plasma free cortisol concentration. To establish its normal and pathological ranges, salivary cortisol concentrations were measured in 101 normal adults, 18 patients with Cushing's syndrome, and 21 patients with adrenal insufficiency. The normal subjects had a mean (+/- SEM) salivary cortisol concentration of 15.5 +/- 0.8 nmol/L (range, 10.2-27.3) at 0800 h and 3.9 +/- 0.2 nmol/L (range, 2.2-4.1) at 2000 h (n = 20). The mean value 60 min after ACTH administration in 58 normal subjects was 52.2 +/- 2.2 nmol/L (range, 23.5-99.4), and it was 1.4 +/- 1.1 nmol/L (range, 1.6-3) at 0800 h in 23 normal subjects given 1 mg dexamethasone 8 h earlier. In patients with primary or secondary adrenal insufficiency (n = 21) the mean salivary cortisol level was 7.5 +/- 0.4 nmol/L (range, 1.9-21.8) 60 min after ACTH. In patients with Cushing's syndrome (n = 7), the mean value after the 1-mg dexamethasone suppression test was 16.1 +/- 7.8 nmol/L (range, 5.8-66.8). No overlap was found between the values in the normal subjects and those in the patients during the dynamic tests. Discrepancies between salivary and total plasma cortisol were found in 8 patients with adrenal insufficiency, which may be explained by the effects of drugs such as thyroid hormones, Op'-dichlorodiphenyldichloroethane, and psychotropic agents. We conclude that salivary cortisol measurements are an excellent index of plasma free cortisol concentrations. They circumvent the physiological, pathological, and pharmacological changes due to corticosteroid-binding globulin alterations and offer a practical approach to assess pituitary-adrenal function.     

SALIVARY CORTISOL LEVELS IN TRUE AND APPARENT HYPERCORTISOLISM

Total plasma cortisol measurements may be misleading when there are variations in the plasma cortisol-binding protein capacity resulting from drugs, pregnancy or congenital alterations in cortisol-binding globulin (CBG). Salivary cortisol levels, which represent the free component of plasma cortisol, are less affected by alterations in protein binding and have been used in the investigation of hypothalamic-pituitary-adrenal disorders. This study compares these two indices of adrenal function in conditions of true hypercortisolism and spurious hypercortisolism (resulting from oral contraceptive medication or pregnancy). The circadian variation of cortisol in plasma and saliva was studied in six patients with unequivocal hypercortisolism and compared with normal volunteers. In the normal group, plasma and salivary cortisol levels taken at 0900 h were significantly higher than those taken at 2400 h. Patients with Cushing's syndrome failed to show a significant difference between plasma and salivary cortisol levels collected at 0900 and 2400 h. Five patients with pituitary-dependent Cushing's disease, one patient with an adrenal carcinoma causing Cushing's syndrome and seven normal subjects each received a dexamethasone suppression test using a continuous infusion of dexamethasone sodium phosphate at a rate of 1 mg/h. There was no significant difference in the half-life disappearance rate of endogenous cortisol in either plasma or saliva comparing grouped data from patients with pituitary-dependent Cushing's disease with that of normal subjects. Failure of suppression of both plasma and salivary cortisol levels was observed in the one patient with adrenal carcinoma during dexamethasone infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Measurement of salivary cortisol in 2012 – laboratory techniques and clinical indications

The utility of measuring salivary cortisol has become increasingly appreciated since the early 1980s. Salivary cortisol is a measure of active free cortisol and follows the diurnal rhythm of serum or plasma cortisol. The saliva sample may be collected by drooling or through the use of absorbent swabs which are placed into the mouth until saturated. Salivary cortisol is therefore convenient for patients and research participants to collect noninvasively on an outpatient basis. Several assay techniques have been used to measure salivary cortisol, including radioimmunoassay and more recently liquid chromatography–tandem mass spectrometry. The analytical sensitivity varies between these assay methods, as does the potential for cross‐reactivity with other steroids. The interpretation of salivary cortisol levels relies on rigorous standardization of sampling equipment, sampling protocols and assay technology with establishment of a local reference range. Clinically, the commonest use for salivary cortisol is measuring late‐night salivary cortisol as a screening test for Cushing's syndrome. Several studies have shown diagnostic sensitivities and specificities of over 90%, which compares very favourably with other screening tests for Cushing's syndrome such as the 24‐h urinary‐free cortisol and the 1‐mg overnight dexamethasone suppression test. There are emerging roles for the use of salivary cortisol in diagnosing adrenal insufficiency, particularly in conditions associated with low cortisol–binding globulin levels, and in the monitoring of glucocorticoid replacement. Finally, salivary cortisol has been used extensively as a biomarker of stress in a research setting, especially in studies examining psychological stress with repeated measurements.     

The value of dehydroepiandrosterone sulfate measurements in the assessment of adrenal function

Dehydroepiandrosterone (DHEA) and its sulfated ester (DHEA-S) are corticotropin-dependent adrenal androgen precursors that are uniformly low in treated patients with corticotropin deficiency. There are no data investigating the diagnostic value of DHEA-S measurements in the prospective assessment of adrenal function. This study examined serum DHEA-S levels as possible markers for hypothalamic- pituitary-adrenal (HPA) function in patients with large pituitary adenomas. Patients were characterized to have normal HPA (n = 47) or abnormal HPA (ABN-HPA, n = 35) function based on their respective responses to insulin-induced hypoglycemia. Patients also underwent low-dose Cortrosyn (1 micro g, LDC) and standard-dose Cortrosyn stimulation testing. All patients with ABN-HPA had very low age- and gender-matched serum DHEA-S levels. When the normal response to LDC was set at a cortisol level of at least 18.1 micro g/dl, 10 of 31 patients with ABN-HPA exhibited normal responses. Receiver operating characteristic curves for baseline DHEA-S and for maximal cortisol responses to LDC had areas of 0.984 (confidence interval, 0.962-1.000) and 0.893 (confidence interval, 0.817-0.969), respectively. LDC- or SDC-stimulated serum cortisol levels have significant limitations in defining HPA function. A normal age- and gender-specific serum DHEA-S level makes the diagnosis of corticotropin deficiency extremely unlikely. However, when serum DHEA-S levels are low, further testing is necessary to define HPA function.     

Comparison of time-integrated measurement of salivary corticosteroids by oral diffusion sink technology to plasma cortisol.

We report preliminary data on the standardization of a device used in the recently developed "Oral Diffusion Sink" (ODS) technology for the time-integrated measurement of salivary corticosteroids. The concentrations of corticosteroids collected with the ODS devices were compared to plasma cortisol and saliva corticosteroid levels measured simultaneously. Six volunteers installed the ODS devices into their mouths during unstimulated and ACTH (250 micrograms) stimulated periods. Blood and saliva samples were also collected during these periods. The integrated plasma cortisol response and saliva corticosteroid levels were strongly correlated with the time-integrated total corticosteroid measurement of the ODS devices as well as with the cortisol and cortisone fractions. This preliminary data suggests that the accuracy of assessing adrenocortical activity by the measurement of salivary corticosteroids collected with the ODS device is high in both normal and stimulated conditions in normal volunteers. Continued standardization and studies in the practical use of this technology could lead to an important tool in assessing adrenocortical abnormalities. The use of such technology would increase the convenience while reducing the cost and invasiveness of current provocative testing of adrenal functioning.     

Pathophysiology of deoxycorticosterone-secreting adrenal tumors

Two patients with hypermineralocorticoidism due to deoxycorticosterone (DOC) excess are described. The plasma 17-deoxysteroids of the zona fasciculata (ZF), namely DOC, corticosterone, 18-hydroxydeoxycorticosterone, and 18-hydroxycorticosterone, were elevated. Plasma androgen concentrations were normal, and plasma aldosterone and renin levels were low. One patient, who had benign adrenocortical adenoma, had normal plasma cortisol levels. The other patient, who had metastatic adrenocortical carcinoma, had low plasma cortisol, presumably due to elevated plasma corticosterone levels. While tumors producing only 17-deoxysteroids are rare, they have provided new insights into the regulation of 17-deoxysteroid secretion by the ZF. Presumptive suppression of a non-ACTH factor by adenoma-produced DOC transiently impaired the early postoperative responses to ACTH of the ZF 17-deoxysteroids of the contralateral adrenal. The dissociation of 17-deoxysteroids from cortisol in normal subjects given either dexamethasone or DOC acetate provides additional evidence for such a factor.     

Effects of repetitive administration of corticotropin-releasing hormone combined with lysine vasopressin on plasma adrenocorticotropin and cortisol levels in secondary adrenocortical insufficiency

To examine the functioning of the hypothalamo-pituitary-adrenocortical axis in secondary adrenocortical insufficiency, we administered 100 micrograms synthetic human CRH, iv, plus 10 U lysine-8-vasopressin (LVP), im, three times daily for 3 consecutive days. The changes in plasma ACTH and cortisol levels during the administration and the response to an insulin tolerance test (ITT) conducted before and after the administration were determined. In three patients with isolated ACTH deficiency, basal plasma ACTH and cortisol levels were undetectablly low, and there was no response noted in the ITT or during CRH-LVP administration throughout the observation period. In four patients with adrenocortical insufficiency who had undergone successful transsphenoidal microadenomectomy for Cushing's disease and in six patients who had undergone curative unilateral adrenalectomy for Cushing's syndrome, basal plasma ACTH levels were low, but responded considerably to both stimulation tests. Along with the 3 days of CRH-LVP stimulation, however, neither the peak nor the time-integrated ACTH response was significantly enhanced, because of the variability of the responses among the patients. Compared with the ACTH response on the last day of CRH-LVP stimulation, the subsequent ITT tended to induce a lower ACTH response in the post-Cushing's disease patients and a higher response in the post-Cushing's syndrome patients. Regarding the plasma cortisol levels, the basal, peak, and integrated responses tended to increase daily during CRH-LVP administration. Conversely, the ITT after repetitive CRH-LVP administration induced a higher cortisol response than the test before CRH-LVP administration in the post-Cushing's disease patients. No serious complications were noted in any of the patients during or after the treatment. The present findings indicate that 1) repetitive administration of CRH in combination with LVP is a safe and valuable provocation test to examine the pituitary ACTH reserve and the integrity of the pituitary-adrenocortical axis; 2) isolated ACTH deficiency is usually due to a defect at the pituitary level; 3) with respect to adrenocortical responsiveness, post-Cushing's disease patients show a better accumulation of the provocative effect than do post-Cushing's syndrome patients; and 4) both hypothalamic and pituitary dysfunction are responsible for adrenal hypofunction in patients after hypercortisolemia, but post-Cushing's syndrome patients (especially those with a short period of hypercortisolemia) appeared to have less impairment of hypothalamic ACTH-releasing activity than post-Cushing's disease patients.     

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.     

Adrenocortical function in patients with macrometastases of the adrenal gland

OBJECTIVE: Metastases of the adrenal gland are a frequent finding in patients with malignant tumors like bronchogenic carcinoma or breast cancer. Only limited and conflicting data on adrenocortical function in these patients are available. DESIGN: Cross-sectional study. METHODS: We investigated the impact of adrenal macrometastases on adrenocortical function in a series of 28 tumor patients using the ACTH(1-24) stimulation test and dexamethasone suppression test. Seven normal controls (Con), eleven patients without adrenal metastases (No Met), eight patients with unilateral (Uni Met) and nine patients with bilateral adrenal metastases (Bil Met) were investigated. RESULTS: The prevalence of adrenal insufficiency was low in our study population, with only two of nine patients with bilateral metastases having subclinical adrenocortical insufficiency. In the remaining patients with uni- or bilateral metastases, baseline and stimulated cortisol concentrations were higher than in controls and cancer patients without metastases (baseline cortisol (in nmol/l): Con: 307+/-33.2 vs Uni Met: 440+/-53.5, and Bil Met: 637.6+/-92.1, P=0.04 by ANOVA; cortisol 60 min after ACTH(1-24): Con: 794.6+/-41.2 vs Uni Met: 990.8+/-92.9, and Bil Met: 1151.4+/-155.5, P=0.03 by ANOVA). Simultaneously, baseline and stimulated serum aldosterone concentrations were significantly blunted in the tumor groups. CONCLUSIONS: Adrenal insufficiency is infrequent and develops only in patients with bilateral metastases. However, the majority of patients have activation of the hypothalamic-pituitary-adrenal axis despite adrenal metastases with strongly elevated cortisol concentrations.     

Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome.

Chronic fatigue syndrome is characterized by persistent or relapsing debilitating fatigue for at least 6 months in the absence of a medical diagnosis that would explain the clinical presentation. Because primary glucocorticoid deficiency states and affective disorders putatively associated with a deficiency of the arousal-producing neuropeptide CRH can be associated with similar symptoms, we report here a study of the functional integrity of the various components of the hypothalamic-pituitary-adrenal axis in patients meeting research case criteria for chronic fatigue syndrome. Thirty patients and 72 normal volunteers were studied. Basal activity of the hypothalamic-pituitary-adrenal axis was estimated by determinations of 24-h urinary free cortisol-excretion, evening basal plasma total and free cortisol concentrations, and the cortisol binding globulin-binding capacity. The adrenal cortex was evaluated indirectly by cortisol responses during ovine CRH (oCRH) stimulation testing and directly by cortisol responses to graded submaximal doses of ACTH. Plasma ACTH and cortisol responses to oCRH were employed as a direct measure of the functional integrity of the pituitary corticotroph cell. Central CRH secretion was assessed by measuring its level in cerebrospinal fluid. Compared to normal subjects, patients demonstrated significantly reduced basal evening glucocorticoid levels (89.0 +/- 8.7 vs. 148.4 +/- 20.3 nmol/L; P less than 0.01) and low 24-h urinary free cortisol excretion (122.7 +/- 8.9 vs. 203.1 +/- 10.7 nmol/24 h; P less than 0.0002), but elevated basal evening ACTH concentrations. There was increased adrenocortical sensitivity to ACTH, but a reduced maximal response [F(3.26, 65.16) = 5.50; P = 0.0015). Patients showed attenuated net integrated ACTH responses to oCRH (128.0 +/- 26.4 vs. 225.4 +/- 34.5 pmol/L.min, P less than 0.04). Cerebrospinal fluid CRH levels in patients were no different from control values (8.4 +/- 0.6 vs. 7.7 +/- 0.5 pmol/L; P = NS). Although we cannot definitively account for the etiology of the mild glucocorticoid deficiency seen in chronic fatigue syndrome patients, the enhanced adrenocortical sensitivity to exogenous ACTH and blunted ACTH responses to oCRH are incompatible with a primary adrenal insufficiency. A pituitary source is also unlikely, since basal evening plasma ACTH concentrations were elevated. Hence, the data are most compatible with a mild central adrenal insufficiency secondary to either a deficiency of CRH or some other central stimulus to the pituitary-adrenal axis. Whether a mild glucocorticoid deficiency or a putative deficiency of an arousal-producing neuropeptide such as CRH is related to the clinical symptomatology of the chronic fatigue syndrome remains to be determined.     

Serum dehydroepiandrosterone sulfate concentrations in secondary adrenal insufficiency

Serum dehydroepiandrosterone sulfate (DHEA-S) concentrations were studied in 84 untreated patients with secondary adrenal insufficiency. Compared to values in normal subjects of corresponding age, DHEA-S levels were decreased in 80 patients. The decrease was unrelated to the cause of the secondary adrenal insufficiency or the serum PRL level. Serum cortisol concentrations, on the other hand, were low in 71 patients and low normal in the remaining 13. Serum DHEA-S levels were decreased in 11 of these 13 patients. The frequency of decreased serum DHEA-S levels in patients with secondary adrenal insufficiency was significantly higher than that of decreased cortisol levels. These results suggest that decreased serum DHEA-S levels reflect deficient ACTH secretion in secondary adrenal insufficiency and that simultaneous determination of serum DHEA-S and cortisol levels is useful in the diagnosis of this pathological state.     

Fat distribution in obese women is associated with subtle alterations of the hypothalamic–pituitary–adrenal axis activity and sensitivity to glucocorticoids

OBJECTIVES: Obesity with abdominal body fat distribution (A-BFD) and hypothalamic-pituitary-adrenal (HPA) axis activity are somehow linked, but the exact interactions still need clarification. Obese subjects display normal circulating plasma cortisol concentrations with normal circadian rhythms. However, when the HPA axis is pharmacologically challenged, body fat distribution matters and then A-BFD obese women differ from those with subcutaneous body fat distribution (P-BFD). We hypothesized that lower dose provocative and suppressive tests than those used to diagnose hypercortisolism of tumour origin or adrenal insufficiency would shed some light on the characteristics of the HPA axis activity in relation with body fat distribution. PATIENTS AND METHODS: Fifty premenopausal obese women were grouped according to their body fat mass distribution. Their plasma cortisol responses to (i) two low doses of dexamethasone (0.25 and 0.5 mg) with (ii) low dose of the ACTH analogue tetracosactrin (1 microg) were assessed. Salivary cortisol was also determined during the ACTH test. RESULTS: A-BFD differed from P-BFD women in terms of HPA axis responsiveness. They had comparatively: (i) increased nocturnal cortisol excretion (9.38 +/- 2.2 vs. 6.82 +/- 0.91 nmol/micromol creatinine, A-BFD vs. P-BFD, respectively, P = 0.03); (ii) increased salivary cortisol response to ACTH stimulation (1 microg) [salivary cortisol peak: 33.4 (14.1-129) vs. 28.5 (13.2-42.8) nmol/l; salivary AUC: 825 (235-44738) vs. 537 (69-1420) nmol/min/l; A-BFD vs. P-BFD, P = 0.04 for both]; and (iii) increased pituitary sensitivity to dexamethasone testing [postdexamethasone (0.25 mg) plasma cortisol levels: 163 (26-472) vs. 318 (26-652) nmol/l and postdexamethasone (0.5 mg) plasma cortisol levels: 26 (26-79) vs. 33 (26-402) nmol/l; A-BFD vs. P-BFD, P = 0.01 for both). CONCLUSIONS: These data demonstrate differences in the HPA axis activity and sensitivity to glucocorticoids between obese women differing in their body fat distribution, with both enhanced negative and positive feedback in those with abdominal obesity. Several mechanisms may explain these differences: central vs. peripheral hypotheses. Thus, abdominal obesity does not appear to be linked solely to one pathophysiological hypothesis.