Response to low-dose pulsatile cortisol in Addison's disease with suspected corticotropinoma

A 65 year old woman with long-standing Addison's disease treated with oral glucocorticoid and mineralocorticoid replacement had persistently high ACTH levels, inadequate suppression of ACTH on low-dose dexamethasone, sellar enlargement, and pigmentation, and thus resembled patients alleged to develop corticotropinomas while on oral replacement for adrenal insufficiency. Since animal studies suggested that rapid rises of corticosteroids within the physiologic range can inhibit ACTH release, we administered brief infusions of cortisol every three hours with total daily dose equal to her chronic dose. Prompt suppression of ACTH and immunoreactive beta-endorphin occurred during each cortisol dose profiled, suggesting a role for ultradian cortisol fluctuations in tonic inhibition of ACTH secretion in humans, and a possible therapeutic benefit of mimicking ultradian cortisol rhythms during replacement therapy.     

Autonomy of cortisol secretion in clinically silent adrenal incidentaloma.

Recent progress in non-invasive imaging techniques have resulted in an increasing frequency of adrenal incidentaloma discovery. In addition, even clinically silent adrenal tumor has been suggested to possess a subtle production of adrenal hormones. The aim of the study was to ascertain the autonomy of cortisol production in clinically silent adrenocortical incidentaloma. We investigated the hypothalamic-pituitary-adrenal axis in 38 patients with adrenal incidentaloma. Basal plasma cortisol level was reproducibly within normal range in all the patients with adrenal incidentaloma, but was also normal in half of the Cushing's syndrome cases studied. Eighteen of 38 patients showed plasma cortisol above 3 microg/dl after 1 mg dexamethasone (Dex) and above 1 microg/dl after 8 mg Dex, respectively, and were defined as preclinical Cushing's syndrome. These patients were subjected to further evaluation of the autonomy of cortisol production. The incidence of positive findings indicating autonomy of cortisol secretion was as follows: suppressed basal plasma ACTH level in 44%, loss of normal diurnal rhythm in 79%, lack of ACTH response to CRF in 35%, decreased plasma DHEA-S level in 28%, significant laterality of 131I-adosterol uptake in 75%, atrophy of the contralateral side of the adrenal on CT scan in 6%, and histological atrophy of the adjacent adrenal cortex in 56%, respectively. The endocrine feature relevant to the hypothalamic-pituitary-adrenal axis varied from patient to patient, ranging from the non-functioning adrenal adenoma to Cushing's syndrome. In addition, the results of each test did not coincide with others in each patient. These results clearly demonstrated that the incidence of autonomy of cortisol production in the clinically silent adrenal incidentaloma is not infrequent, showing significant diversity. Systemic evaluation of the hypothalamic-pituitary-adrenal axis before adrenal surgery is warranted for an appropriate glucocorticoid replacement after adrenal surgery.     

A case of asymptomatic cortisol producing adrenal adenoma.

We describe a man without the clinical findings of Cushing's syndrome, but who harbored an incidentally found cortisol-producing adrenal adenoma. On adrenal 131I-adsterol imaging, there was good uptake to the nodule, but no visualization of the contralateral adrenal. No abnormalities were found in the basal plasma cortisol, ACTH, urinary free cortisol and 17OHCS. However, dynamic hormone assessment revealed the existence of abnormal cortisol secretion: no suppression to dexamethasone, incomplete response to human corticotropin-releasing hormone, and lack of diurnal variation in plasma cortisol. Left adrenalectomy was performed with the diagnosis of cortisol-producing adrenal tumor. The pathological finding was an adrenal adenoma, and the perifusion of the excised tissues revealed a negligible response of the tumor tissue to ACTH though the residual normal cortex responded. Postoperative course was uneventful without replacement therapy with cortisol. It is suggested that the tumor autonomously produced a small amount of cortisol not only insufficient to provide clinical Cushing's syndrome, but also to provide typical suppression of hypothalamo-pituitary corticotroph-adrenal system.     

Familial and iatrogenic cortisol receptor resistance.

Primary cortisol receptor resistance has been reported in 6 patients and 14 asymptomatic family members. We observed an additional 6 patients (2 males and 4 females). The male patients presented with hypertension. The female patients presented with acne, hirsutism and irregular menstruations. Dexamethasone therapy (1-1.5 mg/day) was of considerable clinical benefit. All 6 patients showed insufficient suppression of cortisol after 1 mg dexamethasone. The diurnal rhythm of ACTH and cortisol was intact, albeit at an elevated level. There was a normal increase of ACTH, cortisol, and GH to insulin-induced hypoglycemia, while cortisol production was (slightly) elevated. Adrenal androgen levels were increased in all patients. Glucocorticoid receptors measured in a whole cell dexamethasone binding assay in mononuclear leukocytes showed a lowered affinity in 1, and lowered numbers of receptors in 4 patients. In 1 patient no abnormalities were found. As a "bioassay" for glucocorticoid action dexamethasone suppressibility of mitogen-stimulated incorporation of [3H]thymidine in mononuclear leukocytes was measured. In this last patient dexamethasone suppressibility of [3H]thymidine incorporation was significantly lowered. Twelve months' treatment with 200 mg RU 486 per day in meningioma patients induced a similar biochemical picture as observed in primary cortisol receptor resistance. Partial cortisol receptor resistance might be less rare than previously thought. In the 6 patients presented at least 3 different forms can be recognized. Therapy with dexamethasone was successful in female patients with acne and hirsutism, as the secondary overproduction of adrenal androgens was effectively controlled. Chronic therapy with RU 486 causes a biochemical picture similar to primary cortisol receptor resistance.     

Effects of Short-Term Nocturnal Cortisol Replacement on Cognitive Function and Quality of Life in Patients with Primary or Secondary Adrenal Insufficiency: A Pilot Study

Cortisol replacement in patients with adrenal insufficiency usually consists of hydrocortisone (HC) given orally during day time. Due to the short half-life of hydrocortisone, cortisol levels between midnight and early morning are very low in contrast to the physiological rise of cortisol serum levels during this time. We investigated whether short-term cortisol replacement during the night improves cognitive function and well-being in these patients. Fourteen patients with adrenal insufficiency were put on HC infusion between midnight and 8 a.m. They subsequently underwent neurocognitive testing to measure intellectual functioning, concentration, memory and fine motor skills. Quality of life and mood were also evaluated. All tests were repeated after 2–4 weeks during usual oral glucocorticoid replacement therapy. Blood samples were taken for cortisol, epinephrine and norepinephrine measurement. With the exception of the digit symbol test with better scoring in the oral group (p = 0.005) there were no significant differences in neurocognitive testing, vegetative functions and quality of life on the two occasions. However, a higher cortisol level was associated with a worse performance in short-term memory. Plasma epinephrine concentration was subnormal in both groups, but increased only after intravenous hydrocortisone replacement. Mimicking the physiological rise in cortisol secretion during the night in this pilot study did neither significantly affect quality of life nor cognitive performance and vegetative functions. There was no improvement in general well being. Hydrocortisone infusion during night time might improve adrenomedullary reserve in patients with adrenal insufficiency.     

Exploring the Impact of Short- and Long-Term Hydrocortisone Replacement on Cognitive Function,Quality of Life and Catecholamine Secretion: A Pilot Study

Hydrocortisone (HC) substitution is essential in the treatment for patients with adrenal insufficiency (AI). Current replacement regimens however only incompletely mimic the physiological circadian rhythm of cortisol secretion, thereby resulting in subclinical temporary hypo- and hypercortisolism. Several studies point toward impairment of cognitive functions under these conditions, in part due to affected catecholamine secretion. Aim of this study was to evaluate the influence of long-term versus short-term HC replacement therapy on the adrenomedullary system and cognitive functions. Fourteen patients with primary or secondary AI were divided into two groups, depending on the duration of disease and HC replacement therapy (<15 years). All subjects underwent standardized neurocognitive testing; in addition, cortisol and catecholamine levels as well as physiological parameters and quality of life (QoL) were assessed. Patients with HC replacement therapy ≥15 years (n = 7) received significantly higher equivalent glucocorticoid doses than those with a shorter lasting therapy (n = 7; p = 0.048). Neuropsychological tests, QoL, physiological parameters, and cortisol levels did not differ significantly between both groups. Of note, norepinephrine levels were significantly lower in patients on short-term HC replacement therapy (p = 0.025). However, there were no significant differences in catecholamines with respect to the underlying pathophysiology, gender, or age. Irrespective of the duration of use, male patients scored significantly better for single aspects of QoL, whereas females performed significantly better in the attention test. Overall, we showed that duration of cortisol replacement therapy may have an impact on catecholamine release, but does not seem to affect cognitive functions and QoL.     

Antenatal glucocorticoids reset the level of baseline and hypoxemia-induced pituitary-adrenal activity in the sheep fetus during late gestation

This study examined the effects of dexamethasone treatment on basal hypothalamo-pituitary-adrenal (HPA) axis function and HPA responses to subsequent acute hypoxemia in the ovine fetus during late gestation. Between 117 and 120 days (term: approximately 145 days), 12 fetal sheep and their mothers were catheterized under halothane anesthesia. From 124 days, 6 fetuses were continuously infused intravenously with dexamethasone (1.80 +/- 0.15 microg.kg(-1).h(-1) in 0.9% saline at 0.5 ml/h) for 48 h, while the remaining 6 fetuses received saline at the same rate. Two days after infusion, when dexamethasone had cleared from the fetal circulation, acute hypoxemia was induced in both groups for 1 h by reducing the maternal fraction of inspired O2. Fetal dexamethasone treatment transiently lowered fetal basal plasma cortisol, but not ACTH, concentrations. However, 2 days after treatment, fetal basal plasma cortisol concentration was elevated without changes in basal ACTH concentration. Despite elevated basal plasma cortisol concentration, the ACTH response to acute hypoxemia was enhanced, and the increment in plasma cortisol levels was maintained, in dexamethasone-treated fetuses. Correlation of fetal plasma ACTH and cortisol concentrations indicated enhanced cortisol output without a change in adrenocortical sensitivity. The enhancements in basal cortisol concentration and the HPA axis responses to acute hypoxemia after dexamethasone treatment were associated with reductions in pituitary and adrenal glucocorticoid receptor mRNA contents, which persisted at 3-4 days after the end of treatment. These data show that prenatal glucocorticoids alter the basal set point of the HPA axis and enhance HPA axis responses to acute stress in the ovine fetus during late gestation.     

Dynamics of endogenous glucocorticoid secretion and its metabolism in Kawasaki disease

Objective

Kawasaki disease (KD) is a severe inflammatory disease that occurs in childhood. Recently, the initial corticosteroid therapy for KD has been reconsidered because its efficacy is controversial. The aim of this study was to evaluate the dynamic change in endogenous glucocorticoid levels and their relation with 11beta-hydroxysteroid dehydrogenase (11β-HSD) activity in the acute phase of KD.

Study design

Sixteen KD patients were investigated. Cortisol and cortisone levels, the cortisol/cortisone ratio and C-reactive protein (CRP) levels were measured on admission, before the first intravenous immunoglobulin (IVIG) therapy and convalescence.

Results

The 16 patients were divided into two groups. Group A included patients who received the first IVIG on admission and blood samples were collected before the first IVIG and convalescence. Group B included patients whose blood samples were collected at three different time points (on admission, before the first IVIG, and convalescence). CRP and cortisol levels and the cortisol/cortisol ratio were markedly higher before the first IVIG than those of convalescence in all patients except in one patient. In Group B patients, both serum cortisol levels and the cortisol/cortisone ratio on admission were significantly increased compared with those before the first IVIG (cortisol: p < 0.005, cortisol/cortisone: p < 0.001).

Conclusions

Decreases in cortisol levels and the cortisol/cortisone ratio before the first IVIG may be explained by a reduction in adrenal secretion and/or local glucocorticoid action through 11β-HSD activity. These findings suggest that exogenous glucocorticoid treatment in combination with the first IVIG at the acute stage may play a synergetic role in KD.     

Diagnostic value of salivary cortisol in end stage renal disease

OBJECTIVES: Salivary cortisol has been proposed a surrogate marker for free serum cortisol measurements. The aim of this study was to ascertain the diagnostic value of basal and stimulated salivary cortisol for the detection of adrenal insufficiency (AI) in hypotensive end stage renal disease (ESRD) patients. Basal salivary cortisol and basal total serum cortisol were studied in order to determine the accuracy of both biomarkers in predicting AI. PATIENTS AND METHODS: Twenty-nine ESRD patients with sustained hypotension were investigated for possible AI. Salivary cortisol was assessed at baseline and 30min after 25microg ACTH i.m. (LDTs). The dosage of salivary aldosterone was performed in salivary cortisol hypo-responders. Basal blood samples were drawn for steroids, renin and ACTH measurements. RESULTS: A clear separation between patients with normal and impaired adrenal function was obtained through salivary cortisol levels at 30min after ACTH. AI was detected in six cases (21%) through impaired salivary cortisol responses; stimulated salivary aldosterone helped to differentiate primary (n=3) from secondary AI (n=3). ROC curves showed that cutoff values for basal SAF < or =4.4nM and serum cortisol < or =232.0nM suggest AI (sensitivities: 93% and 69%; specificities: 86.4% and 91%, respectively). CONCLUSIONS: We conclude that ACTH stimulated SAF is an accurate biomarker for the diagnosis of AI in hypotensive ESRD patients. Neither basal salivary cortisol nor serum cortisol showed 100% sensitivities for the detection of AI.     

Plasma cortisol and corticosterone concentrations in the golden hamster, (Mesocricetus auratus)

Because some recent studies of hamster adrenocortical function have depended on older studies that may have been inadequate or misinterpreted, the present study re-examined plasma corticosterone and cortisol concentrations in hamsters under several conditions to determine which plasma glucocorticoid predominated in this animal. Sensitive radioimmunoassays were used to measure separately the two glucocorticoids in the basal condition, after adrenocorticotropin (ACTH) treatment, after acute stress, and after chronic stress. In the basal condition, corticosterone concentrations were 3-4 times higher than those of cortisol. After stimulation, this difference disappeared, but rarely were any hamster's cortisol levels higher than their corticosterone levels. Both ACTH and acute stress elevated plasma corticosterone and cortisol concentrations, but only plasma cortisol concentrations were elevated following chronic stress. The dissociation between cortisol and corticosterone concentrations after chronic stress suggests that the two glucocorticoid hormones in the hamster may be regulated independently. The data also indicate that both corticosterone and cortisol should be measured when assessing adrenocortical function in the hamster.     

Effects of cortisol treatment on brain and adrenal corticotropin-releasing hormone (CRH) content and other parameters regulated by CRH

Corticotropin-releasing hormone (CRH) has been found in both hypothalamic and extrahypothalamic sites of the brain and also in the adrenal medulla. To study the timing and location of delayed glucocorticoid action in rats, we measured the effects of 2-day and 7-day cortisol treatment on immunoreactive CRH concentrations in hypothalamus, cerebral cortex, hippocampus, cerebellum, and adrenal gland. The activity of the hypothalamo-pituitary-adrenal (HPA) axis and the sympathoadrenal system were also measured. Studies were carried out both in the afternoon and/or in the morning, to get information about possible circadian changes. CRH contents were not changed in any brain areas studied, except there was a trend of decrease in the hypothalamus compared to vehicle in the afternoon due to the lack of circadian increase after 7-day cortisol treatment. Pituitary ACTH content decreased significantly after 7-day treatment, while beta-endorphin did not. Plasma levels of ACTH, corticosterone, norepinephrine and epinephrine and adrenal ACTH and beta-endorphin contents decreased after 2-day, adrenal CRH content after 7-day treatment with cortisol. Our findings suggest, that chronic cortisol treatment inhibits the circadian activation of the HPA axis at all levels but has variable effects on baseline measures because it causes different changes in release and synthesis at different sites.     

Insights into endocrine-immunological disturbances in autoimmunity and their impact on treatment

The neuroendocrine immune (NEI) system is regarded as a fundamental network for the maintenance of health status (homeostasis), and it plays an important role in several systemic diseases, including autoimmune disorders. Among the major players of NEI pathways are steroid hormones of the adrenal (cortisol) and gonadal glands (sex hormones), neurohormones such as melatonin, and more recently the vitamin D endocrine system. Estrogens, melatonin and chronic stress (inducing decreased adrenal glucocorticoid release over a long time) strongly modulate the NEI system and stimulate the immune response. The vitamin D endocrine system is regarded as a potential immunosuppressive factor. Consequently, estrogens (especially in patients affected by B-cell-driven immunity) and melatonin should be avoided, and glucocorticoids (as replacement therapy) and vitamin D are allowed in the treatment of autoimmunity.     

Current Controversy Related to Glucocorticoid and Insulin Therapy in the Intensive Care Unit

ObjectiveTo review the controversy related to the widespread use of intensive insulin treatment (IIT) to maintain normoglycemia and of glucocorticoid replacement therapy in patients with sepsis in the intensive care unit (ICU).MethodsWe performed a MEDLINE search of the literature using a combination of words (critical/intensive care, endocrinology/endocrine, glucocorticoid/adrenal, insulin) to identify original studies and reviews on glucocorticoid therapy and IIT in the ICU.ResultsGlucocorticoid replacement therapy is advocated for patients with sepsis who have relative adrenal insufficiency. The current definition of relative adrenal insufficiency is poorly supported, and validated endocrine criteria that consistently identify ICU patients likely to benefit from glucocorticoid therapy are not yet available. IIT benefits postoperative patients at high risk of infection and patients who remain in the ICU more than 3 days. Potential harm caused by early IIT administration in medical ICU patients remains controversial. The role of early nutritional supplementation in major studies about IIT is largely unexplored. Improvements in insulin infusion protocols are needed to reduce the risk of hypoglycemia related to IIT.ConclusionEndocrine therapy in the ICU is entering a new era. Controversies remain related to glucocorticoid and insulin therapy even as interest in new, and old, endocrine therapies is being revived. (Endocr Pract. 2007;13:542-549)     

Clinical use of unbound plasma cortisol as calculated from total cortisol and corticosteroid-binding globulin

A method to calculate unbound cortisol from total cortisol (measured by competitive protein binding) and CBG (measured by radial immunodiffusion) based on the binding equilibrium has been evaluated. The calculated results (y) correlate well with those (x) obtained by centrifugal ultrafiltration at 37 degrees C (y = 1.04 x - 2.11 ng/ml; r = 0.975; n = 150). The concentration of CBG is similar in normal men (37.7 +/- 3.5 (SD) micrograms/ml; n = 12) and women (39.5 +/- 3.7 (SD) micrograms/ml; n = 7) and shows no diurnal variation, but marked diurnal variation is observed for total cortisol (193.7 +/- 35.0 (SD) ng/ml at 08.00 h vs 43.2 +/- 23.3 (SD) ng/ml at 22.00 h; n = 19) and particularly for unbound cortisol (16.5 +/- 5.6 (SD) ng/ml at 08.00 h vs 2.3 +/- 1.8 (SD) ng/ml at 22.00 h; n = 19). The concentration of CBG (89.1 +/- 11.2 (SD) micrograms/ml) and of total cortisol (395.6 +/- 103.3 (SD) ng/ml at 08.00 h; 110.3 +/- 16.6 (SD) ng/ml at 22.00 h) are clearly elevated in estrogen treated women (n = 11) but unbound cortisol levels (17.2 +/- 7.7 (SD) ng/ml at 08.00 h; 2.5 +/- 0.5 (SD) ng/ml at 22.00 h) are similar to the control group. The concentration of CBG is significantly decreased in patients with Cushing's syndrome (33.2 +/- 5.6 micrograms/ml; n = 17) and unbound cortisol is relatively more elevated than total cortisol in these patients. In adrenal insufficiently CBG is normal, but total and unbound cortisol are markedly decreased. There is a significant decrease of CBG in hyperthyroidism (35.7 +/- 5.5 micrograms/ml; n = 22), in cirrhosis (32.0 +/- 8.0 micrograms/ml; n = 14) and in renal disease and a significant increase in patients treated with antiepileptic drugs (47.5 +/- 6.3 micrograms/ml; n = 14), but total and unbound cortisol are normal in all these conditions. We conclude that unbound cortisol can be calculated in a simple and reliable way from total cortisol and CBG and permits a better evaluation of adrenal function, particularly in patients with altered CBG concentrations.     

ACTH sensitivity of isolated human pathological adrenocortical cells: variability of responses in aldosterone, corticosterone, deoxycorticosterone and cortisol production

In vitro aldosterone, deoxycorticosterone, corticosterone and cortisol production of human adrenocortical cells derived from adenomas (Conn's syndrome, Cushing's syndrome), from hyperplastic adrenals (Cushing's syndrome) and from adrenals surrounding aldosteronoma are described. Cells from adenomas causing either Cushing's syndrome or Conn's syndrome harboured the highest basal and ACTH-stimulated corticosteroid production. Adrenocortical cells derived from micronodular hyperplasia causing Cushing's syndrome and cells from cortisol producing adenoma displayed predominantly cortisol and corticosterone secretion both under basal conditions and following stimulation with ACTH. Aldosteronoma cells showed highly variable aldosterone, deoxycorticosterone, corticosterone and cortisol response to ACTH. However, in aldosteronoma cell suspensions, the basal and ACTH-stimulated ratios of aldosterone to cortisol were increased when compared to ratios of steroids produced by cells from other adrenal tissues. Chronic treatment with spironolactone of patients with Conn's syndrome before surgery was associated with a decreased ratio of aldosterone to corticosterone, revealing that 18-hydroxylase in aldosteronoma cells may be inhibited during long-term therapy. Non-tumorous cells isolated from adrenals surrounding aldosteronoma displayed less aldosterone prior to and after stimulation with ACTH than aldosteronoma cells.     

Adrenal Insufficiency Attributable to Adrenal Hemorrhage: Long-Term Follow-Up with Reference to Glucocorticoid and Mineralocorticoid Function and Replacement

ObjectiveTo describe the long-term follow-up of acute adrenal insufficiency attributable to bilateral adrenal hemorrhage.MethodsWe performed a retrospective review of medical records of four patients who underwent follow-up for 6½ to 19 years.ResultsDespite published reports of more than 500 patients with bilateral massive adrenal hemorrhage through 2001, no long-term data assessing the continuing requirements for glucocorticoid and mineralocorticoid replacement are available. After follow-up of four patients with acute bilateral adrenal hemorrhage and glucocorticoid insufficiency for 6½ to 19 years, we document the absence of need for long-term mineralocorticoid replacement on the basis of no occurrence of postural hypotension, normal electrolytes, normal baseline or cosyntropin-stimulated serum aldosterone levels, and generally, though not invariably, normal plasma renin activity levels. We further document the improvement in either or both baseline and cosyntropin-stimulated serum cortisol levels in three of the four patients and the ability of one patient to function normally without cortisol replacement for 4 years. Adrenal histologic findings in this last-mentioned patient revealed previously undescribed changes consistent with regeneration and myelolipoma. Finally, we confirm bilateral atrophic adrenal glands by computed tomography 5½ to 11½ years after bilateral adrenal hemorrhage in three of the four patients.ConclusionLong-term follow-up of patients with acute adrenal insufficiency attributable to adrenal hemorrhage demonstrates, for the first time, absence of need for prolonged mineralocorticoid replacement and some improvement in endogenous glucocorticoid function in at least some of these patients. (Endocr Pract. 2004;10: 55-61)     

Antibody that blocks stimulation of cortisol secretion by adrenocorticotrophic hormone in Addison's disease

To investigate whether Addison''s disease may in some cases be due to the blocking of adrenocorticotrophic hormone''s action at the adrenal cortex by antibodies IgG isolated from a woman with Addison''s disease associated with the autoimmune polyglandular syndrome type I was studied. Its effects on guinea pig adrenal cells in vitro were investigated and compared with those of IgG from three normal subjects and IgG obtained commercially. IgG from the patient inhibited the stimulation of cortisol secretion by adrenocorticotrophic hormone by 77 (SD 2)% and 57 (12)% at concentrations of 0·5 and 0·05 g/l, respectively; IgG prepared five months after she had started treatment with replacement steroids inhibited cortisol secretion by 74 (1)% (0·5 g/l) and 51 (15)% (0·05 g/l). The other IgGs had no inhibitory effects. The IgG from the patient and that obtained commercially did not inhibit the stimulation of cortisol secretion by dibutyryl cyclic adenosine monophosphate or precursors of cortisol. None of the IgGs bound to adrenocorticotrophic hormone.These results suggest that the IgG from the patient acted against the receptor for adrenocorticotrophic hormone, and its presence may explain the patient''s raised concentrations of adrenocorticotrophic hormone, failure to respond to exogenous adrenocorticotrophic hormone, and normal basal cortisol concentrations. Addison''s disease may thus in some instances be a receptor antibody disease.     

Recovery of Adrenal Function after Long-Term Glucocorticoid Therapy for Giant Cell Arteritis: A Cohort Study

Objectives

Giant cell arteritis (GCA) is a chronic systemic vasculitis of large and medium-sized arteries, for which long-term glucocorticoid (GC) treatment is needed. During GC withdrawal patients can suffer adrenal insufficiency. We sought to determine the time until recovery of adrenal function after long-term GC therapy, and to assess the prevalence and predictors for secondary adrenal insufficiency.

Subjects and Design

150 patients meeting the ACR criteria for GCA between 1984 and 2012 were analyzed. All received the same GC treatment protocol. The low-dose ACTH stimulation test was repeated annually until adrenal recovery. Biographical, clinical and laboratory data were collected prospectively and compared.

Results

At the first ACTH test, 74 (49%) patients were non-responders: of these, the mean time until recovery of adrenal function was 14 months (max: 51 months). A normal test response occurred within 36 months in 85% of patients. However, adrenal function never recovered in 5% of patients. GC of >15 mg/day at 6 months, GC of >9.5 mg/day at 12 months, treatment duration of >19 months, a cumulative GC dose of >8.5 g, and a basal cortisol concentration of <386 nmol/L were all statistically associated with a negative response in the first ACTH test (p <0.05).

Conclusion

Adrenal insufficiency in patients with GCA, treated long-term with GC, was frequent but transitory. Thus, physicians’ vigilance should be increased and an ACTH test should be performed when GC causes the above associated statistical factors.     

Morning Serum Cortisol Level After Transsphenoidal Surgery for Pituitary Adenoma Predicts Hypothalamic-Pituitary-Adrenal Function Despite Intraoperative Dexamethasone Use

Objective: Perioperative glucocorticoid (GC) is rarely needed in patients undergoing transsphenoidal surgery (TSS). We instituted a steroid-sparing protocol in the settings of intraoperative dexamethasone use. We evaluated the safety of using a cut off cortisol level of 14 μg/dL on postoperative day (POD)-1 and -6 after dexamethasone use during the surgery. We also analyzed the efficacy of serial morning cortisol levels for weaning GC replacement.Methods: The charts of 48 adult patients who received dexamethasone 4 mg intraoperatively were reviewed. Morning cortisol levels were measured on POD-1. Patients with cortisol ≥14 μg/dL were discharged without CG replacement. Morning cortisol level was checked routinely on POD-6, and GC replacement was initiated when the level was <14 μg/dL. Serial cortisol levels were measured in patients requiring GC after the first postoperative week.Results: Overall, 67% patients had POD-1 cortisol ≥14 μg/dL and did not require GC on discharge. After POD-6, 83% of patients were not on GC replacement. A cosyntropin stimulation testing (CST) was only performed in 3 patients. There were no hospital admissions for adrenal crisis during the postoperative period.Conclusion: A steroid-sparing protocol with POD-1 and -6 morning cortisol levels can be safely and effectively used in the settings of intraoperative dexamethasone administration. It leads to avoidance of GC in more than two-thirds of patients on discharge and more than 80% of patients after the first postoperative week. We found that dynamic adrenal testing could be omitted in the majority of patients by using serial morning cortisol levels to assess the hypothalamic-pituitary-adrenal (HPA) axis.Abbreviations: ACTH = adrenocorticotropic hormone AI = adrenal insufficiency CST = cosyntropin stimulation test ECLIA = electrochemiluminescence immunoassay GC = glucocorticoid HPA = hypothalamic-pituitary-adrenal ITT = insulin tolerance test POD = postoperative day TSS = transsphenoidal surgery     

Timing and type of glucocorticoid replacement in adult congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is one of the commonest inherited diseases. Treatment during childhood is directed towards obtaining normal growth. There is an extensive literature on management of CAH during childhood but little published on how patients should be treated as adults. CAH results in increased adrenocorticotropic hormone levels driving the adrenal to produce cortisol and thereby excessive cortisol precursors which are predominantly androgenic. In normal individuals there is a marked circadian rhythm in cortisol release with the lowest levels occurring shortly after midnight and rising between 02.00 and 03.00 h to peak at around 06.00-08.00 h after waking. The treatment of choice for children with CAH is hydrocortisone three times daily. There is no consensus on treating adults. A recent survey by the UK Society for Endocrinology showed that hydrocortisone was the most popular steroid, followed by dexamethasone and then prednisolone. Sixty percent of respondents used a reverse circadian pattern of glucocorticoid treatment and only 16% used a dose based on weight or surface area. In a recent study we demonstrated that the most important variable determining hydrocortisone bioavailability is weight and we advocated a weight-related dosing regimen monitored using a nomogram for serum cortisol. .