The effects of growth hormone deficiency and replacement on glucocorticoid exposure in hypopituitary patients on cortisone acetate and hydrocortisone replacement

OBJECTIVE: 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1) converts inactive cortisone to active cortisol. 11 beta HSD1 activity is increased in GH deficiency and inhibited by GH and IGF-I in acromegaly. However it is not known whether these changes in cortisol metabolism exert significant effects during hydrocortisone therapy, and the effect has not been studied in patients taking cortisone acetate. We have studied the effect of GH induced 11 beta HSD1 inhibition in hypopituitary adults with severe GH deficiency to determine whether this inhibition has a different magnitude of effect when patients are taking different forms of glucocorticoid replacement therapy. DESIGN, PATIENTS AND MEASUREMENTS: We have taken the ratio of 11-hydroxy/11-oxo cortisol metabolites (Fm/Em), an established measure of net 11 beta HSD activity to reflect the likely balance of cortisol to cortisone exposure in tissues expressing 11 beta HSD1, principally the liver and adipose tissue. We recruited 10 hypopituitary adults all on established glucocorticoid replacement therapy, but who were not receiving GH. Patients were treated with their standard hydrocortisone therapy for one week and an equivalent dose of cortisone acetate in its place for one week in random order. Serial serum cortisol assessments and urine steroid profiles were performed on each treatment. All patients were then established on GH therapy for at least three months before the two-week cycle was repeated. Fm/Em was also measured in a control population (20F, 20M). RESULTS: Prior to GH, the ratio Fm/Em was greater with hydrocortisone compared with cortisone acetate replacement (1.17 +/- 0.28 and 0.52 +/- 0.09 respectively, P < 0.001) or with normal subjects (normal males: 0.81 +/- 0.24, females 0.66 +/- 0.14). Following GH replacement Fm/Em fell in patients on hydrocortisone and cortisone acetate (Pre-GH: 0.84 +/- 0.40, Post-GH: 0.70 +/- 0.34, P < 0.05) confirming the inhibition of 11 beta HSD1 by GH/IGF-I. Conversely, the ratio of urinary free cortisol/cortisone did not change indicating unchanged 11 beta HSD2 activity. Mean circulating cortisol also fell in all subjects after GH. This effect was greater during cortisone acetate treatment (-18.7%, P < 0.0001), than during hydrocortisone replacement (-10.9%, P < 0.05). CONCLUSIONS: Our data suggest that tissue exposure to glucocorticoid is supra-physiological in hypopituitary patients with untreated GH deficiency taking hydrocortisone replacement therapy. This situation is ameliorated by GH replacement therapy. However, local and circulating cortisol concentrations are more vulnerable to the inhibitory effect of GH on 11 beta HSD1 in patients taking cortisone acetate, such that serum cortisol assessments should be made in patients taking cortisone acetate after GH therapy to ensure that glucocorticoid replacement remains adequate.     

Saliva and bloodspot cortisol: novel sampling methods to assess hydrocortisone replacement therapy in hypoadrenal patients

BACKGROUND: In patients with hypoadrenalism, it is often difficult to assess the optimal dose of glucocorticoid replacement. Serial serum cortisol measurements for a cortisol day curve are sometimes used, but this has low acceptability for patients. In this study, we evaluate the reliability of saliva and capillary bloodspot cortisol as alternative methods in assessing cortisol profiles in hypoadrenal patients on hydrocortisone replacement. METHODS: We first examined the correlations between serum cortisol, saliva and bloodspot cortisol in in-hospital patients not on glucocorticoid therapy. We then studied 18 hypoadrenal patients on hydrocortisone therapy and measured their serum, saliva and bloodspot cortisol concurrently at seven different time points in a single day. RESULTS: For in-hospital patients, a significant correlation exists between saliva and serum cortisol (R = 0.7121, P < 0.0001), but there is a stronger correlation between bloodspot and serum cortisol (R = 0.9494, P < 0.0001). The correlations were weaker in hypoadrenal patients on hydrocortisone (saliva and serum cortisol: R = 0.6262, P < 0.001; bloodspot and serum cortisol: R = 0.7871, P < 0.001). When we evaluated each measurement with respect to an arbitrary target range, there was a greater degree of agreement between serum and capillary bloodspot cortisol (85% agreement) than between serum and saliva cortisol (65% agreement) (P < 0.001). CONCLUSION: Bloodspot samplings provide a simple and convenient way for ambulant hypoadrenal patients on hydrocortisone replacement therapy to assess cortisol levels at multiple times in a single day. This may be useful in determining the optimal glucocorticoid dose for hypoadrenal patients.     

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

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

PATTERNS OF PLASMA CORTISOL AND ACTH CONCENTRATIONS IN PATIENTS WITH ADDISON''S DISEASE TREATED WITH CONVENTIONAL CORTICOSTEROID REPLACEMENT

Plasma cortisol and adrenocorticotrophin hormone (ACTH) profiles were estimated in twelve patients with Addison's disease following randomized oral administration of either cortisone acetate (25 mg) or hydrocortisone (20 mg) alternately, at 0900 h on consecutive days. Normal corticosteroid replacement therapy was discontinued from 1200 h on the day prior to the study period. In four patients elevated basal plasma ACTH concentrations were not suppressed to the limit of detection following the administration of either drug, and in three of these no suppression was found following the prolonged administration of pharmacological doses of dexamethasone. Diminished sensitivity of pituitary ACTH secretion to cortisol inhibition may result from chronic loss of negative feedback before and/or after diagnosis and treatment. In three patients elevated basal plasma ACTH concentrations were suppressed adequately during the administration of either drug, but in five, low basal ACTH concentrations following corticosteroid withdrawal suggested chronic inhibition of anterior pituitary corticotrophs by over-replacement with glucocorticoid. However, further study is necessary to determine whether the estimation of ACTH profiles is a more accurate reflection of the adequacy of corticosteroid replacement than the estimation of cortisol profiles alone, and whether this estimation leads to an improvement in patient management. Hydrocortisone (20 mg) achieved higher mean cortisol levels and lower mean ACTH levels than cortisone acetate (25 mg), but either drug may be suitable for glucocorticoid replacement provided the dose is tailored to the individual needs.     

Quality of glucocorticoid replacement in adrenal insufficiency: clinical assessment vs. timed serum cortisol measurements

OBJECTIVE: Evaluation of glucocorticoid replacement quality in adrenal insufficiency (AI) relies primarily on clinical judgement and thus largely depends on the physician's expertise. It is a matter of debate whether cortisol day curves are of value in assessing glucocorticoid replacement quality. Here we compared the results of a structured clinical assessment to the outcome of repeated, timed serum cortisol measurements. DESIGN: Cross-sectional study in the outpatient department of a university teaching hospital. PATIENTS: Forty-six patients (19 men, 27 women, age range 16-76 years) with primary (n = 23) and secondary (n = 23) AI on stable replacement with a median dose of 37.5 mg cortisone acetate (range 25-50 mg) since 10 +/- 7 years (range 1-31 years). MEASUREMENTS: Clinical performance was scored by structured assessment of signs and symptoms, physical examination and routine biochemical tests. Serum cortisol was measured on two to three separate occasions in three timed samples after the morning glucocorticoid dose. Bone mineral density was measured in 15 patients with long-standing glucocorticoid replacement. RESULTS: Thirty-seven patients were considered well replaced, whereas clinical scores suggested over- or under-replacement in five and four, respectively. There was no correlation of the clinical score with total or body weight-adjusted glucocorticoid dose. The mean z score of serum cortisol differed significantly between under- and over-replaced patients (P < 0.05) but neither group differed significantly from well-replaced patients. Bone mineral density was normal in all patients studied. CONCLUSIONS: Our results suggest that serum cortisol day curves are of limited value in the monitoring of glucocorticoid replacement. Bone mineral density in AI is generally normal and does not require routine follow-up.     

Growth hormone deficiency in patients with idiopathic adrenocorticotropin deficiency resolves during glucocorticoid replacement

Glucocorticoids (GC) have stimulatory effects on GH secretion in vitro and suppressive effects when administered in pharmacological amounts in vivo. We studied six patients with ACTH deficiency and severely impaired serum GH responses to insulin tolerance tests and arginine infusion tests. All patients underwent the same tests during GC replacement while receiving cortisone acetate in doses ranging from 12.5-25 mg/day. The three patients with idiopathic ACTH deficiency and no evidence of pituitary mass lesions had impaired GH secretion, which returned to normal during GC replacement. In contrast, the three patients with ACTH deficiency and hypothalamo-pituitary mass lesions detected by a computed tomography scan had impaired GH secretion during GC replacement therapy. Our data indicate that in patients with idiopathic ACTH deficiency, an impaired GH response to stimuli reversible during GC replacement therapy may be the functional consequence of the low levels of circulating cortisol. We conclude that physiological serum cortisol levels are necessary for normal serum GH responses to provocative stimuli in man.     

Comparison of absorption of cortisone acetate and hydrocortisone hemisuccinate.

In four patients who required maintenance glucocorticoid therapy after bilateral adrenalectomy for Cushing's disease, we compared the effects of im injection and oral ingestion of cortisone acetate and hydrocortisone hemisuccinate. By the former route of administration, cortisone acetate was not effective in elevating plasma cortisol levels or in suppressing plasma adrenocorticotropin, although hydrocortisone was. When given by mouth, no significant difference was found between the two steroids. Therefore, in the treatment of acute adrenal insufficiency or in the maintenance of patients with chronic adrenal insufficiency and in their preparation for surgery or other stressful situations, we advise against im injection of cortisone acetate. Oral ingestion, however, is appropriate for maintenance.     

GLUCOCORTICOID MAINTENANCE THERAPY FOLLOWING ADRENALECTOMY: ASSESSMENT OF DOSAGE AND PREPARATION

Plasma cortisol was monitored repeatedly after oral administration of cortisol and cortisone (cortisone acetate) to seven adrenalectomized patients with pituitary-dependent Cushing's syndrome. The amount of glucocorticoid administered was 25 mg cortisol or 33 mg cortisone/g urine creatinine/24 h. Peak plasma cortisol levels were within recommended values in all patients after cortisone and in three of the patients after cortisol. The remaining four patients had elevated peak plasma cortisol levels after cortisol. Transcortin binding capacity in plasma was normal. It is concluded that cortisol as well as cortisone is suitable for oral glucocorticoid substitution therapy in patients with normal liver function, but that cortisone apparently gives a marginally smoother plasma cortisol curve. However, it is essential to monitor plasma cortisol after institution of glucocorticoid maintenance therapy, since different and unpredictable plasma cortisol levels may exist after a given amount of glucocorticoid, although the dose required correlates reasonably well with creatinine excretion in urine.     

Why is the management of glucocorticoid deficiency still controversial: a review of the literature

All endocrinologists would like to make glucocorticoid replacement therapy for their hypoadrenal patients as physiological as possible. Many would like the reassurance of a method of monitoring such treatment to confirm that they are achieving this aim. Advances in our knowledge of the normal physiology are relevant to our attempts to do this. The cortisol production rate in normal subjects is lower than was previously believed. The normal pattern of glucocorticoid secretion includes both a diurnal rhythm and a pulsatile ultradian rhythm. Glucocorticoid access to nuclear receptors is 'gated' by the 11-beta-hydroxysteroid dehydrogenase enzymes, which interconvert active cortisol and inactive cortisone. Such complexities make the target of physiological glucocorticoid replacement therapy hard to achieve. The available evidence suggests that conventional treatment of hypoadrenal patients may result in adverse effects on some surrogate markers of disease risk, such as a lower bone mineral density than age-sex matched controls, and increases in postprandial glucose and insulin concentrations. Although the quality of life of hypoadrenal patients may be impaired, there is no evidence of an improvement on higher doses of steroids, although quality of life is better if the hydrocortisone dose is split up, with the highest dose taken in the morning. Thus the evidence suggests that most patients may safely be treated with a low dose of glucocorticoid (e.g. 15 mg hydrocortisone daily) in two or three divided doses, with education about the appropriate action to take in the event of intercurrent illnesses.     

Which patients benefit from provocative adrenal testing after transsphenoidal pituitary surgery?

OBJECTIVE Recent data suggest that recovery of anterior pituitary function promptly follows surgical decompression and that hypothalamic-pituitary-adrenal axis assessment need not be delayed following transsphenoidal pituitary surgery. We hypothesized that one protocol for both glucocorticoid supplementation and axis investigation prior to discharge may be applied to all transsphenoidal pituitary surgery patients. The protocol examined the merits of preoperative testing and of basal and hypoglycaemia-stimulated cortisol and ACTH measurements in post-operative axis evaluation. DESIGN Rapid tetracosactrin stimulation testing classified patients according to preoperative adrenal integrity. All patients received tapered doses of hydrocortisone beginning on the morning of surgery and discontinued after 48hours. PATIENTS Of 28 consecutive patients with various pituitary tumours, 19 completed all aspects of the protocol. All evaluable information from the other 9 was incorporated into the final conclusions and recommendations. MEASUREMENTS Morning serum cortisol was measured 24 hours after the last hydrocortisone dose. Plasma ACTH and serum cortisol were measured during insulin tolerance testing within 8 days after surgery. Patients received clinical evaluations and repeat testing as clinically indicated during 6–30 months of follow-up. RESULTS Both peak serum cortisol >550nmol/l and peak plasma ACTH of >4.4pmol/l during insulin tolerance testing were 100% sensitive and specific in predicting sustained hypothalamic-pituitary-adrenal axis integrity after surgery. For patients entering surgery with normal tetracosactrin tests, an initial morning serum cortisol >270nmol/l provided 100% specificity for preserved axis integrity, but a low cortisol did not indicate axis dysfunction. For patients entering surgery with cortisol deficiency, an initial morning cortisol <60nmol/l indicated sustained axis failure, but higher values proved inconclusive. However, the basal cortisol, but not ACTH, on the day of insulin tolerance testing conclusively defined axis status in 18 of 19 study patients (95%). CONCLUSIONS We conclude that (1) a 48-hour perioperative hydrocortisone reducing regimen may be used in all uncomplicated transsphenoidal pituitary surgery cases regardless of pituitary-adrenal axis status before surgery; (2) preoperative adrenal testing aids interpretation of the initial morning serum cortisol and may be used to direct further testing; (3) a single morning serum cortisol drawn 24 hours after glucocorticoid withdrawal suffices for pituitary-adrenal axis investigation if results suggest no change in axis function, as occurred in most study patients; (4) while insulin tolerance testing 5–8 days after surgery is 100% accurate in determining the need for sustained glucocorticoid replacement due to clinically significant hypopituitarism, repeat morning cortisol measurement obviates provocative testing in 95% of cases; and (5) basal and stimulated plasma ACTH values provide no information additional to serum cortisol measurements in post-operative axis evaluation.     

Continuous subcutaneous hydrocortisone infusion in Addison's disease

OBJECTIVE: The conventional replacement therapy in Addison's disease (AD) does not restore the normal diurnal cortisol rhythm. We explored the feasibility and safety of continuous s.c. hydrocortisone infusion (CSHI) as a novel mode of glucocorticoid replacement therapy. DESIGN AND METHODS: Seven patients with AD were treated with CSHI in an open-labelled clinical study for up to three months. Adequacy of glucocorticoid replacement was assessed by 24 h blood and saliva sampling in one patient and by salivary cortisol day curves in six outpatients. Subjective health status was monitored by the Short Form-36 questionnaire. RESULTS: CSHI re-established the circadian variation and normal levels of cortisol in the patients, with minor day-to-day variation. Most of the patients could reduce their glucocorticoid dose considerably without adverse reactions. The treatment was well tolerated and positively evaluated by the patients. CONCLUSIONS: CSHI is technically feasible and safe in patients with AD. A daily dose of approximately 10 mg/m(2) body surface area/day restores the circadian variation and normal levels of salivary cortisol in most patients, which is close to the estimated daily requirement. We hypothesise that selected patients will benefit from restoration of the circadian cortisol rhythm.     

Modified-release hydrocortisone for circadian therapy: a proof-of-principle study in dexamethasone-suppressed normal volunteers

Background All existing long‐term glucocorticoid replacement therapy is suboptimal as the normal nocturnal rise and waking morning peak of serum cortisol is not reproduced. Aim To test whether it is possible to reproduce the normal overnight rise and morning peak in serum cortisol using an oral delayed and sustained release preparation of hydrocortisone (Cortisol_ds). Subjects and methods Six healthy normal male volunteers attended on two occasions, in a single‐dose, open‐label, nonrandomized study. Endogenous cortisol secretion was suppressed by administration of dexamethasone. Cortisol_ds (formulation A or B) was administered at 2200 h on day 1. Blood samples for measurement of cortisol were taken from 2200 h every 30 min until 0700 h, then hourly until 2200 h on day 2. Fifteen body mass index (BMI)‐matched control subjects had serum cortisol levels measured at 20‐min intervals for 24 h. Serum cortisol profiles and pharmacokinetics after Cortisol_ds were compared with those in controls. Results Formulations A and B were associated with delayed drug release (by 2 h and 4 h, respectively), with median peak cortisol concentrations at 4·5 h (0245 h) and 10 h (0800 h), respectively, thereby reproducing the normal early morning rise in serum cortisol. Total cortisol exposure was not different from controls. Conclusions For the first time we have shown that it is possible to mimic the normal circadian rhythm of circulating cortisol with an oral modified‐release formulation of hydrocortisone, providing the basis for development of physiological circadian replacement therapy in patients with adrenal insufficiency.     

Glucocorticoid replacement therapy: are patients over treated and does it matter?

BACKGROUND AND OBJECTIVES Adequate assessment of patients on glucocorticoid replacement therapy is of great importance to avoid the consequences of under or over treatment, but no simple test is available for this. The aims of this study were (1) to assess adequacy of glucocorticoid replacement in hypoadrenal patients, (2) to correlate serum cortisol levels (cortisol day curve) with 24-hour urine free cortisol excretion and (3) to assess the impact of glucocorticoid dose optimization on markers of bone formation and bone resorption. DESIGN Cross-sectional study of current replacement therapy and a prospective study of the effect of dose alteration on bone turnover markers. PATIENTS Thirty-two consecutive patients on replacement glucocorticoid therapy (12 Addison’s disease, 20 hypopituitarism) from a University teaching hospital out-patient department. MEASUREMENTS Serum and urinary cortisol, osteocalcin, N-telopeptide of type I collagen (NTX) and bone mineral density. RESULTS 28/32 (88%) patients required a change of therapy; 24/32 (75%) a total reduction in dose, 18/32 (56%) a change in replacement therapy regimen or drug and 14/32 (44%) both changes. The mean daily dose of hydrocortisone was reduced from 29.5 ± 1.2 to 20.8 ± 1.0 mg. A significant correlation was found between peak cortisol and 24-hour urine free cortisol/creatinine (Spearman correlation r = 0.60, P < 0.0001; n = 51). Following hydrocortisone dose reduction, median osteocalcin increased from 16.7 μg/l (range 8.2–65.7) to 19.9 μg/l (8.2–56.3); P < 0.01, with no change in the NTX/creatinine ratio. CONCLUSIONS A high proportion of patients on conventional corticosteroid replacement therapy are over treated or on inappropriate replacement regimens. To reduce the long term risk of osteoporosis, corticosteroid replacement therapy should be individually assessed and over replacement avoided.     

Isolated corticotrophin deficiency

Isolated ACTH deficiency (IAD) is a rare disorder, characterized by secondary adrenal insufficiency (AI) with low or absent cortisol production, normal secretion of pituitary hormones other than ACTH and the absence of structural pituitary defects. In adults, IAD may appear after a traumatic injury or a lymphocytic hypophysitis, the latter possibly due to autoimmune etiology. Conversely, a genetic origin may come into play in neonatal or childhood IAD. Patients with IAD usually fare relatively well during unstressed periods until intervening events spark off an acute adrenal crisis presenting with non specific symptoms, such as asthenia, anorexia, unintentional weight loss and tendency towards hypoglycemia. Blood chemistry may reveal mild hypoglycemia, hyponatremia and normal-high potassium levels, mild anemia, lymphocytosis and eosinophilia. Morning serum cortisol below 3 μg/dl are virtually diagnostic for adrenal insufficiency. whereas cortisol values comprised between 5–18 μg/dl require additional investigations: insulin tolerance test (ITT) is considered the gold standard but—when contraindicated—high or low dose-ACTH stimulation test with serum cortisol determination provides a viable alternative. Plasma ACTH concentration and prolonged ACTH infusion test are useful in differential diagnosis between primary and secondary adrenal insufficiency. For some patients with mild, near-to-asymptomatic disease, glucocorticoid replacement therapy may not be required except during stressful events; for symptomatic patients, replacement doses i.e., mean daily dose 20 mg (0.30 mg/kg) hydrocortisone or 25 mg (0.35 mg/kg) cortisone acetate, are usually sufficient. Administration of mineralocorticoids is generally not necessary as their production is maintained.     

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

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

The clinical utility of alternative, less invasive sampling techniques in the assessment of oral hydrocortisone therapy in children and adolescents with hypopituitarism

OBJECTIVE: The aim of glucocorticoid replacement therapy in ACTH-deficient patients is to mimic the normal diurnal variation of cortisol. However, current hydrocortisone (HC) replacement results in prolonged episodes of hypocortisolaemia and supraphysiological peaks. Plasma cortisol profiles are an accurate yet labour-intensive method of assessing HC replacement. Salivary and bloodspot cortisol sampling methods are less invasive and may be useful tools for assessing glucocorticoid replacement, particularly in children. Therefore, we aimed to define normal salivary and bloodspot cortisol levels in children and their correlations with the gold standard (plasma cortisol). DESIGN: Cross-sectional study in a paediatric teaching hospital. METHODS: Plasma, saliva and bloodspot cortisol profiles were performed on 30 ACTH-deficient children and 22 healthy siblings. RESULTS: In ACTH-deficient patients taking oral HC, the bloodspot-plasma correlation (p=0.90) was stronger than the salivary-plasma correlation (p=0.49). Using target ranges for salivary and bloodspot cortisol levels based on normal data from control subjects, the less invasive sampling methods had low rates of agreement with plasma cortisol target ranges (saliva 65% and bloodspot 75%). Using the plasma-bloodspot correlation regression equation to convert bloodspot to calculated plasma cortisol, there was a high concordance between calculated and actual measured plasma cortisol (88%). CONCLUSION: Bloodspot cortisol sampling is a feasible and accurate method for monitoring oral HC replacement in paediatric patients without necessitating hospital admission, but salivary sampling is not useful.     

Les actualités de l’insuffisance surrénalienne

The congress of the Endocrine Society 2008 approached the diagnostic, etiologic, prognostic and therapeutic novelties of adrenal insufficiency (AI). Diagnosis of AI often requires serum cortisol measurement during dynamic tests. Salivary cortisol measurement was reported to have an equivalent diagnostic performance to serum cortisol and that is even better when CBG levels are altered. Iatrogenic AI is much more frequent than Addison’s disease. Two studies have shown that patients with inhaled corticosteroid and opioid treatments should be tested for AI. A Norwegian study reported an increased mortality in the subgroup of young men that presented Addison’s disease before the age of 40. Plasma cortisol concentration in patients with current glucocorticoid replacement therapy differs notably from those observed in physiological condition. This imperfect replacement may be responsible for adverse physical condition and impaired quality of life. Two formulations of delayed hydrocortisone tablets with different pharmacokinetics from usual hydrocortisone (DuoCort? and Chronocort?) are in development. The first study is promising and shows that these formulations better mimick the body’s natural cortisol release. Its use in the treatment of AI in patients with congenital adrenal hyperplasia has also been tested.     

News for adrenal insufficiency

The congress of the Endocrine Society 2008 approached the diagnostic, etiologic, prognostic and therapeutic novelties of adrenal insufficiency (AI). Diagnosis of AI often requires serum cortisol measurement during dynamic tests. Salivary cortisol measurement was reported to have an equivalent diagnostic performance to serum cortisol and that is even better when CBG levels are altered. Iatrogenic AI is much more frequent than Addison's disease. Two studies have shown that patients with inhaled corticosteroid and opioid treatments should be tested for AI. A Norwegian study reported an increased mortality in the subgroup of young men that presented Addison's disease before the age of 40. Plasma cortisol concentration in patients with current glucocorticoid replacement therapy differs notably from those observed in physiological condition. This imperfect replacement may be responsible for adverse physical condition and impaired quality of life. Two formulations of delayed hydrocortisone tablets with different pharmacokinetics from usual hydrocortisone (DuoCort and Chronocort) are in development. The first study is promising and shows that these formulations better mimick the body's natural cortisol release. Its use in the treatment of AI in patients with congenital adrenal hyperplasia has also been tested.     

An assessment of bone mineral density in patients with Addison's disease and isolated ACTH deficiency treated with glucocorticoid

Glucocorticoid replacement therapy needs to be tailored to individual patient's requirements in order to avoid risk of over or under medication. We measured bone mineral density (BMD) of lumbar spine using dual X-ray absorptiometory in 10 patients with Addison's disease and 5 patients with isolated ACTH deficiency receiving glucocorticoid replacement therapy. We also examined the effect of glucocorticoid replacement on BMD. Decreased %BMD (less than 80% of age-matched controls) was found in 2 female patients who had received hydrocortisone at a dose of 14.8 and 15.4 mg/m(2)/day. In contrast, no patient receiving a hydrocortisone dose of less than 12.4 mg/m (2)/day had decreased %BMD. There was no correlation between %BMD and hydrocortisone dose (mg/m(2)), duration of therapy, or cumulative hydrocortisone dose when treated with appropriate dose of hydrocortisone (<13.6 mg/m(2)). There was also no statistically significant difference in %BMD with age. We concluded that long-term glucocorticoid replacement therapy does not induce bone loss in patients with glucocorticoid deficiency unless an excessive dose of hydrocortisone is given.     

Hydrocortisone replacement dosage influences intraocular pressure in patients with primary and secondary hypocortisolism

BACKGROUND: It has been suggested that the variation of intraocular pressure (IOP) during the day follows the diurnal variation of serum cortisol. There is also a higher risk of ocular hypertension and glaucoma in patients taking excessive oral steroid treatment. We assessed whether different replacement doses of hydrocortisone (HC) influenced IOP. METHODS: Seventeen patients (six Addison's disease, 11 hypopituitarism; seven males) aged 24-58 years mean 42.7 years and 20 control subjects (nine males) aged 20--59 years mean 38.7 years were studied. On the first visit, the 17 patients had been taking HC replacement doses, 20 mg morning and 10 mg afternoon. Serum cortisol and IOP in both eyes (Goldmann applanation tonometer) were measured at 0900, 1100, 1300, 1500, 1700 hours with HC 20 mg taken after the 0900 h assessment. The dose of HC was then reduced to 10 mg morning and 10 mg afternoon for 1 week and the measurements were repeated in 16 patients, with HC 10 mg taken at 0900 h. RESULTS: In the patients the peak serum cortisol occurred at 1100 h after the 0900 h HC dose. Cortisol levels were significantly higher at 1100, 1300, 1500 and 1700 h after taking 20 mg compared to 10 mg HC. The mean (SEM) IOP (mmHg) was significantly higher after 20 mg HC compared with 10 mg HC at 1300 h: 14.7(0.6) v 13.1(0.6) (P = 0.004) and at 1500 h: 14.4(0.6) v 13.1(0.5) (P = 0.04). The total mean (SEM) daily IOP score was significantly higher after 20 mg HC compared with 10 mg HC: 14.5(0.3) v 13.5(0.3) (P = 0.0002). The total mean (SEM) daily IOP score after the 20 mg HC dose compared with the control subjects was: 14.5(0.3) v 13.7(0.3) (P = 0.08). CONCLUSION: Intraocular pressures during the day are influenced by the morning hydrocortisone replacement dosage with significantly higher intraocular pressure levels in the early afternoon following 20 mg compared with 10 mg. A morning hydrocortisone dose of 10 mg leads to a more physiological intraocular pressure profile during the day. These data support the view that a daily replacement dose of 30 mg hydrocortisone may be excessive.