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.     

Optimizing glucocorticoid replacement therapy in severely adrenocorticotropin-deficient hypopituitary male patients

Background The optimal replacement regimen of hydrocortisone in adults with severe ACTH deficiency remains unknown. Management strategies vary from treatment with 15–30 mg or higher in daily divided doses, reflecting the paucity of prospective data on the adequacy of different glucocorticoid regimens. Objective Primarily to define the hydrocortisone regimen which results in a 24 h cortisol profile that most closely resembles that of healthy controls and secondarily to assess the impact on quality of life (QoL). Design Ten male hypopituitary patients with severe ACTH deficiency (basal cortisol <100 nm and peak response to stimulation <400 nm ) were enrolled in a prospective, randomized, crossover study of 3 hydrocortisone dose regimens. Following 6 weeks of each regimen patients underwent 24 h serum cortisol sampling and QoL assessment with the Short Form 36 (SF36) and the Nottingham Health Profile (NHP) questionnaires. Free cortisol was calculated using Coolen’s equation. All results were compared to those of healthy, matched controls. Results Corticosteroid binding globulin (CBG) was significantly lower across all dose regimens compared to controls (P < 0·05). The lower dose regimen C (10 mg mane/5 mg tarde) produced a 24 h free cortisol profile (FCP) which most closely resembled that of controls. Both regimen A(20 mg mane/10 mg tarde) and B(10 mg mane/10 mg tarde) produced supraphysiological post‐absorption peaks. There was no significant difference in QoL in patients between the three regimens, however energy level was significantly lower across all dose regimens compared to controls (P < 0·001). Conclusions The lower dose of hydrocortisone (10 mg/5 mg) produces a more physiological cortisol profile, without compromising QoL, compared to higher doses still used in clinical practice. This may have important implications in these patients, known to have excess cardiovascular mortality.     

What is the best approach to tailoring hydrocortisone dose to meet patient needs in 2012?

Cortisol is an essential stress hormone and replacement with oral hydrocortisone is lifesaving in patients with adrenal insufficiency. Cortisol has a diurnal rhythm regulated by the central body clock and this rhythm is a metabolic signal for peripheral tissue clocks. Loss of cortisol rhythmicity is associated with fatigue, depression and insulin resistance. A general principle in endocrinology is to replace hormones to replicate physiological concentrations; however, the pharmacokinetics of oral immediate‐release hydrocortisone make it impossible to fully mimic the cortisol rhythm and patients still have an increased morbidity and mortality despite replacement. Traditionally, physicians have replaced hydrocortisone with a total daily dose based on the diurnal 24‐h cortisol production rate with hydrocortisone given twice or thrice daily, with the highest dose first thing in the morning. Monitoring treatment and dose titration has been much debated with some clinicians using cortisol day curves and others relying on clinical symptoms. The main challenge is that there is no established biomarker of cortisol activity. In addressing the clinical question, we have taken the view that an understanding of the cortisol circadian rhythm and hydrocortisone pharmacokinetics is essential when tailoring hydrocortisone dose. Using this approach, we have developed a thrice daily, weight‐related, dosing regimen and a pharmacokinetic and clinical method to monitor treatment. Our argument for replicating the cortisol circadian rhythm is based on the observation that disruption of the rhythm is associated with ill health, and the few studies that have compared different treatment regimens. Further studies are required to definitively test the benefits of replacing the cortisol circadian rhythm in patients with adrenal insufficiency.     

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.     

Dose distribution in hydrocortisone replacement therapy has a significant influence on urine free cortisol excretion.

We investigated the influence of dose distribution in hydrocortisone replacement therapy on urine free cortisol excretion. To this end, we measured 24-hour urine free cortisol (24-h UFC) in 13 patients with hypocortisolism. The patients took 25 mg hydrocortisone/day according to the following schedules: either a single 25 mg hydrocortisone dose at 8:00 a.m., or 15 mg hydrocortisone at 8:00 a.m. and 10 mg hydrocortisone at 2:00 p.m., or 5 mg hydrocortisone at 8:00 a.m., 10:00 a.m., 2:00 p.m., 6:00 p.m. and 10:00 p.m. 24-h UFC decreased significantly with increasing division of the daily 25 mg hydrocortisone dose. When taking 25 mg hydrocortisone in a single morning dose, the mean 24-h UFC was 649 +/- 52 nmol/day (mean +/- SEM). When the daily dose was divided into doses of 15 mg and 10 mg hydrocortisone, 24-h UFC was reduced by 28 % to 466 +/- 39 nmol/day (p < 0.002). After division into five doses of 5 mg, 24-h UFC was reduced by 42.8 % to 371 +/- 36 nmol/day (p < 0.001) compared to the single 25 mg dose. These data demonstrate that consideration of the dose distribution in hydrocortisone replacement therapy when analysing 24-h UFC is of clinical importance.     

Glucocorticoid replacement therapy and fibrinolysis in patients with hypopituitarism

Background Hypopituitarism is associated with increased cardiovascular mortality, and it has been suggested that unphysiological glucocorticoid replacement regimens might contribute to this risk. Traditional glucocorticoid replacement regimens have often led to excessive serum cortisol levels. The hypercortisolaemia of Cushing’s syndrome is associated with an increased risk of thromboembolism. Objective To examine whether short‐term higher‐dose hydrocortisone replacement regimens adversely affect the fibrinolytic system. Design Crossover study comparing tailored low‐dose (LD) glucocorticoid regimen (mean, 17·5 mg hydrocortisone daily), with a traditional high‐dose (HD, 30‐mg hydrocortisone daily) regimen for 2 weeks. Patients Ten patients with hypopituitarism and ACTH deficiency – median (range) age, 59 (41–75) years – and 10 age‐ and sex‐matched controls. Nine patients had growth hormone deficiency (five replaced), nine patients had TSH deficiency (nine replaced), eight had gonadotrophin deficiency (five replaced). During the study, other pituitary hormone replacement therapy remained unchanged. Patients with acromegaly and Cushing’s syndrome were excluded. Measurements Hourly serum cortisol for 11 h, plasminogen activator inhibitor‐1 (PAI‐1), tissue plasminogen activator (tPA) and fibrinogen levels after 2 weeks of treatment with both LD and HD regimens. Results No overall significant differences were found between the three groups using the Kruskal–Wallis test: PAI‐1: [median (range)] HD, 25 (5–53) ng/ml; LD, 21 (4–56) ng/ml; controls, 27 (8–51); P = 0·3; tPA: HD, 10 (5–15) ng/ml; LD, 10 (4–13) ng/ml; controls 10 (3–13); P = 0·46; and fibrinogen: HD, 2·5 (1·8–3·5) g/l; LD, 3·0 (2·3–4·4) g/l; controls, 2·6 (1·6–3·2): P = 0·97 In addition, no significant differences between HD and LD using Wilcoxon’s paired test; PAI‐1 (P = 0·91), tPAag (P = 0·47) and fibrinogen (P = 0·09). Conclusions An increased dose of hydrocortisone for 2 weeks creates excessive glucocorticoid exposure, but does not significantly affect fibrinolytic‐coagulation parameters.     

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.     

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

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

Conventional glucocorticoid replacement overtreats adult hypopituitary patients with partial ACTH deficiency

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

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.     

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.     

Variability of Blood Pressure in Ambulatory Hypertensive Patients: Effects of Verapamil on Twice and Thrice Daily Dose Regimens

ABSTRACT The antihypertensive effects of verapamil over 24 hours were assessed on twice and thrice daily dose regimens on 12 patients (25–65 years of age; mean age 50) with essential hypertension (WHO stages I–II) in a randomised, double-blind, cross-over trial. After a dose titration period starting with either verapamil 80 mg tid or 120 mg bid the patients kept their maintenance dose (240, 360 or 480 mg daily) for 4 weeks before crossing over to the other administration schedule. Repeated ambulatory blood pressure (BP) curves were recorded in 10 patients with a non-invasive portable device (Pressurometer III, Del Mar Avionics). The BP reductions (causal BP values) obtained by 2- and 3-dose regimens were of similar magnitude (from 170±19/105±8 on placebo to 140±17/87±7 and to 146±14/88±8 by 2- and 3-dose respectively). Analyses of BP curves revealed close similarity in profiles on the two dose regimens, although DBP was significantly (p<0.05) lower by 3-dose as compared to 2-dose regimen during the period 0.00–2.59 a.m. Long-term (circadian rhythm) and short-term variability did not differ between the regimens. Despite the slight difference in DBP curves after midnight, the overall impression is that verapamil given both twice and thrice daily provides adequate BP control throughout 24 hours.     

Overnight metabolic fuel deficiency in patients treated conventionally for hypopituitarism

BACKGROUND Hormone replacement in hypopituitary adults attempts to reproduce normal physiology. Conventional regimens fail to mimic normal hormone profiles over 24 hours. OBJECTIVE To investigate the metabolic consequences of conventional hormone replacement in hypopituitary adults by measuring circulating levels of the major fuels, glucose, non-esterified fatty acids (NEFA), glycerol and 3-hydroxybutyrate (3-OHB) over 24 hours in hypopituitary subjects and controls. SUBJECTS Ten GH and adrenocorticotrophin deficient hypopituitary adults on conventional replacement and 13 controls matched for age, sex and body mass index were studied. The patients received replacement with hydrocortisone twice daily (at 0730 and 1730 h; mean (range) daily dose 22 (10–30) mg/24 h) but not with GH. Other hormones were replaced as clinically necessary. MEASUREMENTS Circulating glucose, NEFA, glycerol and 3-OHB levels were measured over 24 hours together with concentrations of cortisol (total and free), GH and insulin, and urinary free cortisol. RESULTS Levels of glucose, NEFA and 3-OHB were lower in patients than controls (mean ± SEM) (4.3 ± 0.1 vs 5.3 ± 0.1 mmol/l, P = 0.0001; 291 ± 46 vs 448 ± 48 μmol/l, P = 0.015; 78 ± 8 vs 136 ± 24 μmol/l, P = 0.035, respectively) before breakfast. This decrease in glucose, NEFA and 3-OHB was observed in the patient group throughout the night, from midnight to breakfast. For NEFA, the decrease persisted throughout the 24 hours. Glycerol did not differ significantly in patients and controls. Integrated levels of total and free plasma cortisol, and 24-hour urine cortisol excretion, were normal in patients but total and free plasma cortisol concentrations overnight were markedly decreased (overnight area under the curve (AUC) of total cortisol: 440 ± 154 vs 1593 ± 267 nmol/l h, P = 0.0024; overnight AUC of free cortisol: 24 ± 8 vs 161 ± 26 nmol/l h, P = 0.0001). GH levels were low throughout the whole 24 hours in the patient group (24-hour AUC: 10.6 ± 5.1 vs 74.6 ± 19.6 mU/l h, P = 0.008). CONCLUSIONS Hypopituitary adults on conventional hormone replacement regimens have low concentrations of metabolic fuels, glucose, non-esterified fatty acids and 3-hydroxybutyrate throughout the night, possibly related to GH deficiency or to decreased overnight circulating cortisol levels. This overnight fuel deficiency may underlie the mechanism for the non-specific symptoms, such as fatigue and headache in the early morning, which are frequent in this group of patients.     

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

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

A pharmacokinetic and pharmacodynamic study of delayed‐ and extended‐release hydrocortisone (ChronocortTM) vs. conventional hydrocortisone (CortefTM) in the treatment of congenital adrenal hyperplasia

Objective Existing glucocorticoid treatment for congenital adrenal hyperplasia (CAH) is suboptimal and nonphysiological. We compared hormonal profiles during therapy with a new modified‐release hydrocortisone (MR‐HC), Chronocort^?, to conventional hydrocortisone (HC), Cortef^?, in patients with CAH. Design and patients We conducted a Phase 2, open‐label, crossover pharmacokinetic and pharmacodynamic study in 14 patients (out of whom seven were male subjects, age ranging from 17 to 55) with classic 21‐hydroxylase deficiency. One week of thrice daily HC (10, 5 and 15 mg) was followed by 1 month of once daily MR‐HC (30 mg at 22:00 hours). Twenty four‐hour sampling of cortisol, 17‐hydroxyprogesterone (17‐OHP), androstenedione, and ACTH was performed at steady state. Measurements The primary outcome measures were 8‐ and 24‐h area under the curve (AUC) hormones and 08:00 hours 17‐OHP. Results Hydrocortisone therapy resulted in three cortisol peaks. A single cortisol peak occurred at approximately 06:00 hours on MR‐HC. MR‐HC resulted in significantly (P < 0·001) lower 24‐h afternoon (12:00 to 20:00 hours), and night‐time (20:00 to 04:00 hours) cortisol as compared with HC. From 04:00 to 12:00 hours, when physiological cortisol is highest, cortisol was higher on MR‐HC than HC (P < 0·001). Patients on MR‐HC had significantly (P < 0·05) higher afternoon (12:00 to 20:00 hours) 17‐OHP, androstenedione and ACTH, but significantly (P = 0·025) lower 08:00 hours 17‐OHP. No serious adverse events occurred. Conclusions Modified‐release hydrocortisone represents a promising new treatment for CAH. Overnight adrenal androgens were well‐controlled, but rose in the afternoon with once‐daily dosing suggesting that a morning dose of glucocorticoid is needed. Further studies are needed to determine the optimal dosing regimen and long‐term clinical outcome.     

Doses and steroids to be used in primary and central hypoadrenalism

Traditionally hydrocortisone has been the first choice for replacement therapy in patients with adrenal insufficiency. Paediatricians have used body surface area adjusted dosing and adult physicians have tended to use fixed doses twice or thrice daily. Cortisol secretion has a distinct circadian rhythm being low at the time sleep onset, rising from between 02.00 h and 04.00 h in the morning to peak just after the time of waking then falling during the day. The pharmacokinetics of immediate release hydrocortisone means that no treatment regimen is capable of simulating the normal circadian rhythm of cortisol. Recent data with hydrocortisone infusions suggests that circadian delivery of hydrocortisone can improve biochemical control of patients with adrenal insufficiency. It is anticipated in the future that modified release formulations of hydrocortisone will provide more optimal replacement therapy.     

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

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

Influence of hydrocortisone dosage scheme on health‐related quality of life in patients with adrenal insufficiency

Context Recent studies suggest that current glucocorticoid replacement therapies fail to completely restore well‐being in patients with adrenal insufficiency (AI). Objective The objective of this study was to investigate health‐related quality of life (QoL) in patients with AI depending on dose and frequency of daily intake of hydrocortisone (HC). Design and patients In a cross‐sectional study, primary and secondary AI patients were contacted and asked to complete three validated self‐assessment questionnaires [Short Form‐36 (SF‐36), Giessen Complaint List (GBB‐24), Hospital Anxiety and Depression Scale (HADS)]. HC doses were corrected for body surface area. Results were compared with sex‐ and age‐matched controls drawn from the questionnaire‐specific reference cohort. Results Completed questionnaire sets were available from 334 patients on HC (primary AI n = 194; secondary AI n = 140). Patients on higher doses of HC (>30 mg/day) showed significantly impaired subjective health status in two of eight SF‐36 dimensions, and three of five GBB‐24 scales compared with those on lower HC doses. No significant differences in QoL were found between lower HC doses (15–30 mg/day) or between primary or secondary AI. Patients on HC with thrice daily intake showed significantly impaired QoL in one of eight SF‐36 dimensions (15–20 mg/day, 20–25 mg/day), in one of five GBB‐24 scales (15–20 mg/day), as well as higher anxiety scores. Conclusions Health‐related QoL was impaired in patients with primary and secondary AI. HC doses above 30 mg/day were associated with a worse health status. Thrice daily intake of HC was not superior to twice daily intake. Our data support the perception that current replacement strategies are still insufficient to fully restore well‐being and daily performance.     

Serum cortisol and 17-hydroxyprogesterone interrelation in classic 21-hydroxylase deficiency: is current replacement therapy satisfactory?

One of the main aims in the management of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency is to achieve adequate suppression of the adrenal cortex with the smallest possible dose of glucocorticoid substitution. To evaluate the administration schedule of current replacement therapy regimens, we investigated the cortisol-17-hydroxyprogesterone interrelation in 36 patients (13 males and 23 females; median age, 12.3 yr; range, 6.1-18.8 yr) with salt-wasting congenital adrenal hyperplasia. As sufficient variation in 17-hydroxyprogesterone concentrations was required to allow analysis of the cortisol-17-hydroxyprogesterone interrelation, patients were divided into 2 groups depending on the adequacy of hypothalamic-pituitary-adrenal axis suppression. The first group consisted of 17 patients with suppressed 17-hydroxyprogesterone concentrations (group 1), and the second group consisted of 19 patients with nonsuppressed 17-hydroxyprogesterone concentrations (group 2). We determined serum cortisol and 17-hydroxyprogesterone concentrations at 20-min intervals for a total of 24 h while patients were receiving their usual replacement treatment with hydrocortisone and 9alpha-fludrocortisone. We also determined the lowest dose of dexamethasone required to suppress the 0800 h serum ACTH concentrations when administered as a single dose (0.3 or 0.5 mg/m(2)) the night before. Mean 24-h cortisol and 17-hydroxyprogesterone concentrations were 3.9 microg/dl (SD = 2.1) and 66.2 ng/dl (SD = 92.7), respectively, in group 1 and 4.1 microg/dl (SD = 2.5) and 4865.7 ng/dl (SD = 6951) in group 2. The 24-h 17-hydroxyprogesterone concentrations demonstrated circadian variation, with peak values observed between 0400-0900 h. In group 2, 17-hydroxyprogesterone concentrations decreased gradually in response to the rise in cortisol concentrations during the day, but remained low during the night despite the almost undetectable cortisol concentrations between 1600-2000 h. Mean 0800 h androstenedione concentrations correlated strongly with integrated 17-hydroxyprogesterone concentrations (r = 0.81; P < 0.0001), but not with integrated cortisol concentrations. There was a significant negative correlation between cortisol and 17-hydroxyprogesterone at lag time 0 min (r = -0.187; P < 0.0001), peaking at lag time 60 min (r = -0.302; P < 0.0001), with cortisol leading 17-hydroxyprogesterone by these time intervals. Finally, 0800 h serum ACTH concentrations were sufficiently suppressed after a dexamethasone dose of 0.3 mg/m(2) in all but three patients. These findings indicate that in classic 21-hydroxylase deficiency, hydrocortisone should be administered during the period of increased hypothalamic-pituitary-adrenal axis activity, between 0400-1600 h, with the biggest dose given in the morning. Blood investigations performed as part of monitoring of congenital adrenal hyperplasia patients should include androstenedione and 17-hydroxyprogesterone concentrations determined in the morning before the administration of hydrocortisone. It should also be emphasized that blood investigations are only complementary to the overall assessment of these patients, which is primarily based on the evaluation of growth and pubertal progress.     

Growth hormone treatment in hypopituitary GH deficient adults reduces circulating cortisol levels during hydrocortisone replacement therapy

OBJECTIVES Patients with GH deficiency frequently have multiple hormone deficiencies and require hydrocortisone replacement. We have investigated whether GH treatment alters circulating cortisol levels in hypopituitary patients receiving stable replacement therapy. DESIGN Subjects were studied during 6 or 12 months of S.C. GH at a dose of 0.25 IU/kg/week (0.125 IU/kg/week for the first 4 weeks), and after a wash-out period of at least 2 months off GH (range 2–5 months). PATIENTS Fourteen hypopituitary patients (2F:12M) receiving stable hydrocortisone replacement and thyroxine, gonadal steroids and bromocriptine therapy as required. MEASUREMENTS Serum cortisol values were measured throughout the day over 10.5 hours. Thyroid hormones and cortisol binding globulin (CBG) were measured in the baseline sample. Comparisons of the serum cortisol peak after receiving the first dose of hydrocortisone, the time when the serum cortisol peak was obtained, the area under the curve (AUC) for the cortisol values and the levels of unbound cortisol on and off OH therapy were made. The results are expressed as mean ± SEM. Comparisons were carried out within Individuals, using the Wilcoxon signed rank test. A P-value less than 0.05 was considered statistically significant. RESULTS During OH therapy, there was a significant reduction in the mean cortisol peak (662.2 ± 61.1 vs 848.0 ± 58.6 nmol/l; P= 0.001), and In the AUC for cortisol (185.3 ± 18.3 vs 230 ± 17.9 nmol/l/10.5h; P= 0.03), but there was no significant change in the time of the cortisol peak (55.7 ± 7.6 vs 57.8 ± 4.9 minutes; P= NS). During GH therapy there was a significant reduction In CBG levels (33.64 ± 1.16 vs 40.86 ± 1.34mg/l; P= 0.001); however, no changes were found In the levels of calculated unbound cortisol on and off GH (2.87 ± 0.38 vs 2.90 ± 0.30 nmol/l; P= NS). During OH therapy, there was a significant increase In serum trilodothyronine (T3) (1.88 ± 0.15 vs 1.44 ± 0.11 nmol/l; P= 0.01), and a significant decrease in thyroxine (T4) levels (74.9 ± 11.1 vs 97.6 ± 10.9 nmol/l; P= 0.02) but levels remained within the normal range. No change was observed in serum TSH levels (0.29 ± 0.13 vs 0.83 ± 0.71 mU/I; P = NS). CONCLUSIONS These results suggest that OH therapy In GH deficient adults produces an alteration in the measured serum cortisol profile, with a reduction in concentration of total cortisol in blood after erally administered hydrocortisone. These changes in circulating cortisol probably depend primarily on the fall in CBG levels, as no changes were found in the levels of calculated unbound cortisol on and off GH. Our data show that when measuring circulating cortisol levels, the results should be interpreted with caution in OH deficient patients on GH replacement, and different criteria may have to be applied to the circulating cortlsol profile of these patients. The results highlight the importance of ensuring adequate corticosteroid replacement in patients starting GH therapy.