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.     

An Assessment of Optimal Hydrocortisone Replacement Therapy

OBJECTIVE To assess the management of hydrocortisone replacement therapy in one institution, and derive recommendations for optimum starting and maintenance replacement therapy with hydrocortisone. DESIGN Retrospective survey of clinical management using a clinical information system and the patient case notes. PATIENTS Using the department’s clinical information system, 210 patients were identified who had been treated with hydrocortisone. Case notes were reviewed and 130 patients were identified whose records contained the results of at least one valid hydrocortisone day curve. Data on 174 day curves performed on these patients (65 on twice daily and 109 on thrice daily hydrocortisone regimes) formed the basis of this analysis. METHODS Hydrocortisone day curves had been performed as part of routine clinical management: patients collected a 24 h urine for free cortisol on the day prior to the test and took their morning hydrocortisone at the normal time, at home, on wakening. During a day-case attendance serum cortisol was then measured at 0900 h, 1230 h (prior to any lunchtime dose) and 1730 h (prior to the evening dose). ‘Optimal replacement’ was arbitrarily defined as that dose which achieved a UFC and 09:00h cortisol within the reference range for the normal population (to avoid over-replacement) combined with 1230 h and 1730 h cortisol above 50 nmol/l, and ideally above 100 nmol/l (to avoid under-replacement). Raw data from all hydrocortisone day curves was analysed in an Excel spreadsheet to determine the effect of different dose regimens on the percentage of patients achieving each and all of these 4 criteria, and on an overall ‘quality score’ (comprising 1 point for each of the 4 criteria attained). RESULTS Patients on twice daily hydrocortisone regimes achieved optimal replacement in 15% of cases compared to 60% on thrice daily regimes (P < 0.001 by χ²); mean overall ‘quality scores’ for these regimens were 2.72 and 3.49 respectively (P < 0.001 by t-test). Of individual dose regimens with sufficient cases for valid comparison, a dose of 10 mg/5 mg/5 mg (rising/lunch/evening) achieved optimal replacement in 66% and mean ‘quality score’ of 3.62 (n = 53), compared to 50% and 3.32 for 10 mg/10 mg/5 mg (n = 28) and 10% and 2.48 for 20 mg/–/10 mg (n =29). CONCLUSIONS The use of arbitrary, but logical, criteria to assess the quality of hydrocortisone replacement regimens indicates that optimal replacement is achieved with thrice daily hydrocortisone regimens, and that the traditional twice daily regime results in a 0900 h cortisol above normal in one-third, and late afternoon cortisol below 50 nmol/l in one-half of patients thus treated. An appropriate starting dose of hydrocortisone of 10 mg/5 mg/5 mg (rising/lunch/evening) is suggested, with subsequent individual adjustment based on simple hydrocortisone day curves.     

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.     

Saliva cortisol measurement: simple and reliable assessment of the glucocorticoid replacement therapy in Addison's disease

No ideal parameter is available for assessment of the glucocorticoid replacement therapy in Addison's disease. Serum cortisol day-curves can be used to monitor the therapy, but this technique is cumbersome and expensive. We evaluated the potential for saliva cortisol measurement in this setting. We found excellent correlation between serum and saliva cortisol after oral intake of cortisone acetate (no. 7) or iv administration of hydrocortisone (no. 4) (Pearson's R=0.83-0.98, p<0.002). A morning dose of 12.5 mg cortisone acetate yielded wide interindividual variations in cortisol levels in saliva. Saliva cortisol measurements were successfully adopted to evaluate and adjust doses in outpatients. We conclude that cortisol measurement in saliva is practical and reliable, and is preferable to serum cortisol measurement in the assessment of the glucocorticoid replacement therapy. Our results confirm that only a minority of patients require more than 12.5 mg of cortisone acetate (equivalent to 10 mg hydrocortisone) in the morning to have sufficient cortisol levels during the first part of the day.     

Clinical characteristics, timing of peak responses and safety aspects of two dosing regimens of the glucagon stimulation test in evaluating growth hormone and cortisol secretion in adults

Weight-based (WB: 0.03 mg/kg) and fixed dose (FD: 1–1.5 mg) regimens of the glucagon stimulation test (GST) have been used to evaluate GH and cortisol secretion in children and adults, respectively. However, experience of the WB regimen in assessing GH and cortisol secretion in adults are limited. We describe a multicenter experience using WB and FD regimens in evaluating GH and cortisol secretion in adults suspected of GH deficiency and central adrenal insufficiency. Retrospective case series of GSTs (n = 515) performed at five tertiary centers. Peak and nadir glucose, and peak GH and peak cortisol responses occurred later with WB (mean dose: 2.77 mg) compared to FD (mean dose: 1.20 mg) regimens. Main side-effects were nausea and vomiting, particularly in younger females. Nausea was comparable but vomiting was more frequent in the WB regimen (WB: 10.0 % vs FD: 2.4 %; P < 0.05). Peak and nadir glucose, ΔGH, and peak and Δcortisol were higher in the WB regimen. In both regimens, age correlated negatively with peak cortisol levels, and body mass index (BMI), fasting, peak and nadir glucose correlated negatively with peak GH levels. WB and FD regimens can induce adult GH and cortisol secretion, but peak responses occur later in the WB regimen. Both regimens are relatively safe, and vomiting was more prevalent in the WB regimen. As age, BMI, and glucose tolerance negatively correlated with peak GH and cortisol levels, the WB regimen may be more effective than the FD regimen in older overweight glucose intolerant patients.     

A six month mitotane course induced sustained correction of hypercortisolism in a young woman with PPNAD and Carney complex

A low-dose mitotane (MT) regimen was evaluated as a pharmacological approach for correcting the severe hypercortisolism in a young woman affected by Carney complex (CNC) and primary pigmented nodular adrenocortical disease (PPNAD). In the first 12 week period, the MT daily dose was progressively increased from 0.5 to 4.0 g/day. This dosage was maintained for an additional 16 weeks (cumulative dose 602 g, plasma MT maximum level 12 microg/ml), and then stopped because of sustained signs of hypoadrenalism requiring prednisone replacement. Complete regression of seborrhea, acne, and plethora was observed after 8 weeks of treatment (cumulative dose 95 g). Regular menses returned after 13 weeks (cumulative dose 197 g, plasma MT 8 microg/ml). Profound decrease of both serum cortisol (from 615 to 220 nmol/l) and urinary free cortisol (UFC) values (from 1498 to 477 nmol/day) was noted after 16 weeks of treatment (cumulative dose 314 g, plasma MT 8 microg/ml). MT treatment was associated with mild gastric discomfort and reversible increase of cholesterol plasma levels. Low serum cortisol and UFC were still observed 41 weeks after MT was discontinued (plasma MT 0.2 microg/ml). Our report demonstrates that low dose MT treatment may be a safe and effective modality for a sustained correction of hypercortisolism by PPNAD in subjects with CNC waiting for surgery.     

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.     

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.     

Improvement of treatment of primary adrenal insufficiency by administration of cortisone acetate in three daily doses

In the present study, we compared the effects of 3 daily administrations of cortisone acetate vs a classical regimen with 2 daily administrations, in patients with primary adrenal insufficiency (PAI). We enrolled 34 patients with PAI treated with 2 daily doses of cortisone acetate (2/3 of the total daily dose early in the morning, 1/3 in the afternoon) who were subdivided into two groups: group A (no. = 18; 4 males, 14 females; age: median 55 yr, range 24-88) continued with the standard 2 daily administrations, group B (no. = 16; 8 males, 8 females; age: median 44 yr, range 27-70) switched to 3 daily administrations (3/6 of the daily dose early in the morning, 2/6 after lunch, 1/6 after dinner), but without any change of the total daily dose. After 6 months of therapy, basal and 90-min post-cortisone acetate ACTH levels in group B (219 pg/ml, range 19.9-1197, and 84 pg/ml, range 14.4-480, respectively) were significantly lower than those observed at the beginning of the study (482 pg/ml, range 58-1900 and 215 pg/ml, range 52-1832, respectively; p = 0.001 and p = 0.027, respectively). No statistically significant differences were observed in group A. Similarly, 24-h urinary cortisol (UFC) excretion increased significantly after 6 months of a 3-dose therapy in group B (from 74.6 microg/24 h, range 24-148, to 98.8 microg/24 h, range 48-214; p = 0.006), but not in group A (p = ns). Moreover, UFC excretion after 6 months of a 3-dose therapy was significantly higher than after 6 months of a 2-dose therapy (98.8 microg/24 h, range 48-214 vs 49.8 microg/24 h, range 11-183, p = 0.032). No significant variations of basal and 90-min post-cortisone levels of cortisol were observed in either group. Our study demonstrates that the subdivision of the total daily dose of cortisone acetate in 3 administrations increases total UFC excretion and reduces plasma ACTH levels, thus improving the substitutive therapy.     

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.     

Antihypertensive effects of low doses of hydrochlorothiazide in hypertensive black Zimbabweans.

The antihypertensive effects of low doses of hydrochlorothiazide have not been examined in black African hypertensive patients although hydrochlorothiazide is commonly used as first-line therapy. The antihypertensive effects of hydrochlorothiazide in a daily dose of 6.25, 12.5, 25 and 50 mg were examined in 19 black Zimbabwean hypertensive patients in a double-blind, random order, placebo-controlled, cross-over trial. The mean systolic blood pressure on placebo was 170.2 mmHg (95% CI +/- 9.0 mmHg) and on daily doses of hydrochlorothiazide decreased to: 161.1 mmHg (95% CI + 10.0 mmHg) on 6.25 mg; 156.6 mmHg (95% CI +/- 8.6 mmHg) on 12.5 mg; 154.9 mmHg (95% CI +/- 8.5 mmHg) on 25 mg and 149.1 mmHg (95% CI +/- 9.2 mmHg) on 50 mg. The mean diastolic blood pressure on placebo was 101.4 mmHg (95% CI +/- 5.0 mmHg) and decreased to: 98.0 mmHg (95% CI +/- 5.7 mmHg) on 6.25 mg; 96.1 mmHg (95% CI +/- 4.5 mmHg) on 12.5 mg; 93.6 mmHg (95% CI +/- 5.3 mmHg) on 25 mg and 90.5 mmHg (95% CI +/- 3.9 mmHg) on 50 mg. Hydrochlorothiazide in doses of 25 mg and 50 mg decreased systolic and diastolic blood pressure and the 12.5 mg dose decreased systolic blood pressure significantly more than placebo. We conclude that in this population maximum antihypertensive effect is not seen with the lower doses of hydrochlorothiazide and 25 mg is an appropriate starting dose for most patients.     

Low dose, twice daily captopril and frusemide: a safe, effective and flexible third line treatment regimen for hypertension

Thirty patients with moderate to severe, uncontrolled hypertension were treated with a captopril/frusemide combination. The initial dose of captopril (6.25 mg or 12.5 mg) produced an acute fall in BP from 162 +/- 6/102 +/- 3 to 132 +/- 6/85 +/- 3 mmHg but at a dose of 12.5 mg three times daily outpatient BPs were not controlled. Frusemide (40 mg/day) was added and increased as necessary at two week intervals until BP was satisfactorily controlled or a total daily dose of 160 mg was reached. During long-term follow-up over a mean period of two years good BPs were achieved with an average daily dose of frusemide of 95 mg and captopril 52 mg (148 +/- 3/90 +/- 2 mmHg). There was no overall change in renal function or plasma potassium although small rises in blood urea were seen in some patients. In a group of 28 patients controlled on this regimen a change to a twice daily schedule without alteration of the dose of captopril or frusemide did not affect clinic BPs. In addition, BP remained controlled throughout the day as measured at home with an electronic sphygmomanometer. No case of glucose interolence was observed despite high doses of frusemide (HbA1 = 7.1 +/- 0.12%) and in 12 patients, where prospective measurements of HbA1 were measured, there was a fall from 7.6 +/- 0.21% to 6.9 +/- 0.16% suggesting an effect of captopril on insulin sensitivity. We conclude that low dose captopril with a variable frusemide dosage represents a simple and effective treatment for moderate to severe hypertension.     

Is the antihypertensive effect of captopril influenced by the dosage frequency? A study with ambulatory monitoring

When captopril was first introduced for the management of hypertension, its short plasma half-life led to its use as a thrice daily regimen. However, further experience suggests that the biological action is more prolonged than the plasma half-life might suggest. This study examined the effect of varying the frequency of administration (once, twice and three times daily) of a fixed daily dosage of 75 mg captopril on ambulatory BP in a double-blind cross-over study in 15 patients with mild to moderate hypertension. Each patient had six ambulatory BP recordings with placebo alternating with active phase. The three regimens (75 mg daily, 37.5 mg twice daily and 25 mg three times daily) reduced the daily mean BP equally and significantly compared with placebo. Three patients with very high pretreatment plasma renin values showed some loss of BP control immediately prior to the first dose in the morning in the 75 mg single dose phase (i.e. 24 hours post dose); but group analysis showed no difference in mean BP at this time point with the three treatment regimens. We conclude that in spite of its short plasma half-life, captopril can effectively control BP over the whole day with a once daily regimen.     

Effect of recombinant human growth hormone (GH) replacement on the hypothalamic-pituitary-adrenal axis in adult GH-deficient patients

The aim of the study was to evaluate the hypothalamus-pituitary-adrenal (HPA) axis in patients (nine males, three females; mean age +/- sem 51 +/- 2 yr) with adult-onset GH deficiency (GHD) due to surgically treated pituitary tumors with preserved HPA function and without evidence of tumor recurrence before and during recombinant human (rh) GH replacement therapy (duration 31 +/- 6 months). HPA function was assessed by urinary free cortisol and morning serum cortisol levels as well as cortisol responses to 1 mug ACTH test (n = 7 patients) or insulin tolerance test (n = 5 patients) before and during rhGH therapy, the cut-off for the diagnosis of hypoadrenalism being a cortisol peak less than 18 microg/dl (<500 nmol/liter) after stimulatory tests. Serum cortisol and urinary free cortisol levels were significantly lower on therapy than before [7.6 +/- 0.8 vs. 11.5 +/- 0.9 microg/dl (208 +/- 22 vs. 317 +/- 24 nmol/liter), P < 0.01, and 19.6 +/- 2.5 vs. 32.2 +/- 3.2 microg per 24 h (54 +/- 7 vs. 89 +/- 9 nmol per 24 h), P < 0.05, respectively], whereas no change in cortisol-binding globulin levels was observed. Cortisol peak after either ACTH test or insulin tolerance test was lower on rhGH therapy than before [15.9 +/- 1.5 vs. 20.2 +/- 1.1 microg/dl (437 +/- 43 vs. 557 +/- 31), P = 0.01, and 13.1 +/- 2.6 vs. 20.4 +/- 1.4 microg/dl (362 +/- 71 vs. 564 +/- 37 nmol/liter), P = 0.03, respectively]. Accordingly, central hypoadrenalism was detected in nine of 11 patients. In conclusion, low GH and IGF-I levels, likely enhancing the conversion of cortisone to cortisol, may mask a condition of central hypoadrenalism. Therefore, the reassessment of HPA function in GHD patients during rhGH therapy is mandatory.     

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.     

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.     

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.     

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.     

Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis

Budesonide has been discussed as a potential treatment option in primary biliary cirrhosis (PBC). Therefore, we studied the pharmacokinetics and pharmacodynamics of budesonide in patients with PBC stage I/II and stage IV. Twelve patients with early PBC stage I/II and 7 patients with PBC stage IV under continuous treatment with ursodeoxycholic acid (UDCA) were enrolled in an exploratory trial. Each patient received oral budesonide for 3 weeks at weekly increasing dosages of 3 mg once to thrice per day. Budesonide and cortisol plasma levels, urinary cortisol excretion, serum liver tests, and immunoglobulins were determined on days 1, 7, and 21 of the study. Patients with PBC stage IV showed significantly higher peak plasma concentrations (4.9 +/- 3.5 vs. 1.5 +/- 0.4 ng/mL; P <.05) and areas under the plasma concentration-time curves (AUC) (23.2 +/- 16.8 vs. 5.1 +/- 1.4 hours. ng/mL, P <.01, total AUC extrapolated to infinity [AUC(0- infinity )]) after a single dose of 3 mg budesonide when compared with patients with PBC stage I/II. Equally, AUC of budesonide were significantly increased under a multiple dose regimen on day 21 (14.0 +/- 11.6 vs. 5.0 +/- 1.9 hours. ng/mL, P <.01, AUC at steady state from dosing time to 8 hours [AUC(ss,0-8 h)]). Higher levels of budesonide were related to a significant decrease in plasma cortisol and reduction of urinary cortisol excretion in patients with stage IV disease. Two patients with stage IV disease developed portal vein thrombosis (PVT). In conclusion, administration of budesonide leads to markedly elevated plasma levels in cirrhotic patients with PBC associated with serious adverse drug reactions. Thus, further evaluation of combined treatment with UDCA may be considered in early-stage PBC but not in cirrhotic patients with PBC.     

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.