Clinical Endocrinology (1978) 9,571-576.
PLASMA ACTH A N D CORTISOL PROFILES IN A D D I S O N I A N PATIENTS RECEIVING C O N V E N T I O N A L SUBSTITUTION THERAPY R. S . SCOTT, R. A. D O N A L D A N D E. A. ESPINER The Medical Unit, Princess Margaret Hospital, Christchurch, New Zealand (Received 13 February 1978;revised 1.5 June 1978;accepted 16 June 1978)
SUMMARY
Plasma ACTH and cortisol profiles were studied over 24 h in five Addisonian patients maintained in good health by conventional gluco- and mineralocorticoid treatment. Patients received their usual treatment (15-30 mg cortisol daily) in divided doses at 08.00 and 16.00 hours. Plasma cortisol concentrations differed from those of control subjects in being higher from 08.00 hours-noon and 17.0018.00 hours and were unmeasurable ( 1600 ng/l) occurred at 08.00-09.00 hours in the Addisonian patients and were much greater than those seen in control subjects (60-220 ng/l). Despite this, plasma ACTH fell promptly within 3 h of the morning dose t o less than 100 ng/l and levels were indistinguishable from those seen in normal subjects over the period 12.00-02.00 hours. These results show that there are substantial differences between treated Addisonian and control subjects in respect of plasma cortisol and ACTH concentrations. The findings may lead to a better understanding of ACTH-cortisol relationships in disease states, including congenital adrenal hyperplasia where control of excessive ACTH secretion is clinically desirable. Hypersecretion of ACTH occurs in untreated Addison’s disease (Krieger & Gewirtz, 1974) but secretion is assumed to be more normal Once substitution therapy has been given. Although abnormalities of feedback ,inhibition by glucocorticoids have been reported in Addison’s disease (Krieger & Gewirtz, 1974; Holdaway, 1973), there areno systematic studies of ACTH-cortisol relationships in Addisonian patients maintained in good health by conventional corticosteroid treatment. This study reports plasma ACTH and cortisol profiles during a 24 h observation period in five patients with wellcontrolled Addison’s disease. For the purpose of comparison, identical studies were also made in five hospitalized control subjects without evidence of endocrine disease. Correspondence: Professor E. A. Espiner, Medical Unit, The Princess Margaret Hospital, Christchurch 2, New Zealand. 0300-0664/78/12000S7 1$02.00 0 1978 Blackwell Scientific Publications
57 1
572
Patients
R. S. Scott, R. A . Donald and E. A . Espiner METHODS
Five patients with Addison's disease, aged 43 to 66 years, were admitted to hospital for study. Duration of Addison's disease varied from five t o twenty-four years, adrenal antibodies were present in all cases and there was no adrenocortical response to exogenous ACTH. All patients were considered t o have been in good health for 3 t o 6 months before the study and none was abnormally pigmented. They were maintained on appropriate treatment which varied from 15-30 mg of hydrocortisone and 0-250 pg of fludrocortisone per day; two-thirds of the total daily cortisol dose was taken orally at 07.00-08.00 hours and one-third at 15.00-16.00 hours. The mineralocorticoid was taken as a single dose in the morning. Five healthy male subjects without evidence of endocrine disease aged 18 t o 45 years volunteered for the study. None was receiving drug therapy. No attempt was made to agematch the control group with the Addisonian patients since levels of plasma corticoid and ACTH show no significant change with advancing age (West etal., 1961 ;Blichert-Toft, 1971).
Procedures Both groups of normal subjects and patients were admitted t o the metabolic ward one night before the study. At 07.45 hours the following morning an i.v. cannula with a 3-way stop cock was inserted into a forearm vein for the purpose of venous sampling over the subsequent 24 h period. From 08.00 hours samples for cortisol and ACTH were taken at hourly intervals and additional samples were drawn at 08.30, 16.30 hours and half hourly after 02.00 hours. The blood was centrifuged immediately at 4°C and plasma stored at -20°C until analysis. All subjects and patients were allowed free movement throughout the study and they received meals at 07.30, 12.30 and 17.30 hours. Lights were turned out at 22.00 hours and most subjects slept normally during the nocturnal period of sampling. Addisonian patients received hydrocortisone therapy at 08.05 hours (1 0-20 mg) and 16.05 hours (5-10 mg). In all cases a 24 h urine collection over the study day was analysed for creatinine, 17-oxosteroids (OS), 17-oxogenic steroids (OGS), cortisol and aldosterone.
Laboratory methods Plasma and urine cortisol was measured by a modification of the protein-binding method described by Murphy (1967; 1968) using an ammonium sulphate separation technique. Standard methods were used for measuring urinary oxogenic steroids (Metcalf, 1963). Urine aldosterone was quantitated b y radioimmunoassay (Nicholls et al., 1974) after liberation from the acid labile conjugate at pH l . Plasma ACTH was measured by radioimmunoassay (Donald, 1968). Statistical significance between cortisol and ACTH levels within the two groups was determined using the Wilcoxon test on unpaired samples.
RESULTS Urine steroid excretion is shown in Table 1. Glucocorticoid and metabolite excretion was normal in both control subjects and in patients with Addisons disease but aldosterone excretion was low in the latter group.
ACTH and cortisol in Addison’s disease
573
Table 1. Urinary steroid excretion rates in control subjects and treated Addisonian patients
Number studied Age (yrs) Hydrocortisone dose (w/day) Urinary 17 OGS (wnol/day) Urinary 17 OCS (pmoI/day per mmol creatinine) Urinary free cortisol (nmol/day) Urinary aldosterone (nmol/day)
Control subjects
Addisonian patients
Normal adult range
5 18-45 Nil
5 43-66 15-30
16-59
15-58
15-70
1.5-4.6
2.0-4.8
1.5-4.8
109-409
137-569
100-500
18-36
0-8
9-60
Ranges are indicated for each group
Control subjects Plasma Cortisol levels (Fig. I ) . During the 24 h period of study, a diurnal rhythm was observed in each subject. Peak cortisol levels occurred at 08.00-09.00 hours and ranged from 420-970 nmol/l in the five subjects. Early morning secretory episodes of cortisol were noted within a fairly constant time interval (02.00 to 03.30 hours) and increased over the subsequent 6 h before showing a gradual decline during daylight hours. Plasma ACTH levels (Fig, I ) . A diurnal rhythm of ACTH secretion was present in all subjects but the range of ACTH values varied widely amongst the individuals. ACTH secretory episodes commenced after midnight and were associated with increments in plasma cortisol concentration in most instances. However no correlation between plasma ACTH and simultaneously sampled plasma cortisol concentration was evident. Peak ACTH levels were noted around 08.00 hours and in four of the subjects were below 120 ng/l. The remaining subject had a higher initial plasma ACTH of 228 ng/l just after insertion of the i.v. cannula. Addisonian patients Plasma Cortisol levels. The plasma cortisol patterns in treated patients with Addison’s disease showed two abrupt peaks following each of the doses of oral hydrocortisone (Fig. 1). At 08.00 hours the levels of plasma cortisol were unmeasurable (
PLASMA ACTH A N D CORTISOL PROFILES IN A D D I S O N I A N PATIENTS RECEIVING C O N V E N T I O N A L SUBSTITUTION THERAPY R. S . SCOTT, R. A. D O N A L D A N D E. A. ESPINER The Medical Unit, Princess Margaret Hospital, Christchurch, New Zealand (Received 13 February 1978;revised 1.5 June 1978;accepted 16 June 1978)
SUMMARY
Plasma ACTH and cortisol profiles were studied over 24 h in five Addisonian patients maintained in good health by conventional gluco- and mineralocorticoid treatment. Patients received their usual treatment (15-30 mg cortisol daily) in divided doses at 08.00 and 16.00 hours. Plasma cortisol concentrations differed from those of control subjects in being higher from 08.00 hours-noon and 17.0018.00 hours and were unmeasurable ( 1600 ng/l) occurred at 08.00-09.00 hours in the Addisonian patients and were much greater than those seen in control subjects (60-220 ng/l). Despite this, plasma ACTH fell promptly within 3 h of the morning dose t o less than 100 ng/l and levels were indistinguishable from those seen in normal subjects over the period 12.00-02.00 hours. These results show that there are substantial differences between treated Addisonian and control subjects in respect of plasma cortisol and ACTH concentrations. The findings may lead to a better understanding of ACTH-cortisol relationships in disease states, including congenital adrenal hyperplasia where control of excessive ACTH secretion is clinically desirable. Hypersecretion of ACTH occurs in untreated Addison’s disease (Krieger & Gewirtz, 1974) but secretion is assumed to be more normal Once substitution therapy has been given. Although abnormalities of feedback ,inhibition by glucocorticoids have been reported in Addison’s disease (Krieger & Gewirtz, 1974; Holdaway, 1973), there areno systematic studies of ACTH-cortisol relationships in Addisonian patients maintained in good health by conventional corticosteroid treatment. This study reports plasma ACTH and cortisol profiles during a 24 h observation period in five patients with wellcontrolled Addison’s disease. For the purpose of comparison, identical studies were also made in five hospitalized control subjects without evidence of endocrine disease. Correspondence: Professor E. A. Espiner, Medical Unit, The Princess Margaret Hospital, Christchurch 2, New Zealand. 0300-0664/78/12000S7 1$02.00 0 1978 Blackwell Scientific Publications
57 1
572
Patients
R. S. Scott, R. A . Donald and E. A . Espiner METHODS
Five patients with Addison's disease, aged 43 to 66 years, were admitted to hospital for study. Duration of Addison's disease varied from five t o twenty-four years, adrenal antibodies were present in all cases and there was no adrenocortical response to exogenous ACTH. All patients were considered t o have been in good health for 3 t o 6 months before the study and none was abnormally pigmented. They were maintained on appropriate treatment which varied from 15-30 mg of hydrocortisone and 0-250 pg of fludrocortisone per day; two-thirds of the total daily cortisol dose was taken orally at 07.00-08.00 hours and one-third at 15.00-16.00 hours. The mineralocorticoid was taken as a single dose in the morning. Five healthy male subjects without evidence of endocrine disease aged 18 t o 45 years volunteered for the study. None was receiving drug therapy. No attempt was made to agematch the control group with the Addisonian patients since levels of plasma corticoid and ACTH show no significant change with advancing age (West etal., 1961 ;Blichert-Toft, 1971).
Procedures Both groups of normal subjects and patients were admitted t o the metabolic ward one night before the study. At 07.45 hours the following morning an i.v. cannula with a 3-way stop cock was inserted into a forearm vein for the purpose of venous sampling over the subsequent 24 h period. From 08.00 hours samples for cortisol and ACTH were taken at hourly intervals and additional samples were drawn at 08.30, 16.30 hours and half hourly after 02.00 hours. The blood was centrifuged immediately at 4°C and plasma stored at -20°C until analysis. All subjects and patients were allowed free movement throughout the study and they received meals at 07.30, 12.30 and 17.30 hours. Lights were turned out at 22.00 hours and most subjects slept normally during the nocturnal period of sampling. Addisonian patients received hydrocortisone therapy at 08.05 hours (1 0-20 mg) and 16.05 hours (5-10 mg). In all cases a 24 h urine collection over the study day was analysed for creatinine, 17-oxosteroids (OS), 17-oxogenic steroids (OGS), cortisol and aldosterone.
Laboratory methods Plasma and urine cortisol was measured by a modification of the protein-binding method described by Murphy (1967; 1968) using an ammonium sulphate separation technique. Standard methods were used for measuring urinary oxogenic steroids (Metcalf, 1963). Urine aldosterone was quantitated b y radioimmunoassay (Nicholls et al., 1974) after liberation from the acid labile conjugate at pH l . Plasma ACTH was measured by radioimmunoassay (Donald, 1968). Statistical significance between cortisol and ACTH levels within the two groups was determined using the Wilcoxon test on unpaired samples.
RESULTS Urine steroid excretion is shown in Table 1. Glucocorticoid and metabolite excretion was normal in both control subjects and in patients with Addisons disease but aldosterone excretion was low in the latter group.
ACTH and cortisol in Addison’s disease
573
Table 1. Urinary steroid excretion rates in control subjects and treated Addisonian patients
Number studied Age (yrs) Hydrocortisone dose (w/day) Urinary 17 OGS (wnol/day) Urinary 17 OCS (pmoI/day per mmol creatinine) Urinary free cortisol (nmol/day) Urinary aldosterone (nmol/day)
Control subjects
Addisonian patients
Normal adult range
5 18-45 Nil
5 43-66 15-30
16-59
15-58
15-70
1.5-4.6
2.0-4.8
1.5-4.8
109-409
137-569
100-500
18-36
0-8
9-60
Ranges are indicated for each group
Control subjects Plasma Cortisol levels (Fig. I ) . During the 24 h period of study, a diurnal rhythm was observed in each subject. Peak cortisol levels occurred at 08.00-09.00 hours and ranged from 420-970 nmol/l in the five subjects. Early morning secretory episodes of cortisol were noted within a fairly constant time interval (02.00 to 03.30 hours) and increased over the subsequent 6 h before showing a gradual decline during daylight hours. Plasma ACTH levels (Fig, I ) . A diurnal rhythm of ACTH secretion was present in all subjects but the range of ACTH values varied widely amongst the individuals. ACTH secretory episodes commenced after midnight and were associated with increments in plasma cortisol concentration in most instances. However no correlation between plasma ACTH and simultaneously sampled plasma cortisol concentration was evident. Peak ACTH levels were noted around 08.00 hours and in four of the subjects were below 120 ng/l. The remaining subject had a higher initial plasma ACTH of 228 ng/l just after insertion of the i.v. cannula. Addisonian patients Plasma Cortisol levels. The plasma cortisol patterns in treated patients with Addison’s disease showed two abrupt peaks following each of the doses of oral hydrocortisone (Fig. 1). At 08.00 hours the levels of plasma cortisol were unmeasurable (
