ACTH Values Research Articles

Spontaneous and stimulated adrenocorticotropin and vasopressin pulsatile secretion in the pituitary venous effluent of the horse.

Plasma ACTH, arginine vasopressin (AVP), and catecholamines were measured at 5-min intervals in the pituitary venous effluent of the unanesthetized horse. Pulses of ACTH and AVP were found to be surprisingly brief (usually of less than 10-min duration) and frequent (averaging between 15-25 min). A highly significant relationship in the changes in concentration of these two hormones was demonstrated (P less than 0.0002) both at rest and after a mild hypoglycemic stimulus. Although there was also a significant correlation (P less than 0.005) between simultaneous plasma ACTH and AVP values the pulse amplitude ratio of AVP to ACTH showed a considerable variation. A rise in cortisol appeared to have a greater suppressive effect on the amplitude of ACTH than AVP pulses. The gradient in hormonal concentration between pituitary effluent and jugular plasma was at times over 50-fold for ACTH, and 500-fold for AVP. A gradient was also found for epinephrine, norepinephrine, and dopamine. A highly significant correlation (P less than 0.005) was demonstrated between changes in norepinephrine, ACTH, and AVP concentrations, but no such relationship could be shown for epinephrine and dopamine. It is concluded that there is a close temporal relationship between changes in ACTH, AVP, and norepinephrine concentrations. Pulses of these hormones are greater in amplitude and more frequent than would have been suspected from sampling peripheral plasma. The variability in the pulse amplitude ratio of ACTH and AVP may suggest that other factors are affecting ACTH secretion. The ability to sample frequently for several hormones and to obtain a marked gradient in hormonal secretion between the pituitary venous effluent and jugular plasma suggest that the horse should provide an excellent animal model in which to study the regulation of hypothalamic and pituitary hormone secretion.

Centrally administered inhibitors of the generation and action of angiotensin II do not attenuate the increase in ACTH secretion produced by ether stress in rats.

The role of the brain renin-angiotensin system in the ACTH response to ether stress in rats was investigated by injecting the angiotensin II receptor blocking drug saralasin, the angiotensin II converting enzyme inhibitors enalaprilat and captopril, and the renin inhibitor L 363714 intraventricularly and measuring the ACTH and corticosterone concentration in plasma 10 min after ether stress. ACTH and corticosterone were elevated to at least the same level in rats treated with the inhibitors as they were in rats treated with the corresponding vehicles; indeed, ACTH values were somewhat greater in stressed rats treated with the converting enzyme inhibitors and the renin inhibitor. ACTH values in the absence of ether were not affected by saralasin, enalaprilat, and captopril and were increased by L 363714. The data do not support the hypothesis that the brain renin-angiotensin system is involved in the maintenance of ACTH secretion or that it mediates the increase produced by ether stress.

A direct radioimmunoassay for the determination of adrenocorticotropic hormone (ACTH) and a clinical evaluation.

A direct radioimmunoassay for the determination of ACTH in a small volume of serum was developed using a commercially available antiserum and tracer. A single-stage radioimmunoassay with an incubation period of 4 days gave reliable and reproducible ACTH values. In the incubation medium 0.1% 2-mercaptoethanol was used as the antioxidant. During a 15-month period the assay has been used routinely in the laboratory. The coefficient of variation was less than 10% in the physiological and pathological range. A normal range of 12 to 60 ng/L was found. The reliability of the assay is demonstrated by results obtained in patients with disorders of the pituitary-adrenal axis.

The Effect of Dexamethasone on the 24-Hour Profiles of Adrenocorticotropin and Cortisol in Cushing's Syndrome*

ACTH and cortisol are normally secreted episodically rather than continuously. This characteristic of episodic secretion is preserved in patients with Cushing's syndrome. To determine whether exogenous glucocorticoids modulate this pulsatility and to study its possible etiological implications, we obtained 24-h plasma cortisol profiles in seven patients with Cushing's syndrome (five Cushing's disease, one adrenal adenoma, and one bilateral adrenal cortical macronodular hyperplasia) before and during suppression with various doses of dexamethasone [low (0.5 mg, every 6 h), high (2 mg, every 6 h), and very high (4 mg, every 6 h)]. Simultaneous 24-h plasma ACTH profiles were obtained in two patients with Cushing's disease. Blood was drawn at 30-min intervals for 25 h. Individual profiles were analyzed to determine the 24-h mean level, the presence of a circadian component and its amplitude, and the number and magnitude of significant secretory pulses over the 24-h span. The concordance between significant ACTH and cortisol pulses also was quantified. Baseline values in patients were compared to those in seven normal subjects. Under basal conditions, the 24-h mean cortisol level was 3- to 4-fold higher than normal in all patients with Cushing's syndrome. In contrast, the basal 24-h mean ACTH level was normal in one, and slightly elevated in the other of the two patients with Cushing's disease in whom plasma ACTH concentrations were measured. However, in contrast to the normal subjects, all ACTH values were above 10 pg/ml even during the period of minimal secretion. Basal circadian variation in adrenocortical activity, albeit of reduced amplitude, was found in four of five patients with Cushing's disease; it was absent in the patient with adrenal adenoma. Low dose dexamethasone reduced the 24-h mean cortisol level and increased the amplitude of the circadian rhythm, unmasking a diurnal rhythm in the single patient with Cushing's disease in whom no significant circadian periodicity was present in the basal condition. This effect was further increased with the high dose of dexamethasone, which concomitantly reduced the number and increments of the secretory pulses. A lesser effect was found in the patient with bilateral nodular hyperplasia, and no effect was seen in the patient with adrenal adenoma. ACTH pulsatility, but not diurnal rhythm, also was dampened by dexamethasone. Reduction in the magnitude, but not the number, of ACTH secretory pulses by dexamethasone produced a reduced concordance ratio of ACTH with cortisol pulses of 0.39, compared to 0.64 in the basal state.(ABSTRACT TRUNCATED AT 400 WORDS)

Normal ACTH levels in saltlosing congenital adrenal hyperplasia (CAH) with elevated plasma renin concentration (PRC). The effect of mineralocorticoid treatment

Eleven patients with salt losing CAH (21 OH deficiency), aged 5-19 years were treated with cortisone 20-55 mg/m2/24 h in 3 divided doses and supplementary salt. Normal (< 60 m.i.u./1) and moderately raised (133, 140 m.i.u./1) PRC values in 4 patients were compatible with good control - normal excretion of pregnanetriol (Ptriol). High PRC values (153-522 m.i.u./1) were found in connection with high values of Ptriol (6.5-34.8 μmol/24 h). Plasma Aldosterone (PA) was 3-11 (control values <18) ng/100 ml. Normal ACTH values (11-82 pg/ml) were found in all patients - in one pt. with high PRC (522 m.i.u./1) ACTH was 99 pg/ml. During maintenance of cortisone therapy, mineralocorticoid (Florinef(R) was added to the treatment. The dose was gradually increased over a period (median 15 months) up to 1-4 μg/kg/24 h (2 doses) and normal PRC values were established. PA decreased significantly to values below 4 ng/100 ml. Ptriol excretion decreased markedly (to 0.4 -69 μmol/24 h). ACTH values were still in the normal range. During the observation period no change in growth velocity could be demonstrated.

The Pituitary-Adrenal Response to Stress in the Iron-Deficient Rat

This study was designed to determine the ACTH-corticosterone response to two types of stress in relation to the daily rhythm of food and water intake in the iron-deficient rat. Rats were fed diets containing 2, 10 or 50 mg iron/kg diet between weaning at 21 days and the stress experiments at 38 or 42 days of age. The two iron-deficient diets (2 and 10 mg iron/kg) resulted in mean hemoglobin concentrations of about 6.0 and 8.5 g/dl, respectively, in contrast to about 12.5 g/dl in the control group receiving 50 mg iron/kg diet. Food and water consumption followed the normal nocturnal pattern, irrespective of iron intake. ACTH and corticosterone showed the normal baseline peaks at the 2000 hour lights-out point in all groups. Responses to handling and placement into another cage were similar in most respects but suggested an inappropriately low corticosterone response despite high ACTH values only at the 2000 hour point. However, there was no evidence of similar differences in response to the more potent stress of an i.p. injection of histamine phosphate, 1 mg/100 g body weight. In contrast to the reports of more clear-cut effects of iron deficiency on norepinephrine, the changes in ACTH and corticosterone response to stress seem relatively modest.

HORMONAL CHANGES IN NONCIRRHOTIC MALE ALCOHOLICS DURING ETHANOL WITHDRAWAL

Serum concentrations of iodothyronines, cortisol, prolactin, testosterone and the respective tropic hormones were measured in 32 noncirrhotic male alcoholics, aged 28-51 years, at the end of a long drinking period and subsequently during ethanol withdrawal over 1-2 weeks. Seven men had testicular atrophy. On admission one patient had high values for serum thyroxine (T4) and free thyroxine index (FT4I). A blunted response of serum thyrotropin (TSH) to thyrotropin-releasing hormone (TRH) was found in 9 men. Apart from a blunted TSH-response in one man the abnormalities disappeared during the first week of alcohol abstinence. Simultaneously the mean levels of serum T4, FT4I, triiodothyronine, free triiodothyronine index and reverse triiodothyronine were reduced by 12, 14, 5, 8 and 21%, respectively, and the mean of the maximum TSH-response to TRH was increased by 55%. At the time of stopping drinking two men had high morning values and six an abnormal diurnal rhythm of serum cortisol. High serum ACTH-levels associated with normal serum cortisol concentrations were found in 12 men. During the first week of alcohol abstinence the mean morning values for serum cortisol and ACTH were reduced by 18 and 42%, respectively. The serum ACTH-levels remained high in 6 men but the abnormalities in cortisol secretion disappeared. On admission four men had low serum concentrations of testosterone which were normalized during ethanol withdrawal over one week. At the same time the mean level of serum testosterone was increased by 19%. Mild hyperprolactinaemia found in 7 patients on admission disappeared in 4 men during the first week of ethanol withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

The corticotropin-releasing hormone stimulation test: a possible aid in the evaluation of patients with adrenal insufficiency.

Ten patients with adrenal insufficiency receiving chronic glucocorticoid therapy were studied. All had subnormal plasma cortisol responses to ovine corticotropin-releasing hormone ( CRH ) (1 microgram/kg as an iv bolus) 12-60 h after discontinuation of steroid treatment. Plasma ACTH responses to CRH fell into three different patterns. The first three patients with primary adrenal insufficiency had high basal ACTH levels and augmented ACTH responses to CRH . A fourth such patient, however, treated with pharmacologic doses of prednisone, had a low normal ACTH response. Patients with secondary adrenal insufficiency had either low basal ACTH levels and diminished responses to CRH or low basal ACTH values but prolonged and augmented plasma ACTH responses to CRH with a delayed peak. We postulate that the group of patients with the former pattern have pituitary gland destruction whereas the patients with the latter pattern have hypothalamic CRH deficiency. Thus, CRH may be useful in differentiating between hypothalamic and pituitary causes of adrenal insufficiency.

ACTH in normal children and children with pituitary and adrenal diseases. II. Plasma ACTH (cortisol and growth hormone) values during insulin hypoglycaemia--patients with idiopathic hypopituitarism and intracranial tumour.

During insulin hypoglycaemia (IH) reference values for plasma ACTH are 10 to 88 pg/ml at 0 min and 50 to 300 pg/ml at 40 min. Plasma cortisol reference values are above 400 nmol/l at 40 min. A negative correlation between age and ACTH response was found in normal children. ACTH response during IH in 43 children and adolescents with deficient production of one or several pituitary hormones was significantly lower (median 81 pg/ml at 40 min), than the response in normal children (median 149 pg/ml). Thirty-six patients with idiopathic hypopituitarism could be grouped into 21 with normal, 6 with borderline (50 to 70 pg/ml at 40 min), and 9 with abnormal ACTH response. In 7 patients with intracranial tumour 2 had normal, 3 borderline, and 2 abnormal ACTH response. A good correlation between the ACTH peak at 40 min and the cortisol value at 40 min was found in patients with idiopathic hypopituitarism. ACTH response also correlated well with the plasma growth hormone (GH) response in the patients. It is recommended to study ACTH together with GH when IH is performed, multiple disturbances are often found in children with GH deficiency and demonstration of an ACTH defect has therapeutic implications.

Evidence for Extrapituitary Mechanisms Mediating the Morning Peak of Plasma Cortisol in Man*

There is evidence for the existence of ACTH unrelated mechanisms in the regulation of cortisol secretion in man. This study was designed to elucidate the interrelationship between plasma ACTH and cortisol levels during the increase in cortisol levels, which occurs during morning hours. The results were compared with those of an artificial cortisol peak induced by administration of small amounts of ACTH, and with ACTH and cortisol values during insulin-induced hypoglycemia. In these control groups, the increase in cortisol levels was preceded by a large increase in ACTH levels; in the case of the physiological morning peak there was no adequate rise in mean ACTH levels. Thus, the spontaneously occurring increments in individual ACTH levels appear to be inappropriate for the increases in cortisol. This conclusion was corroborated by the finding that oscillations of plasma cortisol concentrations, comparable to the physiological morning peak, were demonstrable in ACTH-deficient patients when they were supplied with subthreshold amounts of exogenous ACTH. These findings argue against the classic concept that the adrenal cortex is invariably linked to immediately preceding episodes of pituitary ACTH secretion.

Progressive impairment of CSF β-EP levels in migraine sufferers

Common migraine (CM) is an evolutive disease characterized by a progressive increase in the number of attacks and a consequent reduction in the free periods, eventually reaching a state of continuous migraine with interparoxysmal headache (MIH). To evaluate the role of central pro-opiocortin-related peptides in the pathogenesis of the disease, cerebrospinal fluid (CSF) levels of β-lipotropin (β-LPH), β-endorphin (β-EP) and ACTH were measured in two groups of migraine sufferers with increasing severity of the disease (CM and MIH), and in healthy controls. ACTH values were similar in the 3 groups, while β-LPH levels were significantly lower ( P < 0.005) in patients affected by MIH (10.4 ± 8.6 fmol/ ml) than in patients with CM (35.7 ± 8.3) and in controls (32.9 ± 15.33). β-EP levels were closely correlated with the severity of the disease: they decreased significantly from those found in healthy controls (86.1 ± 37 fmol/ ml) to those of CM sufferers (38.5 ± 3.5; P < 0.005) and showed a further significant fall ( P < 0.01) to the lowest levels which were found in MIH patients (14.8 ± 9.8). These data showing that the progressive evolution of migraine is concomitant with a progressive impairment in the CSF levels of β-EP, sustain the concept that non-organic central pain is related to a reduced activity of the neurons responsible for the CSF content of β-EP.

Effects of vasopressin antiserum on the response of adrenocorticotropin and cortisol to hemorrhage.

To determine if arginine vasopressin (AVP) is involved in the response of ACTH and cortisol (F) to hemorrhage, we examined the effect of injections of AVP-antiserum into the third ventricle in chronically prepared awake cats. Cats were trained to remain unrestrained in a cardboard box. Cats were prepared under halothane and nitrous oxide with aseptic technique. Two to 3 days later, experiments began. Antiserum (5 microliters) to AVP or to oxytocin (OXY) as a control was given 26 min before hemorrhage conducted over 3 min. Thirty minutes after hemorrhage, reinfusion was conducted over 3 min. Each cat received each antiserum in randomized sequence 2-3 days apart. Plasma ACTH and F were measured by RIA. Data were analyzed statistically by analysis of variance. In 12 experiments in 6 cats, ACTH and F increased significantly with 10 ml/kg hemorrhage (P less than 0.01) and to the same extent (P greater than 0.1) after either antiserum. In 20 additional experiments in 10 cats, a submaximal dose of dexamethasone was administered sc 2-3 h before hemorrhage of 15 or 17.5 ml/kg. Under this circumstance, ACTH increased significantly (P less than 0.05) after anti-OXY, but not after anti-AVP (P greater than 0.2) so that during hemorrhage the values of ACTH differed significantly (P less than 0.025). F increased significantly more after anti-OXY than after anti-AVP (P less than 0.025). Changes in arterial pressure, heart rate, and plasma glucose with or without pretreatment with dexamethasone did not differ between groups. Changes in F and ACTH in cats receiving sham injections did not differ from those after anti-OXY. These findings suggest that normally a corticotropin-releasing factor (CRF) or factors act independently of AVP to mediate the response to hemorrhage. However, in the presence of steroid feedback by dexamethasone, the release or action of this CRF(s) is suppressed so that AVP is necessary for a full response. As has been proposed previously by others, AVP could potentiate the action of other CRFs, stimulate their release, or act as a CRF.

Angiotensin II increases ACTH release in the absence of endogenous arginine-vasopressin

Recent studies from our laboratory indicate a primary central site of action of Angiotensin II (AII) to release ACTH. The present studies were designed to test whether AII is able to release ACTH in vivo in a similar fashion in intact, cannulated, freely moving Long-Evans (LE) or in vasopressin (AVP)-deficient, Brattleboro (DI) female rats. The in vivo response to AII was compared with that elicited by synthetic CRF. All injected i.v. (0.4 or 2 μg/100 g BW) induced a significant, dose-related increase in plasma ACTH values 5 and 15 min after injection, in both LE and DI rats. CRF given to LE and DI rats at 0.4 μg/100 g BW elicited a larger increase in ACTH plasma values than a similar dose of AII, 5 or 15 min after the injection. Moreover, ACTH levels after CRF in DI rats were significantly greater than those obtained in LE controls. In vitro studies using dispersed anterior pituitary cells indicate that the response of cells from either LE or DI rats to AII or AVP (both at 10 −9 and 10 −8) was similar. Cells from DI donors were hyperresponsive to CRF (2×10 −11 and 10 −10M) in terms of ACTH release when compared with the response of cells from LE rats. The present results suggest that the presence of AVP is not essential to mediate the central response to AII and that AII may act centrally to stimulate CRF release from the hypothalamus in vivo , which would then enhance ACTH output. The results in the DI rat indicate that the increased response to CRF may be an important compensatory mechanism involved in the regulation of adrenocortical function in the DI rat.

Rapid radioimmunoassay for corticotropin in unextracted human plasma.

This RIA for corticotropin (ACTH) involves use of a commercially available antiserum and permits measurement of immunoreactive ACTH in unextracted plasma. The assay takes 2.5 days, detects as little as 5 pg/mL of plasma, and is specific: structurally and (or) biosynthetically related peptides do not cross react. Generally, data on dilutions of almost all human plasma specimens produce curves parallel to that for the ACTH reference standard. Values correlate well with those obtained by a well-established but more laborious RIA. We measured immunoreactive ACTH in normal subjects at various times of the day and after modulation of their pituitary-adrenal axis, and in patients with hypo- and hyper-secretion of ACTH. We conclude that the full range of immunoreactive ACTH values, which accurately reflect the status of the subject's pituitary-adrenal axis, can be quickly and easily determined in samples of unextracted human plasma.

Plasma adrenocorticotropin and cortisol responses to intravenous injection of corticotropin-releasing factor in the morning and evening.

Plasma ACTH and cortisol responses to corticotropin-releasing factor (CRF) were determined in the morning and evening in seven normal men. Either 100 micrograms synthetic ovine CRF or saline was given intravenously at 0900 h and at 2200 h. Blood samples were collected before and 15, 30, 45, 60, 90, and 120 min after CRF or saline injection. Plasma ACTH concentrations before and after CRF injection in the morning were significantly higher (P less than 0.05) than those in the evening at all times except 45 min after injection. Plasma cortisol concentrations before and at all times after CRF injection in the morning were also significantly higher (P less than 0.05) than those in the evening. However, neither the maximum increments in plasma ACTH and cortisol above the control levels nor increments at each time point following CRF injection in the morning differed significantly from those in the evening. Increments in the area under the ACTH and cortisol concentration curves after CRF injection in the morning also did not differ significantly from those in the evening. These results suggest that the responsiveness of the pituitary to CRF in the morning and in the evening does not differ significantly, although actual values of plasma ACTH and cortisol are higher in the morning.

Quantitative characterization of ACTH and adrenocortical episodic secretion in man: An introduction

Publisher Summary This chapter presents an introduction to quantitative characterization of ACTH and adrenocortical episodic secretion in man. A quantitative characterization of hormonal episodic variations aims at the estimation of the number of secretory episodes over a determined period of time. In a study described in the chapter, blood was sampled simultaneously every 5 min from the vena cava superior and from an antecubital vein, over a total period of 245 min. Plasma cortisol was measured by the radioimmunoassay method. Central and peripheral cortisol patterns were identical. Preliminary analysis of data obtained in normal subjects, using 15-min intervals sampling of peripheral blood for 24 h, showed excellent temporal and quantitative correlations between episodic variations of ACTH, cortisol, 11β-hydroxyandrostenedione, and androstenedione. In 15 nyctohemeral profiles, more than 80% of ACTH secretory bursts were accompanied by cortisol peaks. In three other patterns, more than 75% of secretory episodes of cortisol, 11β-hydroxyandrostenedione, and androstenedione occurred simultaneously. The chapter also describes the correlations between simultaneous peak values of ACTH and cortisol in three normal subjects.

Different patterns of central and peripheral βEP, βLPH and ACTH throughout life

The aim of the present study was to evaluate the relationship between central and peripheral concentrations of proopiocortin-related peptides in different periods of life. One hundred and eighty-nine plasma samples from normal subjects (18–87 years) obtained in basal conditions, and 20 cerebrospinal fluid (CSF) samples obtained by lumbar puncture from healthy volunteers (18–75 years) were studied. βLipotropin (βLPH), βendorphin (βEP) and ACTH were measured by specific RIA after silicic acid plasma extraction and gel chromatography (βLPH and βEP). No sex differences were found in the patterns of the three peptides either in the plasma or in CSF. In the plasma samples, both βLPH and βEP concentrations showed a pattern throughout life which was expressed by a paraboloid function with the lowest values found in young and old subjects and with peaks at 51.3 and 48.2 years, respectively. On the contrary, ACTH values failed to be represented by a significant linear or curvilinear regression and presented only a slight decrease in subjects over 75 years of age. CSF levels of βLPH were significantly lower in 45–76 year old subjects ( 18.8±12.6 fmol/ml , M± SD ) than in 18–44 year old subjects ( 34.5±15.8; p<0.05), as were those of βEP (elderly: 41.2±19.7; young: 94.2±36.7; p<0.05), which showed a significantly linear inverse correlation with age ( r=0.6062 , p<0.01). These CSF samples did not show any ACTH variations connected with age. In conclusion, ACTH levels in basal conditions are not correlated to those of βLPH or βEP, either in the plasma or in CSF, while the two opioids show parallel changes. Moreover, the differences in the age-related changes of βLPH and βEP in plasma and CSF markedly sustain the existence of two different compartments in which proopiocortin-related peptides are subject to different forms of control.

Vasopressin, ACTH and neonatal haemodynamics.

In 21 normal deliveries, high concentrations of AVP and ACTH in cord blood were associated with higher blood pressure and lower skin temperature, indicating peripheral vasoconstriction. Following Caesarean section after the onset of labour (n = 8), cord AVP concentrations and blood pressures were lower than after normal delivery but higher than after elective Caesarean section (n = 9). Maternal AVP concentrations at delivery were normal, as were plasma AVP concentrations in all infants 3 days after delivery. The relationship between vasopressin, a potential ACTH releasing factor, and ACTH was interesting. We conclude that the massive release of vasopressin is associated with normal delivery, elevated ACTH values and with peripheral vasoconstriction. These findings reflect favourable adaptation to hypoxia and stress of delivery, intended to redistribute cardiac output to vital organs and may provide for physiological adjustments necessary for extrauterine life.

Beeinflussung endokrinologischer Parameter durch UV-Ganzbestrahlungen

In 49 healthy test persons we measured various endocrine parameters (ACTH, cortisol, prolactin, triiodothyronine, thyroxine, TSH) prior to and after whole-body irradiation with UV light of varying quality and quantity. 60 min after sunlamp and SUP exposure a marked decrease in the average cortisol plasma level appears which is less than the daily circadian variation. After irradiation with a lamp that mainly emits UVA rays these reactions fail to appear. After sunlamp and SUP irradiation also the concentrations of the thyroid hormones triiodothyronine and thyroxine show a decrease of 22.1 and 13.7%, respectively, which is, however, statistically significant for triiodothyronine only. ACTH and TSH values remain unchanged. According to these results we can conclude that depending on the quality of rays defined endocrinological reactions are caused. Peripheral "consumption" of these hormones and concomitant insufficient central stimulation are suggested.

Cushing's Disease Treated by Total Adrenalectomy: Long-term Observations of 43 Patients

Forty-three patients were treated by total adrenalectomy for pituitary-dependent Cushing's disease. The median period of observation was 10 years (range one to 20 years). Thirty-eight patients (88 per cent) had rapid and lasting remissions. Of the 38 in remission, 21 became pigmented but without pituitary enlargement, 11 became pigmented with evidence of further pituitary expansion (Nelson's syndrome) and six neither became pigmented nor showed pituitary expansion. Pituitary expansion was associated with high plasma ACTH values, and treatment of pituitary tumours by surgery or radiotherapy gave poor results. However, when compared with alternative methods of treatment, total adrenalectomy for Cushing's disease is still satisfactory for many patients, despite advances in pituitary surgery, and has advantages over 'medical adrenalectomy' with drugs.