0021-972X/79/4802-0348$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1979 by The Endocrine Society
Vol. 48, No. 2
Printed in U.SA.
Plasma Corticotropin and Cortisol in Patients with Pituitary Adenomas JORGEN LINDHOLM, LOTTE HUMMER, HENRIK KEHLET, JOHN RIISHEDE, MOGENS BLICHERT-TOFT, AND BO DINESEN Department of Neurosurgery, Division of Neuroendocrinology, the Department of Nuclear Medicine, and the Department of Clinical Chemistry, University Clinic-Rigshospitalet, 2100 Copenhagen, Denmark tients with normal and impaired cortisol response to hypoglycemia on the basis of the ACTH results. When all 39 patients were compared to the 26 controls, the cortisol results differed significantly, but those of ACTH did not. These results demonstrate a limited value of ACTH measurements in secondary adrenocortical failure. (J Clin Endocrinol Metab 48: 348, 1979)
ABSTRACT. Plasma ACTH and cortisol were measured during insulin-induced hypoglycemia in 39 patients with a pituitary adenoma or after hypophysectomy and in 26 healthy persons. Adrenocortical insufficiency was defined as failure to increase plasma cortisol to at least 500 nmol/liter (18 /ug/dl) during hypoglycemia. No proper distinction was possible between pa-
R
All subjects were studied after an overnight fast. At about 0830 h, 0.15 IU/kg BW regular insulin was injected iv. Higher doses were given to acromegalics and lower doses to patients suspected of secondary adrenal insufficiency. Blood samples were drawn from a cubital vein into polystyrol tubes (containing heparin) at 0, 15, 30, 45, 60, 75, and 90 min and promptly centrifuged at 4 C. The blood glucose concentration fell to at least 2.2 mmol/liter (40 mg/dl) in all subjects, and all experienced sweating during hypoglycemia. At the time of study, two patients were on substitution with cortisone. This was discontinued 16 h before the test was performed. ACTH was measured by a radioimmunological method. All steps in the assay procedure were performed at 4 C. Plasma samples and standards (200 jul; Medical Research Council Reference Preparation 74/555) prepared in assay buffer were added to 2 ml ACTH antiserum diluted 1:320,000 by 0.02 M diemal buffer, pH 8.6, containing 0.4% mercaptoethanol, 400 klU Trasylol/ml, and 1% bovine serum albumin in polystyrol tubes. After an overnight incubation, the labeling procedure was performed according to Berson and Yalow (3). The labeled ACTH was added to each tube and after 20 h of incubation, the antibody-bound and free ACTH were separated with 200 jul activated charcoal suspension containing 3% Norite and 0.75% Dextran T-80 (Pharmacia) in 0.02 diemal buffer. The tubes were incubated for 15 min and centrifuged for 15 min at 2000 rpm. The supernatant was discarded and the charcoal residue was counted in a y-scintillation counter. The fraction of labeled ACTH bound to antibody was calculated and corrections for nonspecific binding in the individual sample were made. The assay had a detection limit of 2 pg ACTH when assaying 200 ix\ unextracted plasma. The antibody had been obtained by immunizing guinea pigs with synthetic human ACTH1"24 (CIBA) coupled to bovine serum albumin. The selected antibody had an equilibrium constant of 4 X 10u mol"1 in the assay. The antiserum reacted with synthetic human ACTH1"39 and ACTH1"24. The synthetic human ACTH11"24 fragment as well as
OUTINELY, hypofunction of the hypothalamic-pituitary-adrenal system is verified by the finding of subnormal plasma cortisol concentrations during one of the stimulation tests available; the insulin hypoglycemia test is the most widely used. Logically, plasma corticotropin (ACTH) should be the hormone of prime interest. Very few studies have been published on the value of measuring ACTH in the assessment of the hypothalamicpituitary-adrenocortical function, probably because of difficulties in measuring circulating ACTH. Most have dealt with patients with Cushing's disease (1) or with the problem of distinguishing between primary and secondary adrenal insufficiency (2). In this paper, we report the results of a study in which plasma ACTH and cortisol were measured during insulininduced hypoglycemia in patients with a pituitary adenoma. Subjects and Methods Thirty-nine patients were studied. Eight had a pituitary adenoma clinically presenting with acromegaly, 12 had a chromophobe adenoma of the pituitary, as verified at a subsequent operation; 7 were patients who had undergone surgical removal of a chromophobe adenoma at least 6 months previously; and 12 were patients with a small intrasellar tumor demonstrated by computer-assisted tomography. None of the patients had Cushing's disease, Nelson's syndrome, or primary adrenocortical failure (Addison's disease). Controls were 26 subjects without any serious or endocrine disease. Received June 20, 1978. Address requests for reprints to: Dr. Jbrgen Lindholm, Department of Neurosurgery 2092, Division of Neuroendocrinology, Rigshospitalet, 2100 Copenhagen, Denmark.
348
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 20:37 For personal use only. No other uses without permission. . All rights reserved.
349
COMMENTS a- and /3-MSH did not cross-react in the assay. Other known pituitary hormones did not show any inhibition of the binding of labeled ACTH to the antibody. Plasma samples with normal and high concentrations of ACTH produced dose-response curves parallel to the standard curve. The interassay coefficient of variation of replicate estimates was 12%. Further analytical details and the clinical validation of the assay in various pituitary-adrenal diseases have been reported elsewhere (4). Cortisol was measured fluorimetrically (5). The Mann-Whitney test was used for the statistical analysis.
Results The patients were divided into two groups according to the peak plasma cortisol concentration during the insulin-induced hypoglycemia: 1) those responding normally, i.e. plasma cortisol rising to at least 500 nmol/liter (18 /xg/dl), and 2) those with a subnormal response to hypoglycemia, i.e. a peak plasma concentration below 500 nmol/liter. The basal plasma ACTH concentrations did not differ significantly in these groups (P > 0.1). The amount of ACTH and cortisol secreted (total area under the curve) and the peak plasma concentrations in the two groups are shown in Fig. 1. Although the ACTH values were significantly lower in the patients with sub3K299 o o n ng/l 280
i«u -
tJ 380 343
120-
240-
100-
200-
80-
160-
800-
120-
600-
60-
• •
40-
80-
20-
40-
i
400-
:
200-
800-
400-
n AMOUNT SECRETED
PEAK PLASMA CONCENTRATION
AMOUNT SECRETED
PEAK PLASMA CONCENTRATION
FIG. 1. ACTH and cortisol secretion during insulin-induced hypoglycemia in 10 patients with (S) and 29 patients without (N) secondary adrenocortical insufficiency.
normal adrenocortical function (P < 0.05), the overlap was considerable; in fact, the ACTH values from all of the patients with hypocorticism were within the range found in the patients with normal cortisol responses to hypoglycemia. The results from all 39 patients compared to those from the controls are shown in Fig. 2. The difference between the cortisol values in these two groups was highly significant (P < 0.005), while the ACTH values did not differ significantly (P > 0.05). The basal ACTH plasma concentrations were not different in the two groups (P > 0.1). Discussion There is no single test by which adrenocortical hypofunction can be precisely defined clinically (6). On the other hand, it seems indisputable that failure to increase plasma cortisol to at least 500 nmol/liter during severe hypoglycemia is proof of hypofunction of the hypothalamic-pituitary-adrenocortical system (7). Our results demonstrate that measuring ACTH in plasma is of little practical value when investigating patients for secondary adrenocortical insufficiency, because of the substantial overlap between the results from patients with normal and impaired adrenocortical functions. Also, when all of the patients were compared to normal controls, the cortisol values differed highly significantly, but the ACTH values did not. Donald (8) measured plasma ACTH during insulininduced hypoglycemia in six patients with hypopituitarism and found that the patients secreted significantly lower amounts of ACTH and the peak plasma concentrations were significantly lower than in the controls. Basal plasma concentrations did not differ significantly. Besser et al. (2) found basal ACTH concentrations within the normal range in 13 of 27 patients with secondary adrenocortical failure. In all six patients with adrenal insufficiency because of hypopituitarism studied by Holdaway et al. (9), basal ACTH plasma concentrations were low, but in the three patients who had been subjected to an insulin hypoglycemia test there was a significant increase in plasma ACTH. Measuring the pituitary hormones seems to be of relatively little value in the assessment of states of pituitary insufficiency. Thus, normal plasma concentrations of pituitary gonadotropins have been reported repeatedly in secondary gonadal insufficiency (10-14). In secondary hypothyroidism, plasma TSH determinations have not proved helpful (15-17). In explaining the failure to distinguish between patients with secondary adrenocortical insufficiency and normals by plasma ACTH concentrations, several points may be considered. Firstly, the spontaneous ACTH secretion and the daily
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 20:37 For personal use only. No other uses without permission. . All rights reserved.
COMMENTS
350 t 260-
314
t
t
JCE&M • 1979 Vol48 • No 2 t
380 343
299
240220•
200-
FIG. 2. ACTH and cortisol secretion during hypoglycemia in 39 patients with a pituitary adenoma or after hypophysectomy (P) and in 26 normal subjects (C).
180-
1800 -
160-
1600-
uo-
1400:.
120-
1200-
100-
1000-
60-
i. 40-
j
r
80-
•
...
:s
::
b
20-
800600400200-
P PEAK PLASMA CONCENTRATION ng/l
AMOUNT SECRETED area
C
C
PEAK PLASMA CONCENTRATION nmol/l
CORTISOL
ACTH
integrated plasma concentration might be lower in patients with secondary adrenal failure despite similar responses to hypoglycemia. The fact that basal plasma ACTH concentrations in the 39 patients and the 26 controls did not differ significantly is against this view. Secondly, testing ACTH secretion by the insulin test may not be the most accurate method for this purpose. It has been suggested that the metyrapone test is a more sensitive index of reduced ACTH secretion, as some studies have reported patients in whom a normal response to hypoglycemia was found whereas the response to metyrapone was subnormal (18-19). In these studies, however, a complete block of cortisol synthesis was not proved and it was not stated whether clinical symptoms of glucopenia occurred during hypoglycemia. Furthermore, we have recently established a close correlation between adrenocortical responses to ACTH and hypoglycemia (20) and to ACTH and metyrapone (Blichert-Toft, M., J. Lindholm, and H. Kehlet, submitted for publication) and thus indirectly between responses to hypoglycemia and metyrapone also. Identical plasma ACTH increments during insulin-induced hypoglycemia and major surgery have also been demonstrated (21). It seems unlikely that a better separation between patients with
P
AMOUNT SECRETED area
secondary adrenal failure and normals would be possible using the metyrapone test. Thirdly, the corticotropin secreted in the patients might be of subnormal biological activity. At present, there are no data to support or refute this hypothesis. Finally, the possibility of a reduced responsiveness to ACTH in the adrenal cortex should be considered. The present results taken together with the above findings in secondary gonadal and thyroid insufficiency might imply the existence of a factor normally secreted in the pituitary and controlling peripheral sensitivity to pituitary hormones. The finding by Krieger and Allen (22), that ACTH in plasma may rise with no concomitant increase in plasma cortisol, to some extent supports this assumption. This concept merits further investigation.
Acknowledgments The cooperation of Mrs. B. Jensen in the statistical calculations is gratefully acknowledged. The ACTH standard was kindly donated by the National Institute for Biological Standards and Control, Holly Hill, London.
References 1. Besser, G. M., and J. Landon, Plasma levels of immunoreactive
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 20:37 For personal use only. No other uses without permission. . All rights reserved.
COMMENTS
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
corticotrophin in patients with Cushing's syndrome, Br Med J 4: 552, 1968. Besser, G. M., D. R. Cullen, W. J. Irvine, J. G. Ratcliffe, and J. Landon, Immunoreactive corticotrophin levels in adrenocortical insufficiency, Br Med J1: 374, 1971. Berson, S. A., and R. S. Yalow, Radioimmunoassay of ACTH in plasma, J Clin Invest 47: 2725, 1968. Hummer, L., A radioimmunoassay of plasma corticotrophin, In Radioimmunoassay and Related Procedures in Medicine, Vienna, International Atomic Energy Agency, 1978, pp. 391-402. Nielsen, E., and V. H. Asfeldt, Studies on the specificity of fluorimetric determination of plasma corticosteroids ad modum de Moor and Steeno, Scand J Clin Lab Invest 20: 185, 1967. Lindholm, J., Studies on some parameters of adrenal function, Ada Endocrinol (Kbh) [Suppt] 172: 19, 1972. Greenwood, F. C, J. Landon, and T. C. B. Stamp, The plasma sugar, free fatty acid, cortisol, and growth-hormone response to insulin, J Clin Invest 45: 429, 1966. Donald, R. A., Plasma immunoreactive corticotrophin and cortisol response to insulin hypoglycemia in normal subjects and patients with pituitary disease, J Clin Endocrinol Metab 32: 225, 1971. Holdaway, I. M., L. Rees, and J. Landon, Circulating corticotrophin levels in severe hypopituitarism and in the neonate, Lancet 1: 1170, 1973. Charro, A. L., S. R. Levin, N. Becker, F. D. Hofeldt, S. Friedman, and P. H. Forsham, Clomiphene in the evaluation of the pituitarygonadal axis in acromegaly, J Clin Endocrinol Metab 36: 502,1973. Jacobs, H. S., S. Franks, M. A. F. Murray, M. G. R. Hull, S. J. Steele, and J. D. N. Nabarro, Clinical and endocrine features of hyperprolactinaemic amenorrhoea, Clin Endocrinol 5: 439, 1976. Lindholm, J., P. Rasmussen, and O. Korsgaard, Pituitary-testicular function in acromegalic and hypophysectomized patients, Eur J Clin Invest 7: 141, 1977. Kleinberg, D. L., G. L. Noel, and A. G. Frantz, Galactorrhoea: a
351
study of 235 cases, including 48 with pituitary tumors, iV Engl J Med 296: 589, 1977. 14. Franks, S., H. S. Jacobs, N. Martin, and J. D. N. Nabarro, Hyperprolactinaemia and impotence, Clin Endocrinol 8: 277, 1978. 15. Faglia, G., P. Beck-Peccoz, C. Ferrari, B. Ambrosi, A. Spada, P. Travaglini, and S. Paracchi, Plasma thyrotropin response to thyrotropin-releasing hormone in patients with pituitary and hypothalamic disorders, J Clin Endocrinol Metab 37: 595, 1973. 16. Snyder, P. J., L. S. Jacobs, M. M. Rabello, F. H. Sterling, R. N. Shore, R. D. Utiger, and W. H. Daughaday, Diagnostic value of thyrotrophin-releasing hormone in pituitary and hypothalamic disease, Ann Intern Med 81: 751, 1974. 17. Lindholm, J., H. Dige-Petersen, L. Hummer, P. Rasmussen, and O. Korsgaard, Effect of thyrotrophin releasing hormone (TRH) in patients with pituitary disorders, Ada Endocrinol (Kbh) 85: 479, 1973. 18. Jenkins, J. S., and W. Else, Pituitary-adrenal function tests in patients with untreated pituitary tumours, Lancet 2: 940, 1968. 19. Faglia, G., B. Ambrosi, P. Beck-Peccoz, and P. Travaglini, Hypothalamic-pituitary-adrenal function in patients with pituitary tumours, Ada Endocrinol (Kbh) 73: 223, 1973. 20. Lindholm, J., H. Kehlet, M. Blichert-Toft, B. Dinensen, and J. Riishede, Reliability of the 30-minute ACTH test in assessing hypothalamic-pituitary-adrenal function, J Clin Endocrinol Metab 47: 272, 1978. 21. Blichert-Toft, M., C. Christiansen, A. Engquist, H. Kehlet, J. Lindholm, L. Hummer, and B. Dinesen, Comparison of pituitaryadrenocortical response to hypoglycemia and surgery, Ada Anaesthesiol Scand, in press. 22. Krieger, D. T., and W. Allen, Relationship of bioassayable and immunoassayable plasma ACTH and cortisol concentrations in normal subjects and in patients with Cushing's disease, J Clin Endocrinol Metab 40: 675, 1975.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 20:37 For personal use only. No other uses without permission. . All rights reserved.
Vol. 48, No. 2
Printed in U.SA.
Plasma Corticotropin and Cortisol in Patients with Pituitary Adenomas JORGEN LINDHOLM, LOTTE HUMMER, HENRIK KEHLET, JOHN RIISHEDE, MOGENS BLICHERT-TOFT, AND BO DINESEN Department of Neurosurgery, Division of Neuroendocrinology, the Department of Nuclear Medicine, and the Department of Clinical Chemistry, University Clinic-Rigshospitalet, 2100 Copenhagen, Denmark tients with normal and impaired cortisol response to hypoglycemia on the basis of the ACTH results. When all 39 patients were compared to the 26 controls, the cortisol results differed significantly, but those of ACTH did not. These results demonstrate a limited value of ACTH measurements in secondary adrenocortical failure. (J Clin Endocrinol Metab 48: 348, 1979)
ABSTRACT. Plasma ACTH and cortisol were measured during insulin-induced hypoglycemia in 39 patients with a pituitary adenoma or after hypophysectomy and in 26 healthy persons. Adrenocortical insufficiency was defined as failure to increase plasma cortisol to at least 500 nmol/liter (18 /ug/dl) during hypoglycemia. No proper distinction was possible between pa-
R
All subjects were studied after an overnight fast. At about 0830 h, 0.15 IU/kg BW regular insulin was injected iv. Higher doses were given to acromegalics and lower doses to patients suspected of secondary adrenal insufficiency. Blood samples were drawn from a cubital vein into polystyrol tubes (containing heparin) at 0, 15, 30, 45, 60, 75, and 90 min and promptly centrifuged at 4 C. The blood glucose concentration fell to at least 2.2 mmol/liter (40 mg/dl) in all subjects, and all experienced sweating during hypoglycemia. At the time of study, two patients were on substitution with cortisone. This was discontinued 16 h before the test was performed. ACTH was measured by a radioimmunological method. All steps in the assay procedure were performed at 4 C. Plasma samples and standards (200 jul; Medical Research Council Reference Preparation 74/555) prepared in assay buffer were added to 2 ml ACTH antiserum diluted 1:320,000 by 0.02 M diemal buffer, pH 8.6, containing 0.4% mercaptoethanol, 400 klU Trasylol/ml, and 1% bovine serum albumin in polystyrol tubes. After an overnight incubation, the labeling procedure was performed according to Berson and Yalow (3). The labeled ACTH was added to each tube and after 20 h of incubation, the antibody-bound and free ACTH were separated with 200 jul activated charcoal suspension containing 3% Norite and 0.75% Dextran T-80 (Pharmacia) in 0.02 diemal buffer. The tubes were incubated for 15 min and centrifuged for 15 min at 2000 rpm. The supernatant was discarded and the charcoal residue was counted in a y-scintillation counter. The fraction of labeled ACTH bound to antibody was calculated and corrections for nonspecific binding in the individual sample were made. The assay had a detection limit of 2 pg ACTH when assaying 200 ix\ unextracted plasma. The antibody had been obtained by immunizing guinea pigs with synthetic human ACTH1"24 (CIBA) coupled to bovine serum albumin. The selected antibody had an equilibrium constant of 4 X 10u mol"1 in the assay. The antiserum reacted with synthetic human ACTH1"39 and ACTH1"24. The synthetic human ACTH11"24 fragment as well as
OUTINELY, hypofunction of the hypothalamic-pituitary-adrenal system is verified by the finding of subnormal plasma cortisol concentrations during one of the stimulation tests available; the insulin hypoglycemia test is the most widely used. Logically, plasma corticotropin (ACTH) should be the hormone of prime interest. Very few studies have been published on the value of measuring ACTH in the assessment of the hypothalamicpituitary-adrenocortical function, probably because of difficulties in measuring circulating ACTH. Most have dealt with patients with Cushing's disease (1) or with the problem of distinguishing between primary and secondary adrenal insufficiency (2). In this paper, we report the results of a study in which plasma ACTH and cortisol were measured during insulininduced hypoglycemia in patients with a pituitary adenoma. Subjects and Methods Thirty-nine patients were studied. Eight had a pituitary adenoma clinically presenting with acromegaly, 12 had a chromophobe adenoma of the pituitary, as verified at a subsequent operation; 7 were patients who had undergone surgical removal of a chromophobe adenoma at least 6 months previously; and 12 were patients with a small intrasellar tumor demonstrated by computer-assisted tomography. None of the patients had Cushing's disease, Nelson's syndrome, or primary adrenocortical failure (Addison's disease). Controls were 26 subjects without any serious or endocrine disease. Received June 20, 1978. Address requests for reprints to: Dr. Jbrgen Lindholm, Department of Neurosurgery 2092, Division of Neuroendocrinology, Rigshospitalet, 2100 Copenhagen, Denmark.
348
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 20:37 For personal use only. No other uses without permission. . All rights reserved.
349
COMMENTS a- and /3-MSH did not cross-react in the assay. Other known pituitary hormones did not show any inhibition of the binding of labeled ACTH to the antibody. Plasma samples with normal and high concentrations of ACTH produced dose-response curves parallel to the standard curve. The interassay coefficient of variation of replicate estimates was 12%. Further analytical details and the clinical validation of the assay in various pituitary-adrenal diseases have been reported elsewhere (4). Cortisol was measured fluorimetrically (5). The Mann-Whitney test was used for the statistical analysis.
Results The patients were divided into two groups according to the peak plasma cortisol concentration during the insulin-induced hypoglycemia: 1) those responding normally, i.e. plasma cortisol rising to at least 500 nmol/liter (18 /xg/dl), and 2) those with a subnormal response to hypoglycemia, i.e. a peak plasma concentration below 500 nmol/liter. The basal plasma ACTH concentrations did not differ significantly in these groups (P > 0.1). The amount of ACTH and cortisol secreted (total area under the curve) and the peak plasma concentrations in the two groups are shown in Fig. 1. Although the ACTH values were significantly lower in the patients with sub3K299 o o n ng/l 280
i«u -
tJ 380 343
120-
240-
100-
200-
80-
160-
800-
120-
600-
60-
• •
40-
80-
20-
40-
i
400-
:
200-
800-
400-
n AMOUNT SECRETED
PEAK PLASMA CONCENTRATION
AMOUNT SECRETED
PEAK PLASMA CONCENTRATION
FIG. 1. ACTH and cortisol secretion during insulin-induced hypoglycemia in 10 patients with (S) and 29 patients without (N) secondary adrenocortical insufficiency.
normal adrenocortical function (P < 0.05), the overlap was considerable; in fact, the ACTH values from all of the patients with hypocorticism were within the range found in the patients with normal cortisol responses to hypoglycemia. The results from all 39 patients compared to those from the controls are shown in Fig. 2. The difference between the cortisol values in these two groups was highly significant (P < 0.005), while the ACTH values did not differ significantly (P > 0.05). The basal ACTH plasma concentrations were not different in the two groups (P > 0.1). Discussion There is no single test by which adrenocortical hypofunction can be precisely defined clinically (6). On the other hand, it seems indisputable that failure to increase plasma cortisol to at least 500 nmol/liter during severe hypoglycemia is proof of hypofunction of the hypothalamic-pituitary-adrenocortical system (7). Our results demonstrate that measuring ACTH in plasma is of little practical value when investigating patients for secondary adrenocortical insufficiency, because of the substantial overlap between the results from patients with normal and impaired adrenocortical functions. Also, when all of the patients were compared to normal controls, the cortisol values differed highly significantly, but the ACTH values did not. Donald (8) measured plasma ACTH during insulininduced hypoglycemia in six patients with hypopituitarism and found that the patients secreted significantly lower amounts of ACTH and the peak plasma concentrations were significantly lower than in the controls. Basal plasma concentrations did not differ significantly. Besser et al. (2) found basal ACTH concentrations within the normal range in 13 of 27 patients with secondary adrenocortical failure. In all six patients with adrenal insufficiency because of hypopituitarism studied by Holdaway et al. (9), basal ACTH plasma concentrations were low, but in the three patients who had been subjected to an insulin hypoglycemia test there was a significant increase in plasma ACTH. Measuring the pituitary hormones seems to be of relatively little value in the assessment of states of pituitary insufficiency. Thus, normal plasma concentrations of pituitary gonadotropins have been reported repeatedly in secondary gonadal insufficiency (10-14). In secondary hypothyroidism, plasma TSH determinations have not proved helpful (15-17). In explaining the failure to distinguish between patients with secondary adrenocortical insufficiency and normals by plasma ACTH concentrations, several points may be considered. Firstly, the spontaneous ACTH secretion and the daily
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 20:37 For personal use only. No other uses without permission. . All rights reserved.
COMMENTS
350 t 260-
314
t
t
JCE&M • 1979 Vol48 • No 2 t
380 343
299
240220•
200-
FIG. 2. ACTH and cortisol secretion during hypoglycemia in 39 patients with a pituitary adenoma or after hypophysectomy (P) and in 26 normal subjects (C).
180-
1800 -
160-
1600-
uo-
1400:.
120-
1200-
100-
1000-
60-
i. 40-
j
r
80-
•
...
:s
::
b
20-
800600400200-
P PEAK PLASMA CONCENTRATION ng/l
AMOUNT SECRETED area
C
C
PEAK PLASMA CONCENTRATION nmol/l
CORTISOL
ACTH
integrated plasma concentration might be lower in patients with secondary adrenal failure despite similar responses to hypoglycemia. The fact that basal plasma ACTH concentrations in the 39 patients and the 26 controls did not differ significantly is against this view. Secondly, testing ACTH secretion by the insulin test may not be the most accurate method for this purpose. It has been suggested that the metyrapone test is a more sensitive index of reduced ACTH secretion, as some studies have reported patients in whom a normal response to hypoglycemia was found whereas the response to metyrapone was subnormal (18-19). In these studies, however, a complete block of cortisol synthesis was not proved and it was not stated whether clinical symptoms of glucopenia occurred during hypoglycemia. Furthermore, we have recently established a close correlation between adrenocortical responses to ACTH and hypoglycemia (20) and to ACTH and metyrapone (Blichert-Toft, M., J. Lindholm, and H. Kehlet, submitted for publication) and thus indirectly between responses to hypoglycemia and metyrapone also. Identical plasma ACTH increments during insulin-induced hypoglycemia and major surgery have also been demonstrated (21). It seems unlikely that a better separation between patients with
P
AMOUNT SECRETED area
secondary adrenal failure and normals would be possible using the metyrapone test. Thirdly, the corticotropin secreted in the patients might be of subnormal biological activity. At present, there are no data to support or refute this hypothesis. Finally, the possibility of a reduced responsiveness to ACTH in the adrenal cortex should be considered. The present results taken together with the above findings in secondary gonadal and thyroid insufficiency might imply the existence of a factor normally secreted in the pituitary and controlling peripheral sensitivity to pituitary hormones. The finding by Krieger and Allen (22), that ACTH in plasma may rise with no concomitant increase in plasma cortisol, to some extent supports this assumption. This concept merits further investigation.
Acknowledgments The cooperation of Mrs. B. Jensen in the statistical calculations is gratefully acknowledged. The ACTH standard was kindly donated by the National Institute for Biological Standards and Control, Holly Hill, London.
References 1. Besser, G. M., and J. Landon, Plasma levels of immunoreactive
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 20:37 For personal use only. No other uses without permission. . All rights reserved.
COMMENTS
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
corticotrophin in patients with Cushing's syndrome, Br Med J 4: 552, 1968. Besser, G. M., D. R. Cullen, W. J. Irvine, J. G. Ratcliffe, and J. Landon, Immunoreactive corticotrophin levels in adrenocortical insufficiency, Br Med J1: 374, 1971. Berson, S. A., and R. S. Yalow, Radioimmunoassay of ACTH in plasma, J Clin Invest 47: 2725, 1968. Hummer, L., A radioimmunoassay of plasma corticotrophin, In Radioimmunoassay and Related Procedures in Medicine, Vienna, International Atomic Energy Agency, 1978, pp. 391-402. Nielsen, E., and V. H. Asfeldt, Studies on the specificity of fluorimetric determination of plasma corticosteroids ad modum de Moor and Steeno, Scand J Clin Lab Invest 20: 185, 1967. Lindholm, J., Studies on some parameters of adrenal function, Ada Endocrinol (Kbh) [Suppt] 172: 19, 1972. Greenwood, F. C, J. Landon, and T. C. B. Stamp, The plasma sugar, free fatty acid, cortisol, and growth-hormone response to insulin, J Clin Invest 45: 429, 1966. Donald, R. A., Plasma immunoreactive corticotrophin and cortisol response to insulin hypoglycemia in normal subjects and patients with pituitary disease, J Clin Endocrinol Metab 32: 225, 1971. Holdaway, I. M., L. Rees, and J. Landon, Circulating corticotrophin levels in severe hypopituitarism and in the neonate, Lancet 1: 1170, 1973. Charro, A. L., S. R. Levin, N. Becker, F. D. Hofeldt, S. Friedman, and P. H. Forsham, Clomiphene in the evaluation of the pituitarygonadal axis in acromegaly, J Clin Endocrinol Metab 36: 502,1973. Jacobs, H. S., S. Franks, M. A. F. Murray, M. G. R. Hull, S. J. Steele, and J. D. N. Nabarro, Clinical and endocrine features of hyperprolactinaemic amenorrhoea, Clin Endocrinol 5: 439, 1976. Lindholm, J., P. Rasmussen, and O. Korsgaard, Pituitary-testicular function in acromegalic and hypophysectomized patients, Eur J Clin Invest 7: 141, 1977. Kleinberg, D. L., G. L. Noel, and A. G. Frantz, Galactorrhoea: a
351
study of 235 cases, including 48 with pituitary tumors, iV Engl J Med 296: 589, 1977. 14. Franks, S., H. S. Jacobs, N. Martin, and J. D. N. Nabarro, Hyperprolactinaemia and impotence, Clin Endocrinol 8: 277, 1978. 15. Faglia, G., P. Beck-Peccoz, C. Ferrari, B. Ambrosi, A. Spada, P. Travaglini, and S. Paracchi, Plasma thyrotropin response to thyrotropin-releasing hormone in patients with pituitary and hypothalamic disorders, J Clin Endocrinol Metab 37: 595, 1973. 16. Snyder, P. J., L. S. Jacobs, M. M. Rabello, F. H. Sterling, R. N. Shore, R. D. Utiger, and W. H. Daughaday, Diagnostic value of thyrotrophin-releasing hormone in pituitary and hypothalamic disease, Ann Intern Med 81: 751, 1974. 17. Lindholm, J., H. Dige-Petersen, L. Hummer, P. Rasmussen, and O. Korsgaard, Effect of thyrotrophin releasing hormone (TRH) in patients with pituitary disorders, Ada Endocrinol (Kbh) 85: 479, 1973. 18. Jenkins, J. S., and W. Else, Pituitary-adrenal function tests in patients with untreated pituitary tumours, Lancet 2: 940, 1968. 19. Faglia, G., B. Ambrosi, P. Beck-Peccoz, and P. Travaglini, Hypothalamic-pituitary-adrenal function in patients with pituitary tumours, Ada Endocrinol (Kbh) 73: 223, 1973. 20. Lindholm, J., H. Kehlet, M. Blichert-Toft, B. Dinensen, and J. Riishede, Reliability of the 30-minute ACTH test in assessing hypothalamic-pituitary-adrenal function, J Clin Endocrinol Metab 47: 272, 1978. 21. Blichert-Toft, M., C. Christiansen, A. Engquist, H. Kehlet, J. Lindholm, L. Hummer, and B. Dinesen, Comparison of pituitaryadrenocortical response to hypoglycemia and surgery, Ada Anaesthesiol Scand, in press. 22. Krieger, D. T., and W. Allen, Relationship of bioassayable and immunoassayable plasma ACTH and cortisol concentrations in normal subjects and in patients with Cushing's disease, J Clin Endocrinol Metab 40: 675, 1975.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 16 November 2015. at 20:37 For personal use only. No other uses without permission. . All rights reserved.
