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Ketoconazole treatment of type 1 autoimmune polyglandular syndrome: Effects on pituitary-adrenal axis
Volume 109 Number 2
Side effects of therapy
Clinical and laboratory observations
Follow-up
Emesis
2 yr
None
5 mo
None
8 yr
Transient decrease in WBC and increase in liver enzymes
2 yr
Outcome of therapy" Tumor regression (+) Symptoms resolved Tumor regression (+_) Symptoms resolved
Tumor regression (++) Symptoms resolved Tumor regression (++) Symptoms resolved
2. Holden KR, Alexander F. Diffuse neonatal hemangiomatosis. Pediatrics 1970;46:411-421. 3. Kissinger CC, Steanfield E, Zuker SD. Rupture of cavernous hemangioma of the liver as a cause of death in newborn infant. Ohio State Med J 1940;36:383-389. 4. Hurvitz CH, Greenberg SH, Song CH, et al. Hemangiomatosis of the pleura with hemorrhage and disseminated intravascular coagulation. J Pediatr Surg 1982;17:73-75.
363
5. Alkalay AL, Puri RD, Pomerance J J, et al. Mesenchymal hamartoma of the liver responsive to cyclophosphamide therapy: therapeutic approach. J Pediatr Surg 1985;20:125128. 6. Fost NC, Esterly NB. Successful treatment of juvenile hemangiomas with prednisone. J PEDIATR 1968;72:351-357. 7. Koerper MA, Addiego JE, deLorimier AA, et al: Use of aspirin dipyridamole in children with platelet trapping syndromes. J PEDIATR 1983;102:311-314. 8. Warrell RP, Kempin SJ. Treatment of severe coagulopathy in the Kasabach-Merritt syndrome with aminocaproic acid and cryoprecipitate. N Engl J Med 1985;313:309-312. 9. Kasabach HH, Merritt KK. Capillary hemangioma with extensive purpura. Am J Dis Child 1940;59:1063-1070. 10. Brunellc F, Roche A. "Micro" stainless coils for transcatheter vascular occlusion in children. Pediatr Radiol 1983;13:332334. 1I. Shim WKT. Hemangiomas of infancy complicated by thrombocytopenia. Am J Surg 1969;116:896-906. 12. Rush BF: Treatment of a giant cutaneous hemangioma by intraarterial injection of nitrogen mustard. Ann Surg 1966; 164:921-923. 13. AI-Rashid RA. Cyclophosphamide and radiation therapy in the treatment of hemangioendothelioma with disseminated intravascular clotting. Cancer 1971 ;27:364-368. 14. Tewfik H, Latourette H, Christie JH. Infantile hepatic hemangioendothelioma: a surviving case. Pediatr Radiol 1977;123:723-724.
Ketoconazole treatment of type I autoimmune polyglandular syndrome: Effects on pituitary-adrenal axis Penelope Feuillan, M.D., Merrily Poth, M.D., William Reilly, M.D., George Bright, M.D., D. Lynn Loriaux, M.D., Ph.D., and George P. Chrousos, M.D. From the Developmental Endocrinology Branch, National Institute of Child Health and Human Development, and the Department of Pediatrics, U.S. Public Health Service, Bethesda, Maryland; the Department of Pathology, University of Florida College of Medicine, Gainesvilte; and the Department of Pediatrics, Medical University of South Carolina, Charleston
Presented at the 15th Acta Endocrinologica Congress, Helsinki, Finland, 1985. Supported in part by the Children's Fund of the Medical University of South Carolina. Submitted for publication Oct. 25, 1985; accepted March 28, 1986. Reprint requests: Penelope Feuillan, M.D., Developmental Endocrinology Branch, NICHHD, National Insititutes of Health, Bethesda, MD 20892.
Autoimmune polyglandular syndrome type 1 is an autosomal recessive endocrine disorder of childhood. Chronic candidiasis of the oral mucosa is frequently the earliest clinical manifestation of APS-1; Candida may involve the nails as well, causing thickening and disfigurement. HypoACTH APS-I OCRH
Adrenocorticotropin; Cortrosyn Autoimmune polyglandular syndrome Ovine eorticotropin releasing hormone
364
Clinical and laboratory observations
The Journal of Pediatrics August 1986
Table. Clinical and laboratory findings in three patients with autoimmune polyglandular syndrome type 1 ACTH-stimulated plasma cortlsol" (~g/dl) Patient
Age (yr)
Sex
Candidiasis
Hypopara. thyroldlsm
Adrenal antibodies
1
12
F
+
+
-
2 3
10 9
M M
+ +
+ +
+
Before ketoconazole
During ketoconazole
After ketoconazole
24 27 13
20 20 5
NT NT 10
NT, not tested. *Cortisol response30 minutesafter 250 #g ACTH (Cortrosyn).Mean _+ 1 SD plasmacortisolresponse30 minutesafter ACTH in 20 normalsubjects,21 _+4 ~zg/dl (range 16 to 32 #g/dl).
parathyroidism characteristically appears later, in midchildhood, and primary adrenal insufficiency may occur in early adolescence?. 2 The adrenal insufficiency may be life threatening if not recognized and treated promptly. Autoantibodies to adrenal tissue have been demonstrated in the serum of patients with this form of adrenal destruction? The candidiasis of APS- 1 can be resistant to treatment. Recently, satisfactory results have been reported with the antifungal agent ketoconazole.4 This drug is an imidazole derivative that is also known to inhibit the biosynthesis of cortisol and testosterone in viva in a dose- and timedependent fashion?'6 Impaired cortisol biosynthesis has been demonstrated in normal subjects, who have shown suppressed cortisol responses to synthetic ACTW -24 (Cortrosyn) stimulation up to 8 hours after ketoconazole administration? Thus this drug should be used with caution in patients who are already at risk for adrenal insufficiency. We undertook this study to assess the effect of ketoconazole therapy on the pituitary-adrenal axis in three siblings with APS- 1, one of whom had evidence of partial adrenal failure. METHODS Three children from a sibship of five were examined (Table). A 12-year-old girl (patient 1) and a 10-year-old boy (patient 2) had oral candidiasis and hypoparathyroidism; neither had clinical evidence of adrenal failure, and their serum did not contain antiadrenal antibodies. Their 9-year-old brother (patient 3) had oral candidiasis, nail dystrophy, alopecia, and hypoparathyroidism. Although he had no electrolyte abnormalities, hypotension, or hyperpigmentation to suggest adrenal insufficiency, serum antiadrenal antibodies were present. All three children were receiving 0.5 to 1.75 #g/day 1,25-dihydroxyvitamin D (Rocaltrol) and 2 to 6 gm/day Ca ++ for treatment of hypoparathyroidism, but none had required treatment with glucocorticoids or mineralocorticoids. All three were given
ketoconazole 100 mg/day (2.5 to 4.5 mg/kg/day) in a single 8:00 AM dose, and responded with complete clearing of oral lesions, and some improvement of nail dystrophy in patient 3. Screening for anti-adrenal antibodies was done by indirect immunofluorescence with human adrenal tissue as previously described? As a preliminary test of adrenal function, baseline and peak plasma cortisol levels were measured at 0 and 30 minutes after a 250 #g dose of ACTH given at 12 noon. This test was performed before ketoconazole treatment was started, and was repeated during treatment with ketoconazole, 4 hours after the last dose of drug. Cortisol and ACTH responses were also measured after a 1 #g/kg dose of ovine corticotropin releasing hormone given at 8:00 PM. Patients were tested with oCRH both during treatment with ketoconazole (12 hours after the last dose), and again after the drug had been withheld for 2 weeks. All testing was done in the pediatric ward of the Clinical Center of the National Institutes of Health. Informed consent was obtained from a parent and from the patients before administering oCRH, using a protocol approved by an institutional review board. RESULTS ACTH response (Table). Before treatment, patients 1 and 2 had normal cortisol responses to ACTH. Patient 3 had a subnormal cortisol response consistent with partial adrenal insufficiency. During ketoconazole treatment, the cortisol response to ACTH decreased in patients 1 and 2, but remained within the normal range. In patient 3 there was a further decrease in cortisol response during treatment. He was retested with ACTH after ketoconazole had been withheld for 5 days, and demonstrated a partial recovery of the cortisol response. oCRH response (Figure). Nighttime (8:00 PM) basal plasma ACTH and cortisol levels were normal in patients 1
Volume 109 Number 2
and 2 both during and after discontinuation of ketoconazole. After oCRH stimulation, plasma ACTH and cortisol responses were also within the normal range, demonstrating unchanged pituitary-adrenal function 12 hours after the ketoconazole dose. Patient 3, on the other hand, had an attenuated cortisol response and an increased ACTH response to oCRH during both testing periods. Although cortisol responses to oCRH during and after discontinuation of ketoconazole therapy were not different, plasma ACTH response during treatment was dramatically exaggerated and prolonged (peak 209 pg/ml at 150 minutes).
Clinical and laboratory observations
PATIENT 1
PATIENT 3
60-
2O0 180
<
2O
160 i
=
140
25 ~
120
I
100
05
20 10 P ~ S M A IR.ACXH
i
80
PATIENT 2
60
DISCUSSION We evaluated the adrenal function of our patients both with the conventional ACTH test and with the oCRH stimulation test. Pituitary stimulation with oCRH has been used as a diagnostic tool in several types of of pituitary-adrenal disorders/, 8 The test has been standardized in our clinic with administration of 1 #g/kg oCRH at 8:00 PM, when the normal diurnal rhythm of cortisol and ACTH is at its nadir. Plasma ACTH and cortisol responses in children do not differ from those in adults. 9 Patients with primary adrenal insufficiency characteristiCally have elevated basal plasma ACTH or increased ACTH responses to oCRH. Their cortisol responses are attenuated or absent, depending on the degree of adrenal impairment? Our patient 3 had an attenuated cortisol response to oCRH and a disproportionate ACTH versus cortisol response compared with those of normal subjects. His integrated plasma cortisol plotted against integrated plasma ACTH was clearly outside the normal range (Figure). Although his cortisol response after oCRH was not decreased during ketoconazole administration, the dramatic increment in ACTH response during treatment indicated further compromise in adrenal function. The additional decrease in his cortisol response to ACTH during treatment confirmed this finding. In contrast, patients 1 and 2 had no evidence of significant adrenal dysfunction during ketoconazole therapy. Ketoconazole inhibits steroid biosynthesis by blocking several mitochondrial cytochrome P-450-dependent enzymes, including 17,20-desmolase and 17-a-hydroxylase. 6 Clinical trials with normal subjects have shown a blunting of the cortisol response to ACTH 4 to 8 hours after single doses of 400 to 600 mg (5 to 9 mg/kg), 5 and normal cortisol responses 16 hours after dosing. These studies indicate that the suppressive effect of ketoconazole in normal subjects is transient and is probably related to the serum ketoconazole concentration. There is no evidence that prolonged ketoconazole treatment will cause significant impairment of adrenal function
365
-
....
40
4O
20
~=
2sI~
-6 ~5
_
.........
~5115 ----
25
i
0
60
120
Time Imin)
180
0
60
120
180
Time (min)
Figure. Plasma ACTH and cortisol responses to 1 pg/kg oCRH
in patients I, 2, and 3 during (e) and after (o) ketoconazole therapy. Shaded area represents normal range (mean _+ 1 SD) in 24 control subjects. Insert, Dose-response relationship between time-integrated plasma ACTH and cortisol in patient 3. Shaded area represents normal range in 40 subjects who received 0 to 1 pg/kg oCRH."
in normal subjects. Boys with familial male precocious puberty and normal adrenal function have been given high doses (17 to 32 mg/kg/day) of ketoconazole for periods up to 12 months to reduce serum testosterone levels without developing adrenal dysfunction. Although ACTH stimulation after 5 days of treatment showed reductions in peak cortisol response, peak cortisol responses after 9 to 12 months of treatment werereportedly normal. ~~Thus subjects with normal adrenal glands have the capacity to compensate for the drug-induced biosynthetic defect. It is likely that this occurs either by increased enzyme biosynthesis or by enlargement of the gland itself. On the other hand, individuals such as our patient 3, with primary adrenal insufficiency and a limited adrenal reserve, would be unable to mount an adaptive response to long-term ketoconazole administration and could be at risk for developing frank adrenal insufficiency. The increasing applications of ketoconazole should prompt further investigation into its mechanism of action and side effects. Even at low doses, this drug can impair adrenal function in patients with a limited pituitary-
366
Clinical and laboratory observations
adrenal reserve. Physicians should be aware of the adrenal status of their patients before beginning t r e a t m e n t with ketoconazole. We thank Karen Hench, R.N., for technical assistance. REFERENCES
1. Neufeld M, Maclaren N, Blizzard R. Autoimmune polyglandular syndromes. Pediatr Ann 1980;9:1557. 2. Trence DL, Morley JE, Hand,verger BS. Polyglandular autoimmune syndromes. Am J Med 1984;77:109. 3. Ketchum CH, Riley W J, Maclaren NK. Adrenal dysfunction in asymptomatic patients with adrenocortical autoantibodies. J Clin Endocrinol Metab 1984;58:1166. 4. Petersen EA, Ailing DW, Kirkpatrick CH. Treatment of chronic mucocutaneous candidiasis with ketoconazole. Ann Intern Med 1980;93:791. 5. Pont A, Graybill JR, Craven PC, et al. High-dose ketoconazole therapy and adrenal and testicular function in humans. Arch Intern Med 1984;144:2150.
The Journal of Pediatrics August 1986
6. Sikka S, Swerdloff RS, Rajfer J. In vitro inhibition of testosterone biosynthesis by ketoconazole. Endocrinology 1985;116:1920. 7. Chrousos GP, Schurmeyer TS, Doppman J, et al. Clinical applications of corticotropin releasing factor. Ann Intern Med 1985;102:344. 8. Schulte HM, Chrousos GP, Avgerinos P, et al. The corticotropin-releasing hormone stimulation test: a possible aid in the evaluation of patients with adrenal insufficiency. J Clin Endocrinol Metab 1984;58:1064. 9. Levine JL, Schulte HM, Gallucci WT, et al. Ovine corticotropin-releasing hormone stimulation test in children. J Clin Endocrinol Metab 1986;62:390. 10. Holland FJ, Fishman L, Bailey JD, Fazekas ATA. Ketoconazole in the management of precocious puberty not responsive to LHRH-analog therapy. N Engl J Med 1985;312:1023. 11. Scheurmeyer TH, Tsokos GC, Avgerinos PC, et al. Pituitaryadrenal responsiveness to corticotropin-releasing hormone in patients receiving chronic alternate-day glucocorticoid therapy. J Clin Endocrinol Metab 1985;61:22.
Side effects of therapy
Clinical and laboratory observations
Follow-up
Emesis
2 yr
None
5 mo
None
8 yr
Transient decrease in WBC and increase in liver enzymes
2 yr
Outcome of therapy" Tumor regression (+) Symptoms resolved Tumor regression (+_) Symptoms resolved
Tumor regression (++) Symptoms resolved Tumor regression (++) Symptoms resolved
2. Holden KR, Alexander F. Diffuse neonatal hemangiomatosis. Pediatrics 1970;46:411-421. 3. Kissinger CC, Steanfield E, Zuker SD. Rupture of cavernous hemangioma of the liver as a cause of death in newborn infant. Ohio State Med J 1940;36:383-389. 4. Hurvitz CH, Greenberg SH, Song CH, et al. Hemangiomatosis of the pleura with hemorrhage and disseminated intravascular coagulation. J Pediatr Surg 1982;17:73-75.
363
5. Alkalay AL, Puri RD, Pomerance J J, et al. Mesenchymal hamartoma of the liver responsive to cyclophosphamide therapy: therapeutic approach. J Pediatr Surg 1985;20:125128. 6. Fost NC, Esterly NB. Successful treatment of juvenile hemangiomas with prednisone. J PEDIATR 1968;72:351-357. 7. Koerper MA, Addiego JE, deLorimier AA, et al: Use of aspirin dipyridamole in children with platelet trapping syndromes. J PEDIATR 1983;102:311-314. 8. Warrell RP, Kempin SJ. Treatment of severe coagulopathy in the Kasabach-Merritt syndrome with aminocaproic acid and cryoprecipitate. N Engl J Med 1985;313:309-312. 9. Kasabach HH, Merritt KK. Capillary hemangioma with extensive purpura. Am J Dis Child 1940;59:1063-1070. 10. Brunellc F, Roche A. "Micro" stainless coils for transcatheter vascular occlusion in children. Pediatr Radiol 1983;13:332334. 1I. Shim WKT. Hemangiomas of infancy complicated by thrombocytopenia. Am J Surg 1969;116:896-906. 12. Rush BF: Treatment of a giant cutaneous hemangioma by intraarterial injection of nitrogen mustard. Ann Surg 1966; 164:921-923. 13. AI-Rashid RA. Cyclophosphamide and radiation therapy in the treatment of hemangioendothelioma with disseminated intravascular clotting. Cancer 1971 ;27:364-368. 14. Tewfik H, Latourette H, Christie JH. Infantile hepatic hemangioendothelioma: a surviving case. Pediatr Radiol 1977;123:723-724.
Ketoconazole treatment of type I autoimmune polyglandular syndrome: Effects on pituitary-adrenal axis Penelope Feuillan, M.D., Merrily Poth, M.D., William Reilly, M.D., George Bright, M.D., D. Lynn Loriaux, M.D., Ph.D., and George P. Chrousos, M.D. From the Developmental Endocrinology Branch, National Institute of Child Health and Human Development, and the Department of Pediatrics, U.S. Public Health Service, Bethesda, Maryland; the Department of Pathology, University of Florida College of Medicine, Gainesvilte; and the Department of Pediatrics, Medical University of South Carolina, Charleston
Presented at the 15th Acta Endocrinologica Congress, Helsinki, Finland, 1985. Supported in part by the Children's Fund of the Medical University of South Carolina. Submitted for publication Oct. 25, 1985; accepted March 28, 1986. Reprint requests: Penelope Feuillan, M.D., Developmental Endocrinology Branch, NICHHD, National Insititutes of Health, Bethesda, MD 20892.
Autoimmune polyglandular syndrome type 1 is an autosomal recessive endocrine disorder of childhood. Chronic candidiasis of the oral mucosa is frequently the earliest clinical manifestation of APS-1; Candida may involve the nails as well, causing thickening and disfigurement. HypoACTH APS-I OCRH
Adrenocorticotropin; Cortrosyn Autoimmune polyglandular syndrome Ovine eorticotropin releasing hormone
364
Clinical and laboratory observations
The Journal of Pediatrics August 1986
Table. Clinical and laboratory findings in three patients with autoimmune polyglandular syndrome type 1 ACTH-stimulated plasma cortlsol" (~g/dl) Patient
Age (yr)
Sex
Candidiasis
Hypopara. thyroldlsm
Adrenal antibodies
1
12
F
+
+
-
2 3
10 9
M M
+ +
+ +
+
Before ketoconazole
During ketoconazole
After ketoconazole
24 27 13
20 20 5
NT NT 10
NT, not tested. *Cortisol response30 minutesafter 250 #g ACTH (Cortrosyn).Mean _+ 1 SD plasmacortisolresponse30 minutesafter ACTH in 20 normalsubjects,21 _+4 ~zg/dl (range 16 to 32 #g/dl).
parathyroidism characteristically appears later, in midchildhood, and primary adrenal insufficiency may occur in early adolescence?. 2 The adrenal insufficiency may be life threatening if not recognized and treated promptly. Autoantibodies to adrenal tissue have been demonstrated in the serum of patients with this form of adrenal destruction? The candidiasis of APS- 1 can be resistant to treatment. Recently, satisfactory results have been reported with the antifungal agent ketoconazole.4 This drug is an imidazole derivative that is also known to inhibit the biosynthesis of cortisol and testosterone in viva in a dose- and timedependent fashion?'6 Impaired cortisol biosynthesis has been demonstrated in normal subjects, who have shown suppressed cortisol responses to synthetic ACTW -24 (Cortrosyn) stimulation up to 8 hours after ketoconazole administration? Thus this drug should be used with caution in patients who are already at risk for adrenal insufficiency. We undertook this study to assess the effect of ketoconazole therapy on the pituitary-adrenal axis in three siblings with APS- 1, one of whom had evidence of partial adrenal failure. METHODS Three children from a sibship of five were examined (Table). A 12-year-old girl (patient 1) and a 10-year-old boy (patient 2) had oral candidiasis and hypoparathyroidism; neither had clinical evidence of adrenal failure, and their serum did not contain antiadrenal antibodies. Their 9-year-old brother (patient 3) had oral candidiasis, nail dystrophy, alopecia, and hypoparathyroidism. Although he had no electrolyte abnormalities, hypotension, or hyperpigmentation to suggest adrenal insufficiency, serum antiadrenal antibodies were present. All three children were receiving 0.5 to 1.75 #g/day 1,25-dihydroxyvitamin D (Rocaltrol) and 2 to 6 gm/day Ca ++ for treatment of hypoparathyroidism, but none had required treatment with glucocorticoids or mineralocorticoids. All three were given
ketoconazole 100 mg/day (2.5 to 4.5 mg/kg/day) in a single 8:00 AM dose, and responded with complete clearing of oral lesions, and some improvement of nail dystrophy in patient 3. Screening for anti-adrenal antibodies was done by indirect immunofluorescence with human adrenal tissue as previously described? As a preliminary test of adrenal function, baseline and peak plasma cortisol levels were measured at 0 and 30 minutes after a 250 #g dose of ACTH given at 12 noon. This test was performed before ketoconazole treatment was started, and was repeated during treatment with ketoconazole, 4 hours after the last dose of drug. Cortisol and ACTH responses were also measured after a 1 #g/kg dose of ovine corticotropin releasing hormone given at 8:00 PM. Patients were tested with oCRH both during treatment with ketoconazole (12 hours after the last dose), and again after the drug had been withheld for 2 weeks. All testing was done in the pediatric ward of the Clinical Center of the National Institutes of Health. Informed consent was obtained from a parent and from the patients before administering oCRH, using a protocol approved by an institutional review board. RESULTS ACTH response (Table). Before treatment, patients 1 and 2 had normal cortisol responses to ACTH. Patient 3 had a subnormal cortisol response consistent with partial adrenal insufficiency. During ketoconazole treatment, the cortisol response to ACTH decreased in patients 1 and 2, but remained within the normal range. In patient 3 there was a further decrease in cortisol response during treatment. He was retested with ACTH after ketoconazole had been withheld for 5 days, and demonstrated a partial recovery of the cortisol response. oCRH response (Figure). Nighttime (8:00 PM) basal plasma ACTH and cortisol levels were normal in patients 1
Volume 109 Number 2
and 2 both during and after discontinuation of ketoconazole. After oCRH stimulation, plasma ACTH and cortisol responses were also within the normal range, demonstrating unchanged pituitary-adrenal function 12 hours after the ketoconazole dose. Patient 3, on the other hand, had an attenuated cortisol response and an increased ACTH response to oCRH during both testing periods. Although cortisol responses to oCRH during and after discontinuation of ketoconazole therapy were not different, plasma ACTH response during treatment was dramatically exaggerated and prolonged (peak 209 pg/ml at 150 minutes).
Clinical and laboratory observations
PATIENT 1
PATIENT 3
60-
2O0 180
<
2O
160 i
=
140
25 ~
120
I
100
05
20 10 P ~ S M A IR.ACXH
i
80
PATIENT 2
60
DISCUSSION We evaluated the adrenal function of our patients both with the conventional ACTH test and with the oCRH stimulation test. Pituitary stimulation with oCRH has been used as a diagnostic tool in several types of of pituitary-adrenal disorders/, 8 The test has been standardized in our clinic with administration of 1 #g/kg oCRH at 8:00 PM, when the normal diurnal rhythm of cortisol and ACTH is at its nadir. Plasma ACTH and cortisol responses in children do not differ from those in adults. 9 Patients with primary adrenal insufficiency characteristiCally have elevated basal plasma ACTH or increased ACTH responses to oCRH. Their cortisol responses are attenuated or absent, depending on the degree of adrenal impairment? Our patient 3 had an attenuated cortisol response to oCRH and a disproportionate ACTH versus cortisol response compared with those of normal subjects. His integrated plasma cortisol plotted against integrated plasma ACTH was clearly outside the normal range (Figure). Although his cortisol response after oCRH was not decreased during ketoconazole administration, the dramatic increment in ACTH response during treatment indicated further compromise in adrenal function. The additional decrease in his cortisol response to ACTH during treatment confirmed this finding. In contrast, patients 1 and 2 had no evidence of significant adrenal dysfunction during ketoconazole therapy. Ketoconazole inhibits steroid biosynthesis by blocking several mitochondrial cytochrome P-450-dependent enzymes, including 17,20-desmolase and 17-a-hydroxylase. 6 Clinical trials with normal subjects have shown a blunting of the cortisol response to ACTH 4 to 8 hours after single doses of 400 to 600 mg (5 to 9 mg/kg), 5 and normal cortisol responses 16 hours after dosing. These studies indicate that the suppressive effect of ketoconazole in normal subjects is transient and is probably related to the serum ketoconazole concentration. There is no evidence that prolonged ketoconazole treatment will cause significant impairment of adrenal function
365
-
....
40
4O
20
~=
2sI~
-6 ~5
_
.........
~5115 ----
25
i
0
60
120
Time Imin)
180
0
60
120
180
Time (min)
Figure. Plasma ACTH and cortisol responses to 1 pg/kg oCRH
in patients I, 2, and 3 during (e) and after (o) ketoconazole therapy. Shaded area represents normal range (mean _+ 1 SD) in 24 control subjects. Insert, Dose-response relationship between time-integrated plasma ACTH and cortisol in patient 3. Shaded area represents normal range in 40 subjects who received 0 to 1 pg/kg oCRH."
in normal subjects. Boys with familial male precocious puberty and normal adrenal function have been given high doses (17 to 32 mg/kg/day) of ketoconazole for periods up to 12 months to reduce serum testosterone levels without developing adrenal dysfunction. Although ACTH stimulation after 5 days of treatment showed reductions in peak cortisol response, peak cortisol responses after 9 to 12 months of treatment werereportedly normal. ~~Thus subjects with normal adrenal glands have the capacity to compensate for the drug-induced biosynthetic defect. It is likely that this occurs either by increased enzyme biosynthesis or by enlargement of the gland itself. On the other hand, individuals such as our patient 3, with primary adrenal insufficiency and a limited adrenal reserve, would be unable to mount an adaptive response to long-term ketoconazole administration and could be at risk for developing frank adrenal insufficiency. The increasing applications of ketoconazole should prompt further investigation into its mechanism of action and side effects. Even at low doses, this drug can impair adrenal function in patients with a limited pituitary-
366
Clinical and laboratory observations
adrenal reserve. Physicians should be aware of the adrenal status of their patients before beginning t r e a t m e n t with ketoconazole. We thank Karen Hench, R.N., for technical assistance. REFERENCES
1. Neufeld M, Maclaren N, Blizzard R. Autoimmune polyglandular syndromes. Pediatr Ann 1980;9:1557. 2. Trence DL, Morley JE, Hand,verger BS. Polyglandular autoimmune syndromes. Am J Med 1984;77:109. 3. Ketchum CH, Riley W J, Maclaren NK. Adrenal dysfunction in asymptomatic patients with adrenocortical autoantibodies. J Clin Endocrinol Metab 1984;58:1166. 4. Petersen EA, Ailing DW, Kirkpatrick CH. Treatment of chronic mucocutaneous candidiasis with ketoconazole. Ann Intern Med 1980;93:791. 5. Pont A, Graybill JR, Craven PC, et al. High-dose ketoconazole therapy and adrenal and testicular function in humans. Arch Intern Med 1984;144:2150.
The Journal of Pediatrics August 1986
6. Sikka S, Swerdloff RS, Rajfer J. In vitro inhibition of testosterone biosynthesis by ketoconazole. Endocrinology 1985;116:1920. 7. Chrousos GP, Schurmeyer TS, Doppman J, et al. Clinical applications of corticotropin releasing factor. Ann Intern Med 1985;102:344. 8. Schulte HM, Chrousos GP, Avgerinos P, et al. The corticotropin-releasing hormone stimulation test: a possible aid in the evaluation of patients with adrenal insufficiency. J Clin Endocrinol Metab 1984;58:1064. 9. Levine JL, Schulte HM, Gallucci WT, et al. Ovine corticotropin-releasing hormone stimulation test in children. J Clin Endocrinol Metab 1986;62:390. 10. Holland FJ, Fishman L, Bailey JD, Fazekas ATA. Ketoconazole in the management of precocious puberty not responsive to LHRH-analog therapy. N Engl J Med 1985;312:1023. 11. Scheurmeyer TH, Tsokos GC, Avgerinos PC, et al. Pituitaryadrenal responsiveness to corticotropin-releasing hormone in patients receiving chronic alternate-day glucocorticoid therapy. J Clin Endocrinol Metab 1985;61:22.