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Cyproheptadine and adrenocortical function
EDITORIAL CORRESPONDENCE
Editorial correspondence or letters to the Editor relative to articles published in THE JOURNAL or to topics of current interest are subject to critical review and to current editorial policy in respect to publication in part or in full.
Association of joint contractures and diabetes mellitus To the Editor. We read u r b a n and associates' article, 1 "Familial syndrome o f mental retardation, short stature, contractures of hands and genital anomalies," and were interested in the association o f glucose intolerance with this syndrome. Multiple joint contractures, primarily of the fingers, have been described in adult s and juvenile diabetes? 4 This manifestation has been noted to increase in severity and frequency with the duration oi" the diabetes. The exact pathophysiology is unknown, but it is assumed to be a connective tissue abnormality. Grgic et aP found a 28.4% incidence of joint contractures in 229 juvenile diabetic patients, and we found an 8.4% incidence in 310 diabetic patients a 9.4% incidence in 106 nondiabetic siblings of our diabetic patients, and a 2% incidence in 199 nonsibling controls. Glucose tolerance was impaired in four of nine siblings and two of three nonsiblings with joint contractures. We suggest that a glucose tolerance test be performed when joint contractures are present. Howard S. Traisman, M.D. Edward S. Traisman Thomas J. Marr, M.D. Joyce Wise, M.D. Children's Memorial Hospital Department of Pediatrics Northwestern Medical School Chicago, I L 60614 REFERENCES I.
Urban MD, Rogers SG, and Meyer WJ III: Familial syndrome of mental retardation, short stature, contractures of the hands and genital anomalies, J PEDIA'rR 94:52, 1979. 2. Jung Y, Hohmann JA, Gerneth J, et at: Diabetic hand syndrome, Metabolism 20:1008, 1971. 3. Grgic A, Rosenbloom AL, Weber FJ, et al: Joint contract u r e - c o m m o n manifestation Of childhood diabetes mellitus, J PEDIATR 88:584, 1976. 4. Traisman HS, Traisman ES~ Marr TJ, and Wise J: Joint contractures in juvenile diabetics and siblings, Diabetes Care !:360, 1978.
Cyproheptadine and adrenocortical function To the Editor: Kenien et aF recently showed the in vivo effect of cyproheptadine and human growth hormone on adrenocortical function in children with hypopituitarism. We would like to add some experimental findings off the effects of cyproheptadine on cortisol synthesis in vitro. Cyproheptadine is known to be a potent serotonin antagonist; however, the drug possesses antihistaminic, anticholinergic, and antidopaminergic effects as well. The drug has also been shown to have an effect on hypothalamic-pituitary function. Serotoninergic, cholinergic, and adrenergic mechanisms within the hypothalamus are important in the regulation of cort!cotropin (ACTH) secretion by the pituitary and, through this secretion, on cortisol production by the adrenal glands? Cyproheptadine was then used for the treatment of Cushing disease to reduce hypercortisolism; art improvement in both clinical and biologic findings was reported by some workers, 3 whereas rather bad Or negative results were recorded by others. 4 The drug has been thought to be active only on the hypothalamic-pituitary axis, since the administration of cyproheptadirte to normal volunteers blocked hypoglycemia-induced cortisol secretion ~ and reduced pituitary-adrenal responsiveness to metyrapone administration? Indeed, a direct effect of the drug at the adrenal level must not be excluded? The question of whether cyproheptadine inhibits cortisol synthesis thus arises. We report here the in vitro effect of increasing concentrations of cyproheptadine on cortisol synthesis from tritiated deoxycortisol as precursor, by an adrenocortical carcinoma resected from a 26-year-old woman with Cushing syndrome. The direct effect of cyproheptadine on llfl-hydroxylase was evaluated by comparing the conversion rates of de~xycortisol to corfisol by adrenocortical carcinoma homogenates (1 gm, wet weight) incubated with and without (controls) cyproheptadine, concentration up to 5 • 10 ~ M, for two hours at 37 ~ C. An NADPH-generating system made up of NADP + (1 mM) and malate (5 mM) was added to the incubation flasks in order to facilitate hydroxylation. The extraction, purification and characterization of steroids have been published elsewhere. 7 The results Obtained with the highest concentration assayed
TheJournalofPEDIATRICS
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156
Editorial correspondence
showed that the addition of eyproheptadine to the incubated tissue did not alter cortisol synthesis in vitro, as conversion rates of cortisol from I I-deoxycortisol were not different when compared to controls (53% vs 58%). This finding brings experimental evidence of the lack of effects of cyproheptadine in cortisol synthesis by human adrenocortical tissue, and suggests that the alterations in adrenal function of the treated patients cannot be related to a direct effect of cyproheptadine on the last step of cortisol synthesis.
Yvan Touitou Andre Bogdan Andre A uzeby Faculty of Medicine Pitib-Salpktribre Department of Biochemistry 91, Boulevard.de l'Hbpital 75013 Paris France REFERENCES
1. Kenien AJ, Zeidner DL, Pang SJ, Becker D J, Postellon DC, Gutai JP, Foley TP Jr, and Drarh AE: The effect of cyproheptadine and human growth hormone on adrenocortical function in children with hypopituitarism, J P~DIATR 92:491, 1978. 2. Krieger HP, and Krieger DT: Chemical stimulation of the brain: Effect on adrenal corticoid release, Am J Physiol 218:1632, 1970. 3. Krieger DT, Amorosa L, and Liniek F: Cyproheptadineinduced remission of Cushing's disease, N Engl J Med 293:893, 1975. 4. Allgrove J, Husband P, and Brooks COD: Cushing's disease: Failure of treatment with cyproheptadine, Br Med J 1:686, 1977. 5. Plonk JW, Bivens CH, and Feldman JM: Inhibition of hypoglycemic-induced cortisol secretion by the serotonin antagonist cyproheptadine, J Clin Endocrinol Metab 38:836, 1974. 6. Plonk JW, and Feldman JM: Modification of adrenal function by the anti-serotonin agent cyproheptadine, J Clin Endocrinol Metab 42:291, 1976. 7. Touitou Y, Bogdan A, and Luton JP: Changes in corticosteroid synthesis of the human adrenal cortex in vitro, induced by treatment with o,p'-DDD for Cushing's syndrome: evidence for the sites of action of the drug, J Steroid Biochem 9:1217, 1978.
The Journal of Pediatrics July 1979
CASE REPORT
Patient S.W. is a 15-year-old white girl who was referred to Shands, Teaching Hospital in August, 1976, because of a twomonth history of recurrent eechymoses and a one-day history of leukocytosis with immature granuloeytic forms on peripheral blood smear, Two months earlier, the patient had complained of visual difficulties and headaches. At that time she was seen by an ophthalmologist who diagnosed open-angle glaucoma and treated the patient with pilocarpine eye drops. No significant improvement was noted; however, no further investigations were done at that time. The patient appeared in good general health. Lymph nodes were diffusely enlarged. Skin examination revealed numerous ecchymoses. Ophthalmologic evaluation showed mild left ptosis. Visual acuity was 20/20. The fundi were normal. Gonioscopy showed grade IV angles, with extensive deformity of the vessels at the periphery with tortuous vessels extending into the trabecular meshwork in all quadrants. Pressure was 15 mm in the right eye and 35 mm in left eye. NO visual field defect was present. Blood count showed hematocrit 27%, white blood cell count 295,000/mm 3 with 30% polymorphonuclear cells, 21% bands, 2% lymphocytes, 2% eosin0phils, 5% basophils, 4% metamyelocytes, 30% myelocytes, 1% promonocytes, and 5% blast cells. Platelet count was 1,575,000/mm a. Uric acid was 7.4mg/dl~ LDH 72U, SGPT 17U, and SGOT 20U. Bone marrow examination showed markedly increased mye[oid to erythroid ratio, compatible with chronic myelogenous leukemia. Philadelphia chromosome was present, while fetal hemoglobin and leukocyte alkaline phosphatase Were within normal limits. CSF examination was negative for cells, and cytocentrifuge analysis did not reveal any tumor cells. The patient has remained in complete continuous remission on a chemotherapy regimen and has no evidence of acute disease. COMMENTS
Glaucoma in this patient was presumably due to leukemic infiltration of trabecular meshwork, blocking aqueous fluid outflow. Free leukemic cells were not demonstrated and biopsy was not attempted. The temporal relationship of bruising symptoms in association with ophthalmologic findings two months prior to diagnosis of chronic m yelogenous leukemia strongly support a causal relationship. This association of glaucoma with leukemia has been repor(ed, 2. 3 but is quite uncommon. In the absence of inflammatory eye disease, traunra, metabolic disorders, or steroid administration, neoplastic disease should be considered. Bleeding manifestations or other systemic abnormality should alert the physician to request full hematologic evaluation to consider leukemic ophthalmic infiltration.
Paulette Mehta, M,D. Division of Hematology-Oncology Department of Pediatrics University of Florida College of Medicine Gainesville, FL 32610
Ophthalmologic manifestations of leukemia To the Editor: I read with great interest the report of leukemia and hypopyon in a 3-year-old child at the time of onset of acute lymphoblastic leukemia? I report the following case to stress that eye findings may be the initial manifestations of leukemia before systemic or peripheral blood manifestations.
REFERENCES
1. Holbrook CT, Elsas F J, Crist WM, and Castleberry RP: Acute leukemia and hypopyon, J PED~A'rR93:626, 1978. 2. Fonken HA, and Ellis PP: Leukemic infiltrates in the Ms-successful treatment of secondary glaucoma with x-irradiati0n, Arch Ophthalmol 76:32, 1966.
Editorial correspondence or letters to the Editor relative to articles published in THE JOURNAL or to topics of current interest are subject to critical review and to current editorial policy in respect to publication in part or in full.
Association of joint contractures and diabetes mellitus To the Editor. We read u r b a n and associates' article, 1 "Familial syndrome o f mental retardation, short stature, contractures of hands and genital anomalies," and were interested in the association o f glucose intolerance with this syndrome. Multiple joint contractures, primarily of the fingers, have been described in adult s and juvenile diabetes? 4 This manifestation has been noted to increase in severity and frequency with the duration oi" the diabetes. The exact pathophysiology is unknown, but it is assumed to be a connective tissue abnormality. Grgic et aP found a 28.4% incidence of joint contractures in 229 juvenile diabetic patients, and we found an 8.4% incidence in 310 diabetic patients a 9.4% incidence in 106 nondiabetic siblings of our diabetic patients, and a 2% incidence in 199 nonsibling controls. Glucose tolerance was impaired in four of nine siblings and two of three nonsiblings with joint contractures. We suggest that a glucose tolerance test be performed when joint contractures are present. Howard S. Traisman, M.D. Edward S. Traisman Thomas J. Marr, M.D. Joyce Wise, M.D. Children's Memorial Hospital Department of Pediatrics Northwestern Medical School Chicago, I L 60614 REFERENCES I.
Urban MD, Rogers SG, and Meyer WJ III: Familial syndrome of mental retardation, short stature, contractures of the hands and genital anomalies, J PEDIA'rR 94:52, 1979. 2. Jung Y, Hohmann JA, Gerneth J, et at: Diabetic hand syndrome, Metabolism 20:1008, 1971. 3. Grgic A, Rosenbloom AL, Weber FJ, et al: Joint contract u r e - c o m m o n manifestation Of childhood diabetes mellitus, J PEDIATR 88:584, 1976. 4. Traisman HS, Traisman ES~ Marr TJ, and Wise J: Joint contractures in juvenile diabetics and siblings, Diabetes Care !:360, 1978.
Cyproheptadine and adrenocortical function To the Editor: Kenien et aF recently showed the in vivo effect of cyproheptadine and human growth hormone on adrenocortical function in children with hypopituitarism. We would like to add some experimental findings off the effects of cyproheptadine on cortisol synthesis in vitro. Cyproheptadine is known to be a potent serotonin antagonist; however, the drug possesses antihistaminic, anticholinergic, and antidopaminergic effects as well. The drug has also been shown to have an effect on hypothalamic-pituitary function. Serotoninergic, cholinergic, and adrenergic mechanisms within the hypothalamus are important in the regulation of cort!cotropin (ACTH) secretion by the pituitary and, through this secretion, on cortisol production by the adrenal glands? Cyproheptadine was then used for the treatment of Cushing disease to reduce hypercortisolism; art improvement in both clinical and biologic findings was reported by some workers, 3 whereas rather bad Or negative results were recorded by others. 4 The drug has been thought to be active only on the hypothalamic-pituitary axis, since the administration of cyproheptadirte to normal volunteers blocked hypoglycemia-induced cortisol secretion ~ and reduced pituitary-adrenal responsiveness to metyrapone administration? Indeed, a direct effect of the drug at the adrenal level must not be excluded? The question of whether cyproheptadine inhibits cortisol synthesis thus arises. We report here the in vitro effect of increasing concentrations of cyproheptadine on cortisol synthesis from tritiated deoxycortisol as precursor, by an adrenocortical carcinoma resected from a 26-year-old woman with Cushing syndrome. The direct effect of cyproheptadine on llfl-hydroxylase was evaluated by comparing the conversion rates of de~xycortisol to corfisol by adrenocortical carcinoma homogenates (1 gm, wet weight) incubated with and without (controls) cyproheptadine, concentration up to 5 • 10 ~ M, for two hours at 37 ~ C. An NADPH-generating system made up of NADP + (1 mM) and malate (5 mM) was added to the incubation flasks in order to facilitate hydroxylation. The extraction, purification and characterization of steroids have been published elsewhere. 7 The results Obtained with the highest concentration assayed
TheJournalofPEDIATRICS
155
156
Editorial correspondence
showed that the addition of eyproheptadine to the incubated tissue did not alter cortisol synthesis in vitro, as conversion rates of cortisol from I I-deoxycortisol were not different when compared to controls (53% vs 58%). This finding brings experimental evidence of the lack of effects of cyproheptadine in cortisol synthesis by human adrenocortical tissue, and suggests that the alterations in adrenal function of the treated patients cannot be related to a direct effect of cyproheptadine on the last step of cortisol synthesis.
Yvan Touitou Andre Bogdan Andre A uzeby Faculty of Medicine Pitib-Salpktribre Department of Biochemistry 91, Boulevard.de l'Hbpital 75013 Paris France REFERENCES
1. Kenien AJ, Zeidner DL, Pang SJ, Becker D J, Postellon DC, Gutai JP, Foley TP Jr, and Drarh AE: The effect of cyproheptadine and human growth hormone on adrenocortical function in children with hypopituitarism, J P~DIATR 92:491, 1978. 2. Krieger HP, and Krieger DT: Chemical stimulation of the brain: Effect on adrenal corticoid release, Am J Physiol 218:1632, 1970. 3. Krieger DT, Amorosa L, and Liniek F: Cyproheptadineinduced remission of Cushing's disease, N Engl J Med 293:893, 1975. 4. Allgrove J, Husband P, and Brooks COD: Cushing's disease: Failure of treatment with cyproheptadine, Br Med J 1:686, 1977. 5. Plonk JW, Bivens CH, and Feldman JM: Inhibition of hypoglycemic-induced cortisol secretion by the serotonin antagonist cyproheptadine, J Clin Endocrinol Metab 38:836, 1974. 6. Plonk JW, and Feldman JM: Modification of adrenal function by the anti-serotonin agent cyproheptadine, J Clin Endocrinol Metab 42:291, 1976. 7. Touitou Y, Bogdan A, and Luton JP: Changes in corticosteroid synthesis of the human adrenal cortex in vitro, induced by treatment with o,p'-DDD for Cushing's syndrome: evidence for the sites of action of the drug, J Steroid Biochem 9:1217, 1978.
The Journal of Pediatrics July 1979
CASE REPORT
Patient S.W. is a 15-year-old white girl who was referred to Shands, Teaching Hospital in August, 1976, because of a twomonth history of recurrent eechymoses and a one-day history of leukocytosis with immature granuloeytic forms on peripheral blood smear, Two months earlier, the patient had complained of visual difficulties and headaches. At that time she was seen by an ophthalmologist who diagnosed open-angle glaucoma and treated the patient with pilocarpine eye drops. No significant improvement was noted; however, no further investigations were done at that time. The patient appeared in good general health. Lymph nodes were diffusely enlarged. Skin examination revealed numerous ecchymoses. Ophthalmologic evaluation showed mild left ptosis. Visual acuity was 20/20. The fundi were normal. Gonioscopy showed grade IV angles, with extensive deformity of the vessels at the periphery with tortuous vessels extending into the trabecular meshwork in all quadrants. Pressure was 15 mm in the right eye and 35 mm in left eye. NO visual field defect was present. Blood count showed hematocrit 27%, white blood cell count 295,000/mm 3 with 30% polymorphonuclear cells, 21% bands, 2% lymphocytes, 2% eosin0phils, 5% basophils, 4% metamyelocytes, 30% myelocytes, 1% promonocytes, and 5% blast cells. Platelet count was 1,575,000/mm a. Uric acid was 7.4mg/dl~ LDH 72U, SGPT 17U, and SGOT 20U. Bone marrow examination showed markedly increased mye[oid to erythroid ratio, compatible with chronic myelogenous leukemia. Philadelphia chromosome was present, while fetal hemoglobin and leukocyte alkaline phosphatase Were within normal limits. CSF examination was negative for cells, and cytocentrifuge analysis did not reveal any tumor cells. The patient has remained in complete continuous remission on a chemotherapy regimen and has no evidence of acute disease. COMMENTS
Glaucoma in this patient was presumably due to leukemic infiltration of trabecular meshwork, blocking aqueous fluid outflow. Free leukemic cells were not demonstrated and biopsy was not attempted. The temporal relationship of bruising symptoms in association with ophthalmologic findings two months prior to diagnosis of chronic m yelogenous leukemia strongly support a causal relationship. This association of glaucoma with leukemia has been repor(ed, 2. 3 but is quite uncommon. In the absence of inflammatory eye disease, traunra, metabolic disorders, or steroid administration, neoplastic disease should be considered. Bleeding manifestations or other systemic abnormality should alert the physician to request full hematologic evaluation to consider leukemic ophthalmic infiltration.
Paulette Mehta, M,D. Division of Hematology-Oncology Department of Pediatrics University of Florida College of Medicine Gainesville, FL 32610
Ophthalmologic manifestations of leukemia To the Editor: I read with great interest the report of leukemia and hypopyon in a 3-year-old child at the time of onset of acute lymphoblastic leukemia? I report the following case to stress that eye findings may be the initial manifestations of leukemia before systemic or peripheral blood manifestations.
REFERENCES
1. Holbrook CT, Elsas F J, Crist WM, and Castleberry RP: Acute leukemia and hypopyon, J PED~A'rR93:626, 1978. 2. Fonken HA, and Ellis PP: Leukemic infiltrates in the Ms-successful treatment of secondary glaucoma with x-irradiati0n, Arch Ophthalmol 76:32, 1966.