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Superoxide dismutase in prevention of bronchopulmonary dysplasia
EDITORIAL CORRESPONDENCE
Male pseudohermaphroditism resulting from Leydig cell hypoplasia To the Editor: We read with interest the Saenger's ~ review on abnormal sex differentiation and wondered about the absence of Leydig cell hypoplasia as a cause of male pseudohermaphroditism. The following features characterize this disorder: (1) predominantly female external genitalia, leading to female sex assignment~ (2) no development of either male or female secondary sexual Characteristics at puberty; (3) presence of epidydimis and vas deferens, and absence of uterus and fallopian tubes; (4) 46,XY karyotype; (5) 10w testosterone Values despite elevated gonadotropin values; (6) unresponsiveness to human chorionic gonadotropin stimulation; (7) no abnormal step up in testosterone biosynthesis precursors; and (8) only slightly smaller undescended testes with relatively preserved seminiferous tubules and absence of mature Leydig cells. We recently saw such a patient. At 24 years of age our patient had 3 x 2 cm testes; serum luteinizing hormone 27.5 m I U / m l (normal males 7.7 _+ 4.7, mean +_ 1 SD), follicle stimulating hormone 47.7 m I U / m l (normal 6.9 _+ 4.9), dehydroepiandrosterone 223 ng/dl (normal 367 +_ 87), 17-hydroxyprogestcrone 37 ng/dl (normal 120 +_ 27), androstenedione 75 ng/dl (normal 153 _+ 28), estradiol <20 pg/mt (normal 59 +_ 9), basal testosterone 15 ng/dl (normal 614 +-77), and testosterone after hCG stimulation 12 ng/dl (normal 1339 _+ 535). Schwartz et al. 2 reported a prepubertal boy with ambiguous genitalia Who after hCG stimulation had low testosterone values and absent Leydig cells on testicular biopsy. There was diminished binding of 13q-hCG to testicular tissue in vitro, and a selective abnormality in Leydig ceil differentiation was suggested. Milder forms of Leydig cell hypoplasia are probably a more common cause of male pseudohermophroditism than has been hitherto reported. This diagnosis in prepubertal patients is only possible after establishing the lower limits of normal for serum testosterone values, testicular Leydig cell number, 0r h C G / L H binding after a protocol of hCG stimulation. ivo J. P. Arnhold, M.D. Berenice B. Mendon(a, M.D. Walter Bloise, M.D. SOrgio P. A. Toledo, M.D. lntersex and Endocrine Genetics Units Division o f Endocrinology Hospital das Clinicas da Faculdade de Medicina da Universidade de Sho Paulo Silo Paulo, Brazil
Superoxide dismutase in prevention
of bronchopulmonary dysplasia To the Editor: R0senfeld et al) have provided an interesting and well-designed study On the "effects of exogenously administered superox~de dfgmutase ( s o D ) in the prevention of bronehopulmonary dysplasia (BPD). However, their conclusion that SOD treatment may prevent BPD may not be justified. Although the data that radiographic and clinical signs of BPD are reduced are impressive, both the SOD treated and untreated groups had similar duration of oxygen therapy. The functional problem of oxygen requirement is at least as important as radiogrpahic or clinical criteria in determining the diagnosis and severity of BPD. Also, there is a distinct trend toward higher peak inspiratory pressure use during the first 3 days of life in the placebo group. It is not stated whether this difference is significant during the first 3 days; the standard deviation is Wide, and it is therefore difficult to exclude barotrauma in the placebo group in excess of that in the treatment group. AS the authors imply, there is no direct evidence that SOD ,'deficiency" is operative in the pathogenesis of lung injury in neonates with respiratory distress syndrome (RDS). In humans, the data are limited to the finding of low SOD levels in the lungs of three infants who died of RDS. 2 SOD levels increase with increasing gestational and postnatal age? Yet in most species, the neonatal lung tolerates hyperoxia better than that of the adult, associated with the neonate's ability to increase the production of SOD rapidly on exposure to oxygen. 4 The capacity of the human neonate to increase SOD production when exposed to hyperoxic stress is not known. As for the safety of the bovine SOD preparation, the lack of clinically noticeable immediate reaction to the drug does not exclude the Possibility of long-term effects from SOD antibodies or antigen-antibody complexes. One should be reluctant to administer foreign animal proteins to human infants tO treat presumed deficiencies that are not ~vell documented. Jeffrey S. Gerdes, M.D. Department o f Pediatrics University Of Pennsylvania School o f Medicine Section on Newborn Pediatrics Pennsylvania Hospital Philadelphia, PA 19107~
REFERENCES 1.
REFERENCES 1. 2.
Saenger P: Abnormal sex differentiation. J PEDIATR 104:1, 1984. Schwartz M, Imperato McGinley J, Peterson RE, Cooper G, Morris PL, MacGillivray M, Hensle T: Male pseudohermaphroditism secondary to an abnormality in Leydig cell differentiation9 J Clin Endocrinol Metab 53:123, 1981.
2.
3.
Rosenfeld W, Evans H, Concepcion L, et M: Prevention of bronchopulmonary dysplasia by administration of bovine superoxide dismutase in preterm infants with respiratory distress syndrome. r PEDIATR 105:781, 1984. Autor AP, Frank L, Roberts R J: Developmental characteristics Of pulmonary superoxide dismutase: Relationship to idiopathic respiratory distress syndrome. Pediatr Res 10:154, 1976. Frank L, Groseclose E: Preparation for birth into an O2-rich
The Journal o f P E D I A T R I C S Vol. 106, No. 6, June 1985
1057
1058
Editorial correspondence
The Journal of Pediatrics June 1985
tration, we hope to evaluate human SOD, produced by recombinant DNA techniques, in the prevention of BPD.
Table. M e a n p e a k inspiratory p r e s s u r e
BPD (n = 15)' No BPD (n = 16)
Day 1
Day 4
Day 7
25.9 _+ 6.0 24.4 • 7.4
24.8 • 8.4 23.2 + 7.8
2l.l + 3.8 19.3 _+ 4.6
9 environment: The antioxidant enzymes in the developing rabbit lung. Pediatr Res 18:240, 1984. 4. Frank L, Bucher JR, Roberts R J: Oxygen toxicity in neonatal and adult animals of various species. J Appl Physiol 45:699, 1979.
Rep& To the Editor: We thank Dr. Gerdes for his thoughtful comments. He is concerned that the duration of oxygen therapy was similar in both the treated and untreated groups and that this is "at least as important" as other factors in determining the severity of bronch0pulmonary dysplasia (BPD). This may be true, but the duration of oxygen therapy in the initial days of life may also reflect the severity o f respiratory distress syndrome, apnea, and inability to maintain sufficient oxygenation in very premature neonates. We believe that the recurrent need for oxygen and episodes of respiratory difficulty following discharge from the neonatal intensive care unit may be a better indicator of BPD. In our study group, these clinical problems occurred less frequently in the treated patients. Although peak inspiratory pressures during the first 3 days of life were slightly lower in the nontreated patients, we do not believe this represents a trend. No differences were significant. In addition, when peak inspiratory pressures of patients who developed BPD were compared with those who did not, regardless of whether they received superoxide dismutase (SOD), there were no significant differences during the first week of life (Table). This lack of significant differences in treated vs nontreated and BPD vs No BPD patients would seem to indicate that barotrauma, which certainly may play a role in the development of BPD, was not a significant factor in our study: Dr. Gerdes' comments concerning the lack of direct evidence of the role of SOD in the pathogenesis of BPD are correct. Although in many species the neonate may better tolerate hyperoxia and can increase SOD production during oxygen exposure, the significant incidence of hyperoxic damage in human neonates seems to indicate that this does not occur or, if it does, that the response is inadequate. We did believe that this indirect evidence and our previous investigation of the safety of SOD in human neonates provided an ample basis on which to base our controlled study. In turn, these results appear to warrant further controlled clinical investigations to establish the role of SOD in BPD. Dr. Gerdes' reluctance to administer foreign animal proteins to humans is a theoretical but important consideration. We share this concern, and after approval of the Food and Drug Adminis-
Warren Rosenfeld, M.D. Director, Newborn Medicine Interfaith Medical Center Brooklyn, N Y 11213
Thyroid abnormalities in type 1 diabetes To the Editor: Gilani et al? reported thyroid hormone abnormalities characteristic for the low T3 syndrome in 56 children at time of diagnosis of type 1 diabetes. Mean reverse T3 (rT3) levels were significantly higher, and mean T3, T4, and free T4 levels were significantly lower than in a group of normal controls; mean TSH levels were significantly higher than in a group of normal controls. In 1983, we also reported alterations in thyroxine metabolism at diagnosis of diabetes i n children. 2 In 27 children with newly diagnosed type 1 diabetes prior to institution of treatment, rT3 concentrations were elevated in 59%, T4 concentrations were low in 19%, and T~ concentrations were low in 37% compared with normal values for age? TSH concentrations, however, were within the normal range in all our patients. The ratio rTJT3 was elevated in 78% of the patients; the mean value was 0.68 _+ 0.5 SD. The ratio rTJT3 was significantly higher in the group of patients with low pH values (P <0.0005), high blood glucose values (P <0.05), and high serum osmolality (P <0.05). All alterations normalized within 4 weeks after institution of therapy. Our findings of altered peripheral thyroxine metabolism in the majority of children with newly diagnosed diabetes me[litus are in agreement with ihe study of Gilani et al. The alterations reported in our study were more pronounced in the group with severe metabolic derangement, but in contrast to the study of Gilani, we found normal TSH values in all children with newly diagnosed diabetes. We therefore do not believe that the alterations reflect hypothyroidism. The pathogenesis of the low T3 syndrome in diabetes is not completely clear, but there seems to be a strong pH dependency in iodothyronine metabolism? This might be a possible explanation for our findings of highest rTJT3 ratio in children with low pH values.
Martin H. Borkenstein, M.D. Department of Pediatrics University of Graz ,4-8036 Graz, Austria REFERENCES
1.
2.
Gilani BB, MacGillivray MH, Voorhess ML, Mills BJ, Riley W J, MacLaren NK: Thyroid hormone abnormalities at diagnosis of insulin-dependent diabetes mellitus in children. J PEDIAI'R 105:218, 1984. Borkenstein M, Zobel G, Fueger GF: Ver~nderungen der Thyroxinkonversion ("low T3-syndrome") bei Kindern mit Typ-I-Diabetes zum Zeitpunkt der Erstmanifestation. Wr Kiln Wochenschr 95:23, 1983.
Male pseudohermaphroditism resulting from Leydig cell hypoplasia To the Editor: We read with interest the Saenger's ~ review on abnormal sex differentiation and wondered about the absence of Leydig cell hypoplasia as a cause of male pseudohermaphroditism. The following features characterize this disorder: (1) predominantly female external genitalia, leading to female sex assignment~ (2) no development of either male or female secondary sexual Characteristics at puberty; (3) presence of epidydimis and vas deferens, and absence of uterus and fallopian tubes; (4) 46,XY karyotype; (5) 10w testosterone Values despite elevated gonadotropin values; (6) unresponsiveness to human chorionic gonadotropin stimulation; (7) no abnormal step up in testosterone biosynthesis precursors; and (8) only slightly smaller undescended testes with relatively preserved seminiferous tubules and absence of mature Leydig cells. We recently saw such a patient. At 24 years of age our patient had 3 x 2 cm testes; serum luteinizing hormone 27.5 m I U / m l (normal males 7.7 _+ 4.7, mean +_ 1 SD), follicle stimulating hormone 47.7 m I U / m l (normal 6.9 _+ 4.9), dehydroepiandrosterone 223 ng/dl (normal 367 +_ 87), 17-hydroxyprogestcrone 37 ng/dl (normal 120 +_ 27), androstenedione 75 ng/dl (normal 153 _+ 28), estradiol <20 pg/mt (normal 59 +_ 9), basal testosterone 15 ng/dl (normal 614 +-77), and testosterone after hCG stimulation 12 ng/dl (normal 1339 _+ 535). Schwartz et al. 2 reported a prepubertal boy with ambiguous genitalia Who after hCG stimulation had low testosterone values and absent Leydig cells on testicular biopsy. There was diminished binding of 13q-hCG to testicular tissue in vitro, and a selective abnormality in Leydig ceil differentiation was suggested. Milder forms of Leydig cell hypoplasia are probably a more common cause of male pseudohermophroditism than has been hitherto reported. This diagnosis in prepubertal patients is only possible after establishing the lower limits of normal for serum testosterone values, testicular Leydig cell number, 0r h C G / L H binding after a protocol of hCG stimulation. ivo J. P. Arnhold, M.D. Berenice B. Mendon(a, M.D. Walter Bloise, M.D. SOrgio P. A. Toledo, M.D. lntersex and Endocrine Genetics Units Division o f Endocrinology Hospital das Clinicas da Faculdade de Medicina da Universidade de Sho Paulo Silo Paulo, Brazil
Superoxide dismutase in prevention
of bronchopulmonary dysplasia To the Editor: R0senfeld et al) have provided an interesting and well-designed study On the "effects of exogenously administered superox~de dfgmutase ( s o D ) in the prevention of bronehopulmonary dysplasia (BPD). However, their conclusion that SOD treatment may prevent BPD may not be justified. Although the data that radiographic and clinical signs of BPD are reduced are impressive, both the SOD treated and untreated groups had similar duration of oxygen therapy. The functional problem of oxygen requirement is at least as important as radiogrpahic or clinical criteria in determining the diagnosis and severity of BPD. Also, there is a distinct trend toward higher peak inspiratory pressure use during the first 3 days of life in the placebo group. It is not stated whether this difference is significant during the first 3 days; the standard deviation is Wide, and it is therefore difficult to exclude barotrauma in the placebo group in excess of that in the treatment group. AS the authors imply, there is no direct evidence that SOD ,'deficiency" is operative in the pathogenesis of lung injury in neonates with respiratory distress syndrome (RDS). In humans, the data are limited to the finding of low SOD levels in the lungs of three infants who died of RDS. 2 SOD levels increase with increasing gestational and postnatal age? Yet in most species, the neonatal lung tolerates hyperoxia better than that of the adult, associated with the neonate's ability to increase the production of SOD rapidly on exposure to oxygen. 4 The capacity of the human neonate to increase SOD production when exposed to hyperoxic stress is not known. As for the safety of the bovine SOD preparation, the lack of clinically noticeable immediate reaction to the drug does not exclude the Possibility of long-term effects from SOD antibodies or antigen-antibody complexes. One should be reluctant to administer foreign animal proteins to human infants tO treat presumed deficiencies that are not ~vell documented. Jeffrey S. Gerdes, M.D. Department o f Pediatrics University Of Pennsylvania School o f Medicine Section on Newborn Pediatrics Pennsylvania Hospital Philadelphia, PA 19107~
REFERENCES 1.
REFERENCES 1. 2.
Saenger P: Abnormal sex differentiation. J PEDIATR 104:1, 1984. Schwartz M, Imperato McGinley J, Peterson RE, Cooper G, Morris PL, MacGillivray M, Hensle T: Male pseudohermaphroditism secondary to an abnormality in Leydig cell differentiation9 J Clin Endocrinol Metab 53:123, 1981.
2.
3.
Rosenfeld W, Evans H, Concepcion L, et M: Prevention of bronchopulmonary dysplasia by administration of bovine superoxide dismutase in preterm infants with respiratory distress syndrome. r PEDIATR 105:781, 1984. Autor AP, Frank L, Roberts R J: Developmental characteristics Of pulmonary superoxide dismutase: Relationship to idiopathic respiratory distress syndrome. Pediatr Res 10:154, 1976. Frank L, Groseclose E: Preparation for birth into an O2-rich
The Journal o f P E D I A T R I C S Vol. 106, No. 6, June 1985
1057
1058
Editorial correspondence
The Journal of Pediatrics June 1985
tration, we hope to evaluate human SOD, produced by recombinant DNA techniques, in the prevention of BPD.
Table. M e a n p e a k inspiratory p r e s s u r e
BPD (n = 15)' No BPD (n = 16)
Day 1
Day 4
Day 7
25.9 _+ 6.0 24.4 • 7.4
24.8 • 8.4 23.2 + 7.8
2l.l + 3.8 19.3 _+ 4.6
9 environment: The antioxidant enzymes in the developing rabbit lung. Pediatr Res 18:240, 1984. 4. Frank L, Bucher JR, Roberts R J: Oxygen toxicity in neonatal and adult animals of various species. J Appl Physiol 45:699, 1979.
Rep& To the Editor: We thank Dr. Gerdes for his thoughtful comments. He is concerned that the duration of oxygen therapy was similar in both the treated and untreated groups and that this is "at least as important" as other factors in determining the severity of bronch0pulmonary dysplasia (BPD). This may be true, but the duration of oxygen therapy in the initial days of life may also reflect the severity o f respiratory distress syndrome, apnea, and inability to maintain sufficient oxygenation in very premature neonates. We believe that the recurrent need for oxygen and episodes of respiratory difficulty following discharge from the neonatal intensive care unit may be a better indicator of BPD. In our study group, these clinical problems occurred less frequently in the treated patients. Although peak inspiratory pressures during the first 3 days of life were slightly lower in the nontreated patients, we do not believe this represents a trend. No differences were significant. In addition, when peak inspiratory pressures of patients who developed BPD were compared with those who did not, regardless of whether they received superoxide dismutase (SOD), there were no significant differences during the first week of life (Table). This lack of significant differences in treated vs nontreated and BPD vs No BPD patients would seem to indicate that barotrauma, which certainly may play a role in the development of BPD, was not a significant factor in our study: Dr. Gerdes' comments concerning the lack of direct evidence of the role of SOD in the pathogenesis of BPD are correct. Although in many species the neonate may better tolerate hyperoxia and can increase SOD production during oxygen exposure, the significant incidence of hyperoxic damage in human neonates seems to indicate that this does not occur or, if it does, that the response is inadequate. We did believe that this indirect evidence and our previous investigation of the safety of SOD in human neonates provided an ample basis on which to base our controlled study. In turn, these results appear to warrant further controlled clinical investigations to establish the role of SOD in BPD. Dr. Gerdes' reluctance to administer foreign animal proteins to humans is a theoretical but important consideration. We share this concern, and after approval of the Food and Drug Adminis-
Warren Rosenfeld, M.D. Director, Newborn Medicine Interfaith Medical Center Brooklyn, N Y 11213
Thyroid abnormalities in type 1 diabetes To the Editor: Gilani et al? reported thyroid hormone abnormalities characteristic for the low T3 syndrome in 56 children at time of diagnosis of type 1 diabetes. Mean reverse T3 (rT3) levels were significantly higher, and mean T3, T4, and free T4 levels were significantly lower than in a group of normal controls; mean TSH levels were significantly higher than in a group of normal controls. In 1983, we also reported alterations in thyroxine metabolism at diagnosis of diabetes i n children. 2 In 27 children with newly diagnosed type 1 diabetes prior to institution of treatment, rT3 concentrations were elevated in 59%, T4 concentrations were low in 19%, and T~ concentrations were low in 37% compared with normal values for age? TSH concentrations, however, were within the normal range in all our patients. The ratio rTJT3 was elevated in 78% of the patients; the mean value was 0.68 _+ 0.5 SD. The ratio rTJT3 was significantly higher in the group of patients with low pH values (P <0.0005), high blood glucose values (P <0.05), and high serum osmolality (P <0.05). All alterations normalized within 4 weeks after institution of therapy. Our findings of altered peripheral thyroxine metabolism in the majority of children with newly diagnosed diabetes me[litus are in agreement with ihe study of Gilani et al. The alterations reported in our study were more pronounced in the group with severe metabolic derangement, but in contrast to the study of Gilani, we found normal TSH values in all children with newly diagnosed diabetes. We therefore do not believe that the alterations reflect hypothyroidism. The pathogenesis of the low T3 syndrome in diabetes is not completely clear, but there seems to be a strong pH dependency in iodothyronine metabolism? This might be a possible explanation for our findings of highest rTJT3 ratio in children with low pH values.
Martin H. Borkenstein, M.D. Department of Pediatrics University of Graz ,4-8036 Graz, Austria REFERENCES
1.
2.
Gilani BB, MacGillivray MH, Voorhess ML, Mills BJ, Riley W J, MacLaren NK: Thyroid hormone abnormalities at diagnosis of insulin-dependent diabetes mellitus in children. J PEDIAI'R 105:218, 1984. Borkenstein M, Zobel G, Fueger GF: Ver~nderungen der Thyroxinkonversion ("low T3-syndrome") bei Kindern mit Typ-I-Diabetes zum Zeitpunkt der Erstmanifestation. Wr Kiln Wochenschr 95:23, 1983.