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TESTICULAR ENDOCRINE FUNCTION IN MALES WITH NOOMAN'S SYNDROME
1078 It is of course possible that some of our patients had a serious arrhythmia before admission. The problem of whether elevation of plasma-F.F.A. precedes arrhythmia, or is caused by it, can only be answered experimentally when monitoring is available from the time of infarction. We have now been able to show that elevation of plasma-F.F.A. levels, through a system other than one activated by catecholamines, is associated with the development of serious ventricular arrhythmias in dogs in which the myocardium has been infarcted.ll This evidence, together with results soon to be published, reaffirms our view that substantial elevation of plasma-F.F.A. can lead to serious ventricular arrhythmias after acute myocardial infarction. M. F. OLIVER Departments of Cardiology and Medicine, V. A. KURIEN. Royal Infirmary, Edinburgh.
TESTICULAR ENDOCRINE FUNCTION IN MALES WITH NOOMAN’S SYNDROME SIR,-In the past few years there have been several reports concerning the Turner phenotype in the male (or Nooman’s syndrome).1-8 Cryptorchidism has very often been noted and testicular function has varied from less than normal to normal. Nevertheless, in most cases some degree of testicular deficiency has been recorded. Diminished androgen secretion has been suggested both in children9 and in adults 10 on the basis of the very slight rise in the urinary excretion of androsterone which follows the injection of human chorionic gonadotrophin (H.C.G.). TABLE I-CLINICAL FINDINGS IN TWO CHILDREN WITH SYNDROME
NOOMAN’S
IMMUNOGLOBULIN LEVELS IN IDIOPATHIC PULMONARY HÆMOSIDEROSIS SIR,-The bronchial mucosa contains a number of
plasma-cells which are capable of producing IgA immunoglobulins.12 The setiology of idiopathic pulmonary hsemosiderosis (I.P.H.) is not known.13 Steiner 14 has suggested an immunological basis for the disease, with the lung as the shock organ ". "
SERUM-IgA-IMMUNOGLOBULIN LEVELS
TABLE II-PLASMA ANDROGENS BEFORE AND AFTER H.C.G. IN TWO CHILDREN WITH NOOMAN’S SYNDROME
Increased globulin fractions have been reported in a high proportion of the few reported cases of I.P.H.15-18 Quantitative immunoelectrophoretic studies have been done in only one case." This patient was found to have IgA deficiency. We have repeatedly studied the serum-immunoglobulin levels in eleven children between the ages of 2 and 12 years with I.P.H., and have compared them with the levels in eleven healthy children of the same age. Raised IgA levels were found in all patients (see accompanying table). The levels of IgG and IgM were normal. An increase of plasma-cells in the reticuloendothelial system has been reported in r.P.H.2o,21 We wonder whether this increase of plasma cells is associated with the raised IgA levels in
this disease. N. MATSANIOTIS University Department of Pædiatrics, A. CONSTANTOPOULOS Saint Sophia’s Children’s Hospital, J. KARPOUZAS. Athens, Greece. Kurien, V. A., Yates, P. A., Oliver, M. F. Lancet, July 26, 1969, p. 185. 12. South, M. A., Warwick, W. J., Wollheim, F. A., Good, R. A. J. Pediatrics, Springfield, 1967, 71, 645. 13. Matsaniotis, N., Karpouzas, J., Apostolopoulou, E., Messaritakis, J. Archs Dis. Childh. 1968, 43, 307. 14. Steiner, B. ibid. 1954, 29, 391. 15. Skogrand, A., Myhre, E. Acta path. microbiol. scand. 1957, 40, 96. 16. Curewich, V., Thomas, M. A. New Engl. J. Med. 1959, 261, 1154. 17. Ognibene, A. J., Johnson, D. E. Archs intern Med. 1963, 111, 503. 18. Marty, J., Roux, M., Lagarde, C., Nicholas, J., Mollaret, N. Presse méd. 1957, 65, 1959. 19. Krieger, I., Brough, J. A. New Engl. J. Med. 1967, 276, 886. 20. Gluck, E. Acta path. microbiol. scand. 1959, 37, 241. 21. Campbell, S., Macaffee, C. A. J. Archs Dis. Childh. 1959, 34, 218. 11.
However, to our knowledge, plasma levels of testosterone have not been reported in males with this syndrome. We present our results for the plasma-androgens in two affected children. Clinical findings are summarised in table I. Plasma concentrations of testosterone and dehydroepiandrosterone and its sulphate were measured before and after administration of H.c.G. (1500 i.u. every 2 days for 15 days) using a method published elsewhere." The results are given in table 11. Under basal conditions, patient 1 had levels similar to those in normal prepubertal boys and patient 2 had values comparable to those found at the onset of puberty. After H.C.G., both patients showed a sharp rise in plasma-testosterone. The response was three 1. Flavell, G. Br. J. Surg. 1943, 31, 150. 2. Steiker, D. D., Mellman, W. J., Bongiovanni, A. M., Eberlein, W. R., Leboeuf, G. J. Pediatrics, 1961, 58, 324. 3. Meller, R. H. ibid. 1965, 66, 48. 4. Grumbach, M. M., Morishima, A., Liu, N. Proc. Soc. pediat. Res.
1965, p. 63. Ferrier, P. E., Ferrier, S. A. Pediatrics, Springfield, 1967, 40, 575. Chaves-Carballo, E., Hayles, A. B. Proc. Staff Meet. Mayo Clin. 1966, 44, 843. 7. Noonan, J. A. Am. J. Dis. Child. 1968, 116, 373. 8. Dupuis, C., Nuyts, J. P., Maillard, E., Bouvier, C., Lefebvre, P., Fontaine, G., Gaudier, B. Archs fr. pediat. 1968, 25, 511. 9. Shoen, E. J. Clin. Endocr. 1965, 25, 101. 10. Gerbaux, A., de Gennes, J. L., Emerit, I., Milhaud, A., de Grouchy, J., Lenegre, J. Bull. Soc. Med. Hôp. Paris, 1965, 116, 445. 11. Saez, J. M., Bertrand, J. J. Steroids, 1968, 12, 749. 5. 6.
1079
four times greater than that in 16 normal prepubertal boys receiving the same dose of H.C.G., but was similar to that of pubertal boys. In patient 1, this response is rather surprising since unilateral testicular biopsy had indicated an infantile testis. However, these results strongly suggest that the testicular capacity to secrete androgens in both of these patients is normal or above normal and that virilisation will happen normally at puberty. Indeed, some 8 months after the completion of this study, patient 2 had clinical signs of the onset of puberty and at this stage his plasmatestosterone level was 350 ng. per 100 ml. to
I.N.S.E.R.M., Hôpital Debrousse, Lyon 5e, France.
J. M. SAEZ A. M. MORERA J. BERTRAND.
EFFECT OF NEPHRECTOMY ON BLOODTRANSFUSION REQUIREMENTS SIR,-Iam rather grateful for the response of Dr. Shaldon (Oct. 18, p. 849) to the article by Dr. van Ypersele de Strihou and M. Stragier (Oct. 4, p. 705). These workers seem to have had a rather shaky basis for their conclusions. It is impossible to relate transfusion incidence to red-cell production in an illness as complicated as uraemia and during therapy as potentially damaging to red-cells as is chronic dialysis. They may have been measuring unknown combinations of red-cell production, destruction, and dilution.
previous work 1,2 was misquoted. We conclusions concerning erythropoiesis in anephric man on plasma radio-iron clearance data. We studied marrow morphology, counted reticulocytes, and measured red-cell iron turnover before and after total nephrectomy. We also noted increased erythropoietic responses to anoxic stress in anephric patients. The point is that anephric men do maintain a basal level of erythropoiesis that equals that of severely ursemic individuals whose kidneys remain in situ. Furthermore,
did
not
base
our
our
Division of Hematology, Children’s Hospital Medical Center. Boston, Massachusetts.
DAVID G. NATHAN.
PARACERVICAL BLOCK
SiR,-Dr. Stern and his colleagues (Aug. 9, p. 322), describing the death of a newborn child following paracervical block in the mother, cite a letter3 in which I questioned the explanation that paracervical block had been responsible for deaths in similar cases. The case they report also seems doubtful. The level of mepivacaine in the infant’s serum at 3112 hours of age was 2-5 pg. per ml., and the authors infer that it was probably about 5 pg. per ml. at birth. It is difficult to accept that this blood-level was responsible for the serious clinical state of the child at birth, especially since the disorders persisted when the level had fallen by half. In cases of mepivacaine intoxication treated by exchange transfusion it has been shown that once blood-levels have fallen to about 8 p,g. per ml. convulsions cease and infants recover without further complications.5,4 Levels of 7-1-8-6 ug. per ml. in the umbilical artery have been found in infants with Apgar scores of 8, blood pH higher than 7-2, who have shown bradycardia in 1.
Nathan, D. G., Schupak, E., Stohlman, Jr., F., Merrill, J. P. J. clin. Invest. 1964, 43, 2158. 2. Nathan, D. G., Beck, L. H., Hampers, C. L., Merrill, J. P. Ann. N.Y. Acad. Sci. 1968, 149, 539. 3. Gomez, D. F. Lancet, 1969, i, 1163. 4. Finster, M., Poppers, P. J., Morishima, H. O., Daniel, S. S. Am. J. Obstet. Gynec. 1965, 92, 922. 5. O’Meara, O. P. New Engl. J. Med. 1968, 278, 1127.
utero.4 The clinical picture in the newborn proved that there had been serious brain damage, which could well have been caused by severe anoxia (whatever the cause), by spontaneous obstetric trauma, or by forceps (even if delivery was easily accomplished). If the anoxia had been caused by mepivacaine intoxication, the fetus would probably have shown signs of distress in utero, in the 4/2 hours between the last injection and birth. Although the responsibility of mepivacaine has not been established beyond doubt in the case reported by Dr. Stern and his colleagues, I am definitely against the use of a dose of 400 mg. in a woman in labour. It has been shown that doses in excess of 300 mg., especially when injected repeatedly into the epidural space or paracervical area, cause substantial amounts to reach the maternal blood and thus the fetal blood. The peak is achieved after 10-30 minutes, and then remains at relatively high levels for periods of time of over 250 minutes. 6,7 Should the child be born during the period in which the concentration is highest, the blood-level at birth will be high, and, because the child lacks a placenta as exchange organ and has insufficient enzymatic maturity to detoxify the drug, its chances of eliminating the drug are small. Also, if labour is protracted the fetus will be exposed to a sustained high concentration of drug, which may exceed the safety limit. I believe that paracervical block is safe provided that certain principles are adhered to.3 The prevention of overdose, and the choice of the drug, are of the utmost importance. Mepivacaine is probably not the drug of choice,8 Clinico Modelo, Department of Gynaecology and Obstetrics, DANIEL F. GOMEZ. Moron, Argentina.
CYCLAMATES SiR,-In view of the recent banning of cyclamates it would be of interest to the profession, and reassuring to the public, if the Secretary of Health in Washington who made the decision, or the Minister of Agriculture in Whitehall who followed suit, would spell out in detail the answers to two
questions:
1. What were the specific scientific criteria of the experiments done in animals, and the results obtained, which demanded a sudden and dramatic withdrawal of a synthetic compound which apparently has had no ill effects on consumers during the 15 years it has been in use ? 2. To what extent do this scientific evidence and the criteria on which it was based differ, both qualitatively and quantitatively, in applicability to other synthetic compounds taken regularly by healthy people for non-disease-related purposesfor example, the oral contraceptives ?
I ask these questions because I think the medical profession has the right to know the details, particularly in view of the widespread belief that pressures are being exerted by the sugar and fruit industry in the one instance, and by the pharmaceutical industry in the other. The fact that there are other products available for the same purposes makes the political overtones all the more disturbing. All three major medico-scientific journals in Britain carried leading articles expressing reservations about the scientific background and validity of the decision banning the cyclamates. You commented (Nov. 1, p. 941) that " very few details of the new American findings have been published. It seems certain, however, that the chief cause for the ban is the appearance of papillary carcinoma of the bladder in rats fed large doses of cyclamates." The British Medical Journal (Nov. 1, p. 251), while acknowledging the 6. Gordon, H. R. ibid. 1968, 279, 910. 7. Morishima, H. O., Daniels, S. S., Finster, James, L. S. Anesthesiology, 1966, 27, 147. 8. New Engl. J. Med. 1968, 279, 941.
M., Poppers, P. J.,
TESTICULAR ENDOCRINE FUNCTION IN MALES WITH NOOMAN’S SYNDROME SIR,-In the past few years there have been several reports concerning the Turner phenotype in the male (or Nooman’s syndrome).1-8 Cryptorchidism has very often been noted and testicular function has varied from less than normal to normal. Nevertheless, in most cases some degree of testicular deficiency has been recorded. Diminished androgen secretion has been suggested both in children9 and in adults 10 on the basis of the very slight rise in the urinary excretion of androsterone which follows the injection of human chorionic gonadotrophin (H.C.G.). TABLE I-CLINICAL FINDINGS IN TWO CHILDREN WITH SYNDROME
NOOMAN’S
IMMUNOGLOBULIN LEVELS IN IDIOPATHIC PULMONARY HÆMOSIDEROSIS SIR,-The bronchial mucosa contains a number of
plasma-cells which are capable of producing IgA immunoglobulins.12 The setiology of idiopathic pulmonary hsemosiderosis (I.P.H.) is not known.13 Steiner 14 has suggested an immunological basis for the disease, with the lung as the shock organ ". "
SERUM-IgA-IMMUNOGLOBULIN LEVELS
TABLE II-PLASMA ANDROGENS BEFORE AND AFTER H.C.G. IN TWO CHILDREN WITH NOOMAN’S SYNDROME
Increased globulin fractions have been reported in a high proportion of the few reported cases of I.P.H.15-18 Quantitative immunoelectrophoretic studies have been done in only one case." This patient was found to have IgA deficiency. We have repeatedly studied the serum-immunoglobulin levels in eleven children between the ages of 2 and 12 years with I.P.H., and have compared them with the levels in eleven healthy children of the same age. Raised IgA levels were found in all patients (see accompanying table). The levels of IgG and IgM were normal. An increase of plasma-cells in the reticuloendothelial system has been reported in r.P.H.2o,21 We wonder whether this increase of plasma cells is associated with the raised IgA levels in
this disease. N. MATSANIOTIS University Department of Pædiatrics, A. CONSTANTOPOULOS Saint Sophia’s Children’s Hospital, J. KARPOUZAS. Athens, Greece. Kurien, V. A., Yates, P. A., Oliver, M. F. Lancet, July 26, 1969, p. 185. 12. South, M. A., Warwick, W. J., Wollheim, F. A., Good, R. A. J. Pediatrics, Springfield, 1967, 71, 645. 13. Matsaniotis, N., Karpouzas, J., Apostolopoulou, E., Messaritakis, J. Archs Dis. Childh. 1968, 43, 307. 14. Steiner, B. ibid. 1954, 29, 391. 15. Skogrand, A., Myhre, E. Acta path. microbiol. scand. 1957, 40, 96. 16. Curewich, V., Thomas, M. A. New Engl. J. Med. 1959, 261, 1154. 17. Ognibene, A. J., Johnson, D. E. Archs intern Med. 1963, 111, 503. 18. Marty, J., Roux, M., Lagarde, C., Nicholas, J., Mollaret, N. Presse méd. 1957, 65, 1959. 19. Krieger, I., Brough, J. A. New Engl. J. Med. 1967, 276, 886. 20. Gluck, E. Acta path. microbiol. scand. 1959, 37, 241. 21. Campbell, S., Macaffee, C. A. J. Archs Dis. Childh. 1959, 34, 218. 11.
However, to our knowledge, plasma levels of testosterone have not been reported in males with this syndrome. We present our results for the plasma-androgens in two affected children. Clinical findings are summarised in table I. Plasma concentrations of testosterone and dehydroepiandrosterone and its sulphate were measured before and after administration of H.c.G. (1500 i.u. every 2 days for 15 days) using a method published elsewhere." The results are given in table 11. Under basal conditions, patient 1 had levels similar to those in normal prepubertal boys and patient 2 had values comparable to those found at the onset of puberty. After H.C.G., both patients showed a sharp rise in plasma-testosterone. The response was three 1. Flavell, G. Br. J. Surg. 1943, 31, 150. 2. Steiker, D. D., Mellman, W. J., Bongiovanni, A. M., Eberlein, W. R., Leboeuf, G. J. Pediatrics, 1961, 58, 324. 3. Meller, R. H. ibid. 1965, 66, 48. 4. Grumbach, M. M., Morishima, A., Liu, N. Proc. Soc. pediat. Res.
1965, p. 63. Ferrier, P. E., Ferrier, S. A. Pediatrics, Springfield, 1967, 40, 575. Chaves-Carballo, E., Hayles, A. B. Proc. Staff Meet. Mayo Clin. 1966, 44, 843. 7. Noonan, J. A. Am. J. Dis. Child. 1968, 116, 373. 8. Dupuis, C., Nuyts, J. P., Maillard, E., Bouvier, C., Lefebvre, P., Fontaine, G., Gaudier, B. Archs fr. pediat. 1968, 25, 511. 9. Shoen, E. J. Clin. Endocr. 1965, 25, 101. 10. Gerbaux, A., de Gennes, J. L., Emerit, I., Milhaud, A., de Grouchy, J., Lenegre, J. Bull. Soc. Med. Hôp. Paris, 1965, 116, 445. 11. Saez, J. M., Bertrand, J. J. Steroids, 1968, 12, 749. 5. 6.
1079
four times greater than that in 16 normal prepubertal boys receiving the same dose of H.C.G., but was similar to that of pubertal boys. In patient 1, this response is rather surprising since unilateral testicular biopsy had indicated an infantile testis. However, these results strongly suggest that the testicular capacity to secrete androgens in both of these patients is normal or above normal and that virilisation will happen normally at puberty. Indeed, some 8 months after the completion of this study, patient 2 had clinical signs of the onset of puberty and at this stage his plasmatestosterone level was 350 ng. per 100 ml. to
I.N.S.E.R.M., Hôpital Debrousse, Lyon 5e, France.
J. M. SAEZ A. M. MORERA J. BERTRAND.
EFFECT OF NEPHRECTOMY ON BLOODTRANSFUSION REQUIREMENTS SIR,-Iam rather grateful for the response of Dr. Shaldon (Oct. 18, p. 849) to the article by Dr. van Ypersele de Strihou and M. Stragier (Oct. 4, p. 705). These workers seem to have had a rather shaky basis for their conclusions. It is impossible to relate transfusion incidence to red-cell production in an illness as complicated as uraemia and during therapy as potentially damaging to red-cells as is chronic dialysis. They may have been measuring unknown combinations of red-cell production, destruction, and dilution.
previous work 1,2 was misquoted. We conclusions concerning erythropoiesis in anephric man on plasma radio-iron clearance data. We studied marrow morphology, counted reticulocytes, and measured red-cell iron turnover before and after total nephrectomy. We also noted increased erythropoietic responses to anoxic stress in anephric patients. The point is that anephric men do maintain a basal level of erythropoiesis that equals that of severely ursemic individuals whose kidneys remain in situ. Furthermore,
did
not
base
our
our
Division of Hematology, Children’s Hospital Medical Center. Boston, Massachusetts.
DAVID G. NATHAN.
PARACERVICAL BLOCK
SiR,-Dr. Stern and his colleagues (Aug. 9, p. 322), describing the death of a newborn child following paracervical block in the mother, cite a letter3 in which I questioned the explanation that paracervical block had been responsible for deaths in similar cases. The case they report also seems doubtful. The level of mepivacaine in the infant’s serum at 3112 hours of age was 2-5 pg. per ml., and the authors infer that it was probably about 5 pg. per ml. at birth. It is difficult to accept that this blood-level was responsible for the serious clinical state of the child at birth, especially since the disorders persisted when the level had fallen by half. In cases of mepivacaine intoxication treated by exchange transfusion it has been shown that once blood-levels have fallen to about 8 p,g. per ml. convulsions cease and infants recover without further complications.5,4 Levels of 7-1-8-6 ug. per ml. in the umbilical artery have been found in infants with Apgar scores of 8, blood pH higher than 7-2, who have shown bradycardia in 1.
Nathan, D. G., Schupak, E., Stohlman, Jr., F., Merrill, J. P. J. clin. Invest. 1964, 43, 2158. 2. Nathan, D. G., Beck, L. H., Hampers, C. L., Merrill, J. P. Ann. N.Y. Acad. Sci. 1968, 149, 539. 3. Gomez, D. F. Lancet, 1969, i, 1163. 4. Finster, M., Poppers, P. J., Morishima, H. O., Daniel, S. S. Am. J. Obstet. Gynec. 1965, 92, 922. 5. O’Meara, O. P. New Engl. J. Med. 1968, 278, 1127.
utero.4 The clinical picture in the newborn proved that there had been serious brain damage, which could well have been caused by severe anoxia (whatever the cause), by spontaneous obstetric trauma, or by forceps (even if delivery was easily accomplished). If the anoxia had been caused by mepivacaine intoxication, the fetus would probably have shown signs of distress in utero, in the 4/2 hours between the last injection and birth. Although the responsibility of mepivacaine has not been established beyond doubt in the case reported by Dr. Stern and his colleagues, I am definitely against the use of a dose of 400 mg. in a woman in labour. It has been shown that doses in excess of 300 mg., especially when injected repeatedly into the epidural space or paracervical area, cause substantial amounts to reach the maternal blood and thus the fetal blood. The peak is achieved after 10-30 minutes, and then remains at relatively high levels for periods of time of over 250 minutes. 6,7 Should the child be born during the period in which the concentration is highest, the blood-level at birth will be high, and, because the child lacks a placenta as exchange organ and has insufficient enzymatic maturity to detoxify the drug, its chances of eliminating the drug are small. Also, if labour is protracted the fetus will be exposed to a sustained high concentration of drug, which may exceed the safety limit. I believe that paracervical block is safe provided that certain principles are adhered to.3 The prevention of overdose, and the choice of the drug, are of the utmost importance. Mepivacaine is probably not the drug of choice,8 Clinico Modelo, Department of Gynaecology and Obstetrics, DANIEL F. GOMEZ. Moron, Argentina.
CYCLAMATES SiR,-In view of the recent banning of cyclamates it would be of interest to the profession, and reassuring to the public, if the Secretary of Health in Washington who made the decision, or the Minister of Agriculture in Whitehall who followed suit, would spell out in detail the answers to two
questions:
1. What were the specific scientific criteria of the experiments done in animals, and the results obtained, which demanded a sudden and dramatic withdrawal of a synthetic compound which apparently has had no ill effects on consumers during the 15 years it has been in use ? 2. To what extent do this scientific evidence and the criteria on which it was based differ, both qualitatively and quantitatively, in applicability to other synthetic compounds taken regularly by healthy people for non-disease-related purposesfor example, the oral contraceptives ?
I ask these questions because I think the medical profession has the right to know the details, particularly in view of the widespread belief that pressures are being exerted by the sugar and fruit industry in the one instance, and by the pharmaceutical industry in the other. The fact that there are other products available for the same purposes makes the political overtones all the more disturbing. All three major medico-scientific journals in Britain carried leading articles expressing reservations about the scientific background and validity of the decision banning the cyclamates. You commented (Nov. 1, p. 941) that " very few details of the new American findings have been published. It seems certain, however, that the chief cause for the ban is the appearance of papillary carcinoma of the bladder in rats fed large doses of cyclamates." The British Medical Journal (Nov. 1, p. 251), while acknowledging the 6. Gordon, H. R. ibid. 1968, 279, 910. 7. Morishima, H. O., Daniels, S. S., Finster, James, L. S. Anesthesiology, 1966, 27, 147. 8. New Engl. J. Med. 1968, 279, 941.
M., Poppers, P. J.,