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ORAL CONTRACEPTIVES AND SERUM-LIPIDS
1314 resemble Farber’s diseasein which there is also abnormal storage of a M.p.s. lipid complex, but which is differentiated by the additional findings of gliosis and granuloma formation. Excess of ht.P.s.s and lipids in the viscera was found in three patients with metachromatic leucodystrophy with some of the features of gargoylism (granules in the lymphocytes and skele. tal deformities),23but excess sulphatide in urine and peripheral nerve in particular distinguished them from our patients. We wish to thank Prof. H. G. Hers for
ele’ctron-microscopic
studies, Prof. G. Astaldi and Prof. E. Bertolotti for help in histochemical research, and Dr. E. Rampini and Dr. F. Crovato for histochemical studies on skin biopsies. P. DURAND Third Department of Pædiatrics, G. Gaslini Institute, Genoa 4, Italy.
showing
many cytoplasmic and Fig. 4-Liver biopsy-specimen intravacuolar lipid inclusions (lamellar bodies). (Reduced to about a third from x 29,000.)
abundant mucus, but the duodenal enzymes were normal. Excess amount of an acid-mucoid, unidentified, abnormal material which was not M.P.s. was present in urinary sediment. The acid-M.p.s. content of urine samples was always within normal limits. Sulphatide excretion in the urine was normal. Histochemical study at skin biopsy showed a diffuse connectivetissue abnormality, and anomalous accumulation of deposits of homogeneous, eosinophil, picrophil, M.p.s. material between dermis and epidermis. Liver biopsy showed hepatic cells constored substance, producing the clear, swollen taining abundant " " " appearance of balloon " or pseudo-gargoyle cells (fig. 2). No metachromatic lipids were found in frozen section at suralnerve biopsy. Electron-microscopic examination showed round or oval vacuoles of different sizes, surrounded by a single membrane, containing inclusions, as in gargoylism (fig. 3), and many cytoplasmic and intravacuolar lipid inclusions (lamellar bodies) (fig. 4). In mitochondria, which had an abnormal appearance, abnormal laminated bodies were also present. Although precise chemical identification of the deposited material is not possible with histochemical techniques available at present, a general idea of its composition has been obtained. Electron-microscopy showed that the deposits could consist of a mixture of M.p.s.s and lipids. The clinical, microscopic, and histochemical studies suggest that the disease of these two patients is a specific entity-a familial, severe, progressive metabolic disease, with autosomal recessive mode of transmission, in which there is neurovisceral and cutaneous accumulation of a M.p.s./lipid complex. Most signs and symptoms of our patients can be related to the abnormal deposits in various organs. The thick skin and the sweat-electrolyte abnormality may be due to M.p.s. deposits between dermis and epidermis, and M.p.s.s and lipids were found filling peripheral-blood lymphocytes, and in the liver. It is probable that there may be deposits within the central nervous system, sublingual glands, and myocardial fibres. These deposits result in the clinical picture of severe progressive cerebral degeneration, enlarged salivary glands, and cardiomegaly with signs of myocardial disease. Bronchial epithelium may be involved, which may lead to diminished respiratory function. Involvement of the duodenojejunal mucosa, skeletal muscle, and renal tissue is also probable. Further chemical analyses will undoubtedly lead to better understanding of this condition, which is different from the lipid-storage diseases (Niemann-Pick, Tay-Sachs, Gaucher’s, and Fabry’s), the mucopolysaccharidoses (chondroitin-sulphateB/heparitin-sulphate [C.S.B/H.S.]/M.P.S. types of Hurler, and of Hunter, H.S./M.P.S. type of Sanfilippo, C.S.B/M.P.S. type of Maroteaux and Lamy, K.S./M.P.S. type of Morquio-Brailsford, Scheie type, and Dyggve type), gangliosidosis, sulphatidosis, and glycogen-storage disease types 11 (generalised glycogenstorase
disease) and
VIII.
The disease of
our
patients
mav
C. BORRONE G. DELLA CELLA,
ORAL CONTRACEPTIVES AND SERUM-LIPIDS SIR,-We read with great interest the articles by Dr. Wynn and his co-workers (Oct. 1, pp. 715, 720) on the metabolic effects of oral contraceptives. Their findings are in accordance with our observationswhich indicated that during administration ofanovlar ’(ethinyl oestradiol 0-05 mg., norethisterone acetate 4-0 mg.) serum lipids and lipoproteins in young women changed towards patterns seen in men and postmeno-
pausal
women.
Wynn and his co-workers drew attention to the importquestion of reversibility of the lipid changes observed during administration of oral contraceptives. This prompts us to give here the results in the 8 women we reported who were reinvestigated 24 months after the administration of anovlar had been started (see accompanying figure), by the same Dr.
ant
Serum-triglycerides and L.D.L.-triglycerides before, during, and after administration of anovlar.
Arrow points to subject who had stopped administration only month before this investigation. Solid lines =administration continued; broken lines =administration discontinued. mM/L= mmoles per litre. 1
analytical methods. In the past 12 months 4 women discontinued the drug (broken lines in the figure) while 4 subjects continued to take it regularly (solid lines). The difference in reaction of serum-triglycerides and serum-low-density-lipoprotein (L.D.L.)-triglycerides between these two small groups seems to indicate that the lipid changes are reversible, at least after shorter-term administration (1-2 years). The return to preadministration serum level of cholesterol, phospholipids, and L.D.L. protein was less consistent than that of triglycerides, 1. 2.
Abdul-Haj, S. K., Martz, D. G., Douglas, W. F., Geppert, L. J. J. Pediat. 1962, 61, 221. Austin, J. H. in Brain Lipids and Lipoproteins and the Leukodystrophies (edited by J. Folch-Pi and H. J. Bauer); p. 120. Amsterdam, 1963.
Moser, H. W., Lees, M. in The Metabolic Basis of Inherited Disease (edited by J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson); p. 549. London, 1966. 4. Aurell, M., Cramér, K., Rybo, G. Lancet, 1966, i, 291. 3.
1315 but this might be attributed to the fact that the group of those who discontinued anovlar consisted of 1 woman who had discontinued it for 12 months, one (indicated by arrow in figure) who had discontinued it for 1 month, and two who had discontinued it for 6 months before this investigation. Inspection of the results in the group who continued the medication revealed that the serum-lipids and lipoproteins remained at the level attained after 12 months of administration. Medical Service I,
Sahlgrenska Sjukhuset,
M. AURELL K. CRAMÉR.
Gothenburg SV, Sweden.
LEGALISING ABORTION his letter SIR,-In (Nov. 26, p. 1186) Dr. Sim refers to the Royal Medico-Psychological Association’s memorandum on therapeutic abortion. This memorandum was prepared by a special committee set up by the council of the Association under the chairmanship of the president, and the memorandum was submitted to, and approved by, the council in June, 1966. The special committee’s recommendations were based on the knowledge and experience of a group of senior psychiatrists who, during the course of their deliberations, considered many expert views and publications, including those submitted to them by Dr. Sim. The memorandum was published in the British Journal of Psychiatry, which is received by the 3300 members of the Royal Medico-Psychological Association, and Dr. Sim’s has been the only dissentient voice. One must therefore conclude that most of the membership does not disagree with the recommendations contained in the memorandum. Chandos House, Queen Anne Street, London, W.1.
SIR,-Dr. Sim
WILLIAM SARGANT Chairman, Public Relations Committee, The Royal Medico-Psychological Association.
is the lack of scientific evidence on which the reformers base their case and their casual rejection of the substantial evidence from various sources which suggest that therapeutic abortion should be a rare event." This is a surprising statement. The most comprehensive follow-up study on therapeutic abortionshowed that 3 years later 75% of the women were well and contented with the operation, while only 11 % expressed serious regrets or selfreproach--of these the author remarks, " It is probable they would have developed equally severe symptoms of insufficiency even if they had not been granted legal abortion." An oftenquoted study from Switzerland2 is almost alone in finding a little over half the women with some regrets or conflicts 2-3 years later, though these were generally mild or transitory, and in several instances appeared to be related to sterilisation, which was performed in 51 of the 61 women, rather than to the abortion itself. Admission to a mental hospital after abortion is rare-the rate is less than 2% within 1 year.3 The same conclusion holds for illegal abortion.4 Seeing that tens of thousands of women are said to undergo illegal abortion annually in this country, one might have expected, if abortion were mentally harmful, to find many of them attending psychiatric clinics, when not occupying gynxcological beds, as a result of their experience; but this seems not to be so. In so far as women whose pregnancies are terminated on psychiatric grounds (and also many of those aborted illegally 5) must be psychiatrically ill at the time, these results provide prima-facie evidence of the efficacy of this method of treatment. Since, moreover, a large part of the so-called sequelas occur in patients with chronic personality disorders or neuroses(which abortion cannot be expected to cure, and 1 2. 3. 4.
states:
"My main
only alleviate), therapeutic abortion may be considered to be about as successful a form of treatment as could be hoped for, and it would be hard to find better results in any other definable psychiatric group. In stable women the outcome can hardly be described as other than excellent. The crucial question is whether the prognosis is as good without abortion. Long-term studies in refused cases are scanty; but two very thorough ones show that both mothers6 and childrenrun substantial hazards. In necropsies on suicides in Sweden it was found that, in the period before the reform of the law, 11-12% of suicides among women of childbearing age occurred during pregnancy.88 Dr. Sim’s 9 own work, from which he concluded that no psychiatric indications for abortion exist, concerned psychosis; but, since psychosis is rarely the issue, his findings are only of marginal relevance-and in the case of schizophrenia they have not been confirmed.lo If abortion is to be judged on the evidence, then the obligation appears to rest on Dr. Sim to show that other treatments are better, or carry less risk, or by impartial studies to help define the indications. From work abroad, a picture is beginning to emerge of those factors which affect the outcome; they include the personality, parity, age, and civil state of the mother, her previous illnesses and current symptomatology, the dependability of the father of the child, and pressure from relatives.136 These criteria are being used as a guide to the best therapeutic approach, which may be psychiatric treatment or social support without abortion, abortion with contraceptive advice, abortion with sterilisation, or sterilisation after the birth of the child.11 It would be tragic if this hard-won knowledge were to be lost to this country and replaced by an attitude that insists that all that is worth knowing about the subject is already known. can
University Department of Psychological Medicine, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne 1.
D. W. K. KAY.
concern
Ekblad, M. Acta psychiat. neurol. scand. 1955, suppl. 99. Siegfried, S. Schweizer Arch. Neurol. Psychiat. 1951, 67, 365. Jansson, B. Acta psychiat. scand. 1965, 41, 87. Gebhard, P. H., Pomeroy, W. B., Martin, C. E., Christenson, C. V. Pregnancy, Birth and Abortion; p. 205. London, 1959. 5. Freundt, L. Acta psychiat. scand. 1964, 40, 235.
SIR,-Whereas it
seems
that
most
psychiatrists would dis-
agree with the extreme views of Dr. Sim on the question of termination of pregnancy, he is surely right at this stage in
calling for
a Royal Commission to collect and assess the facts. For much confusion arises from too much emotion, and too few real facts and controlled assessments. Certainly the problem is more complicated than the speeches and letters of doctors and politicians seem to suggest. One group of young women who illustrate this point are those who believe that they have produced an illicit cyesis and as a result of pressure from society, family, " friends ", and their own moral conscience demand a termination, believing that this will put everything right. On close questioning it is often obvious that most of these women are deeply motivated towards having a successful pregnancy. They want the baby, firstly, as part of their maturing process, secondly as a way of reinforcing the relationship with the man, and, thirdly, as a way of asserting their own independence. This is confirmed by the fact that most of these women give a history of regular sexual intercourse over a period with a boy-friend without either taking any contraceptive measures. These cases therefore should not be terminated, since there is a greater threat to health-e.g., from a severe depressive reaction following a termination-than if the pregnancy is allowed to proceed
normally. It has been suggested that a termination is advisable for such women, so that they will be more amenable to psychiatric treatment later, but in fact these women are more likely to be further depressed as a result of their loss and accompanying severe guilt feelings. Two recent cases illustrate this. 6. 7. 8. 9. 10. 11.
Hook, K. ibid. 1963, suppl. 168. Forssman, H., Thuwe, I. ibid. 1966, 42, 71. Bengtsson, L. Svensk. Läkartidn. 1947, 44, 1469. Sim, M. Br. med. J. 1963, ii, 145. Yarden, P. E., Max, D. M., Eisenbach, Z. Br. J. Psychiat. 1966, 112, 491. Baird, D. Br. med. J. 1965, ii, 1141.
ele’ctron-microscopic
studies, Prof. G. Astaldi and Prof. E. Bertolotti for help in histochemical research, and Dr. E. Rampini and Dr. F. Crovato for histochemical studies on skin biopsies. P. DURAND Third Department of Pædiatrics, G. Gaslini Institute, Genoa 4, Italy.
showing
many cytoplasmic and Fig. 4-Liver biopsy-specimen intravacuolar lipid inclusions (lamellar bodies). (Reduced to about a third from x 29,000.)
abundant mucus, but the duodenal enzymes were normal. Excess amount of an acid-mucoid, unidentified, abnormal material which was not M.P.s. was present in urinary sediment. The acid-M.p.s. content of urine samples was always within normal limits. Sulphatide excretion in the urine was normal. Histochemical study at skin biopsy showed a diffuse connectivetissue abnormality, and anomalous accumulation of deposits of homogeneous, eosinophil, picrophil, M.p.s. material between dermis and epidermis. Liver biopsy showed hepatic cells constored substance, producing the clear, swollen taining abundant " " " appearance of balloon " or pseudo-gargoyle cells (fig. 2). No metachromatic lipids were found in frozen section at suralnerve biopsy. Electron-microscopic examination showed round or oval vacuoles of different sizes, surrounded by a single membrane, containing inclusions, as in gargoylism (fig. 3), and many cytoplasmic and intravacuolar lipid inclusions (lamellar bodies) (fig. 4). In mitochondria, which had an abnormal appearance, abnormal laminated bodies were also present. Although precise chemical identification of the deposited material is not possible with histochemical techniques available at present, a general idea of its composition has been obtained. Electron-microscopy showed that the deposits could consist of a mixture of M.p.s.s and lipids. The clinical, microscopic, and histochemical studies suggest that the disease of these two patients is a specific entity-a familial, severe, progressive metabolic disease, with autosomal recessive mode of transmission, in which there is neurovisceral and cutaneous accumulation of a M.p.s./lipid complex. Most signs and symptoms of our patients can be related to the abnormal deposits in various organs. The thick skin and the sweat-electrolyte abnormality may be due to M.p.s. deposits between dermis and epidermis, and M.p.s.s and lipids were found filling peripheral-blood lymphocytes, and in the liver. It is probable that there may be deposits within the central nervous system, sublingual glands, and myocardial fibres. These deposits result in the clinical picture of severe progressive cerebral degeneration, enlarged salivary glands, and cardiomegaly with signs of myocardial disease. Bronchial epithelium may be involved, which may lead to diminished respiratory function. Involvement of the duodenojejunal mucosa, skeletal muscle, and renal tissue is also probable. Further chemical analyses will undoubtedly lead to better understanding of this condition, which is different from the lipid-storage diseases (Niemann-Pick, Tay-Sachs, Gaucher’s, and Fabry’s), the mucopolysaccharidoses (chondroitin-sulphateB/heparitin-sulphate [C.S.B/H.S.]/M.P.S. types of Hurler, and of Hunter, H.S./M.P.S. type of Sanfilippo, C.S.B/M.P.S. type of Maroteaux and Lamy, K.S./M.P.S. type of Morquio-Brailsford, Scheie type, and Dyggve type), gangliosidosis, sulphatidosis, and glycogen-storage disease types 11 (generalised glycogenstorase
disease) and
VIII.
The disease of
our
patients
mav
C. BORRONE G. DELLA CELLA,
ORAL CONTRACEPTIVES AND SERUM-LIPIDS SIR,-We read with great interest the articles by Dr. Wynn and his co-workers (Oct. 1, pp. 715, 720) on the metabolic effects of oral contraceptives. Their findings are in accordance with our observationswhich indicated that during administration ofanovlar ’(ethinyl oestradiol 0-05 mg., norethisterone acetate 4-0 mg.) serum lipids and lipoproteins in young women changed towards patterns seen in men and postmeno-
pausal
women.
Wynn and his co-workers drew attention to the importquestion of reversibility of the lipid changes observed during administration of oral contraceptives. This prompts us to give here the results in the 8 women we reported who were reinvestigated 24 months after the administration of anovlar had been started (see accompanying figure), by the same Dr.
ant
Serum-triglycerides and L.D.L.-triglycerides before, during, and after administration of anovlar.
Arrow points to subject who had stopped administration only month before this investigation. Solid lines =administration continued; broken lines =administration discontinued. mM/L= mmoles per litre. 1
analytical methods. In the past 12 months 4 women discontinued the drug (broken lines in the figure) while 4 subjects continued to take it regularly (solid lines). The difference in reaction of serum-triglycerides and serum-low-density-lipoprotein (L.D.L.)-triglycerides between these two small groups seems to indicate that the lipid changes are reversible, at least after shorter-term administration (1-2 years). The return to preadministration serum level of cholesterol, phospholipids, and L.D.L. protein was less consistent than that of triglycerides, 1. 2.
Abdul-Haj, S. K., Martz, D. G., Douglas, W. F., Geppert, L. J. J. Pediat. 1962, 61, 221. Austin, J. H. in Brain Lipids and Lipoproteins and the Leukodystrophies (edited by J. Folch-Pi and H. J. Bauer); p. 120. Amsterdam, 1963.
Moser, H. W., Lees, M. in The Metabolic Basis of Inherited Disease (edited by J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson); p. 549. London, 1966. 4. Aurell, M., Cramér, K., Rybo, G. Lancet, 1966, i, 291. 3.
1315 but this might be attributed to the fact that the group of those who discontinued anovlar consisted of 1 woman who had discontinued it for 12 months, one (indicated by arrow in figure) who had discontinued it for 1 month, and two who had discontinued it for 6 months before this investigation. Inspection of the results in the group who continued the medication revealed that the serum-lipids and lipoproteins remained at the level attained after 12 months of administration. Medical Service I,
Sahlgrenska Sjukhuset,
M. AURELL K. CRAMÉR.
Gothenburg SV, Sweden.
LEGALISING ABORTION his letter SIR,-In (Nov. 26, p. 1186) Dr. Sim refers to the Royal Medico-Psychological Association’s memorandum on therapeutic abortion. This memorandum was prepared by a special committee set up by the council of the Association under the chairmanship of the president, and the memorandum was submitted to, and approved by, the council in June, 1966. The special committee’s recommendations were based on the knowledge and experience of a group of senior psychiatrists who, during the course of their deliberations, considered many expert views and publications, including those submitted to them by Dr. Sim. The memorandum was published in the British Journal of Psychiatry, which is received by the 3300 members of the Royal Medico-Psychological Association, and Dr. Sim’s has been the only dissentient voice. One must therefore conclude that most of the membership does not disagree with the recommendations contained in the memorandum. Chandos House, Queen Anne Street, London, W.1.
SIR,-Dr. Sim
WILLIAM SARGANT Chairman, Public Relations Committee, The Royal Medico-Psychological Association.
is the lack of scientific evidence on which the reformers base their case and their casual rejection of the substantial evidence from various sources which suggest that therapeutic abortion should be a rare event." This is a surprising statement. The most comprehensive follow-up study on therapeutic abortionshowed that 3 years later 75% of the women were well and contented with the operation, while only 11 % expressed serious regrets or selfreproach--of these the author remarks, " It is probable they would have developed equally severe symptoms of insufficiency even if they had not been granted legal abortion." An oftenquoted study from Switzerland2 is almost alone in finding a little over half the women with some regrets or conflicts 2-3 years later, though these were generally mild or transitory, and in several instances appeared to be related to sterilisation, which was performed in 51 of the 61 women, rather than to the abortion itself. Admission to a mental hospital after abortion is rare-the rate is less than 2% within 1 year.3 The same conclusion holds for illegal abortion.4 Seeing that tens of thousands of women are said to undergo illegal abortion annually in this country, one might have expected, if abortion were mentally harmful, to find many of them attending psychiatric clinics, when not occupying gynxcological beds, as a result of their experience; but this seems not to be so. In so far as women whose pregnancies are terminated on psychiatric grounds (and also many of those aborted illegally 5) must be psychiatrically ill at the time, these results provide prima-facie evidence of the efficacy of this method of treatment. Since, moreover, a large part of the so-called sequelas occur in patients with chronic personality disorders or neuroses(which abortion cannot be expected to cure, and 1 2. 3. 4.
states:
"My main
only alleviate), therapeutic abortion may be considered to be about as successful a form of treatment as could be hoped for, and it would be hard to find better results in any other definable psychiatric group. In stable women the outcome can hardly be described as other than excellent. The crucial question is whether the prognosis is as good without abortion. Long-term studies in refused cases are scanty; but two very thorough ones show that both mothers6 and childrenrun substantial hazards. In necropsies on suicides in Sweden it was found that, in the period before the reform of the law, 11-12% of suicides among women of childbearing age occurred during pregnancy.88 Dr. Sim’s 9 own work, from which he concluded that no psychiatric indications for abortion exist, concerned psychosis; but, since psychosis is rarely the issue, his findings are only of marginal relevance-and in the case of schizophrenia they have not been confirmed.lo If abortion is to be judged on the evidence, then the obligation appears to rest on Dr. Sim to show that other treatments are better, or carry less risk, or by impartial studies to help define the indications. From work abroad, a picture is beginning to emerge of those factors which affect the outcome; they include the personality, parity, age, and civil state of the mother, her previous illnesses and current symptomatology, the dependability of the father of the child, and pressure from relatives.136 These criteria are being used as a guide to the best therapeutic approach, which may be psychiatric treatment or social support without abortion, abortion with contraceptive advice, abortion with sterilisation, or sterilisation after the birth of the child.11 It would be tragic if this hard-won knowledge were to be lost to this country and replaced by an attitude that insists that all that is worth knowing about the subject is already known. can
University Department of Psychological Medicine, Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne 1.
D. W. K. KAY.
concern
Ekblad, M. Acta psychiat. neurol. scand. 1955, suppl. 99. Siegfried, S. Schweizer Arch. Neurol. Psychiat. 1951, 67, 365. Jansson, B. Acta psychiat. scand. 1965, 41, 87. Gebhard, P. H., Pomeroy, W. B., Martin, C. E., Christenson, C. V. Pregnancy, Birth and Abortion; p. 205. London, 1959. 5. Freundt, L. Acta psychiat. scand. 1964, 40, 235.
SIR,-Whereas it
seems
that
most
psychiatrists would dis-
agree with the extreme views of Dr. Sim on the question of termination of pregnancy, he is surely right at this stage in
calling for
a Royal Commission to collect and assess the facts. For much confusion arises from too much emotion, and too few real facts and controlled assessments. Certainly the problem is more complicated than the speeches and letters of doctors and politicians seem to suggest. One group of young women who illustrate this point are those who believe that they have produced an illicit cyesis and as a result of pressure from society, family, " friends ", and their own moral conscience demand a termination, believing that this will put everything right. On close questioning it is often obvious that most of these women are deeply motivated towards having a successful pregnancy. They want the baby, firstly, as part of their maturing process, secondly as a way of reinforcing the relationship with the man, and, thirdly, as a way of asserting their own independence. This is confirmed by the fact that most of these women give a history of regular sexual intercourse over a period with a boy-friend without either taking any contraceptive measures. These cases therefore should not be terminated, since there is a greater threat to health-e.g., from a severe depressive reaction following a termination-than if the pregnancy is allowed to proceed
normally. It has been suggested that a termination is advisable for such women, so that they will be more amenable to psychiatric treatment later, but in fact these women are more likely to be further depressed as a result of their loss and accompanying severe guilt feelings. Two recent cases illustrate this. 6. 7. 8. 9. 10. 11.
Hook, K. ibid. 1963, suppl. 168. Forssman, H., Thuwe, I. ibid. 1966, 42, 71. Bengtsson, L. Svensk. Läkartidn. 1947, 44, 1469. Sim, M. Br. med. J. 1963, ii, 145. Yarden, P. E., Max, D. M., Eisenbach, Z. Br. J. Psychiat. 1966, 112, 491. Baird, D. Br. med. J. 1965, ii, 1141.