- Email: [email protected]
No regrets
1188
numbers of individuals, but several factors suggest strongly that insulin receptor mutations are not of great importance in this type of diabetes. First, there is little evidence for heritable defects in receptor function in NIDDM. Insulin-binding affinity appears normal, and receptor number is modulated only as an apparently reversible consequence of hyperinsulinaemia.17 Mild impairment of receptor tyrosine kinase activity in NIDDM and obesityll,18 may be an acquired defect reflecting regulation by other hormones. Second, it is not certain that all insulin-regulated processes in NIDDM show the uniformity of resistance to insulin that would be expected as a consequence of a primary defect in the receptor.19 Lack of uniformity in this regard would be compatible with defects distal to the receptor in signalling pathways. Third, individuals with even moderately severe insulin resistance due to receptor mutations do not necessarily display hyperglycaemia. 15 Their insulin resistance may be compensated by hyperinsulinaemia without development of diabetes. It appears that additional factors acting to intensify insulin resistance or impair insulin secretion would be required to cause diabetes. Fourth, the best available estimate of the frequency of mutant receptor alleles in the population (although for various reasons this could be an underestimate) suggests that as few as 1% of individuals who will get NIDDM might have an important mutation.15 Finally, in a few insulin resistant or diabetic Pima Indians who have been examined, the receptor sequence is normal.20,21 Thus it seems that receptor mutations may at best occur in only a small subset of cases of NIDDM, and then only as one of several factors contributing to the aetiology of the disease.
1. DeFronzo RA. The triumvirate: &bgr;-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988; 37: 667-87. 2. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-607. 3. Taylor R. Aetiology of non-insulin dependent diabetes. Br Med Bull 1989; 45: 73-91. 4. Czech MP. The nature and regulation of the insulin receptor: structure and function. Ann Rev Physiol 1985; 47: 357-81. 5. Goldfine ID. The insulin receptor: molecular biology and transmembrane signalling. Endocr Rev 1987; 8: 235-55. 6. Zick Y. The insulin receptor: structure and function. Crit Rev Biochem Mol Biol 1989; 24: 217-69. 7. Rosen OM. After insulin binds. Science 1987; 237: 1452-58. 8. Housley MD, Siddle K. Molecular basis of insulin receptor function. Br Med Bull 1989; 45: 264-84. 9. Goldstein JL, Brown MS, Anderson RGW, Russell DW, Schneider WJ. Receptor mediated endocytosis: concepts emerging from the LDL receptor system. Annu Rev Cell Biol 1985; 1: 1-39. 10. Taylor SI. Receptor defects in patients with extreme insulin resistance. Diabetes Metab Rev 1985; 1: 171-202. 11. Reddy SSK, Kahn CR. Insulin resistance: a look at the role of insulin receptor kinase. Diabetic Med 1988; 5: 621-29. 12. Atkinson AB, Kennedy L, Andrews WJ, et al. Diverse endocrine presentations of the syndrome of acanthosis nigricans and insulin resistance. J R Coll Physicians Lond 1989; 23: 165-69. 13. Flier JS, Eastman RC, Minaker KL, Matteson D, Rowe JW. Acanthosis nigricans in obese women with hyperandrogenism: characterization of an insulin-resistance state distinct from the type A and B syndromes. Diabetes 1985; 34: 101-07. 14. Seino S, Seino M, Bell GI. Human insulin-receptor gene. Diabetes 1990; 39: 129-33.
15.
Taylor SI, Kadowaki T, Kadowaki H, Accili D, Cama A, McKeon C. Mutations in insulin receptor gene in insulin-resistant patients.
Diabetes Care 1990; 13: 257-79. 16. Taira M, Taira M, Hashimoto N, et al. Human diabetes associated with a deletion of the tyrosine kinase domain of the insulin receptor. Science 1989; 245: 63-66. 17. Flier JS. Insulin receptors and insulin resistance. Annu Rev Med 1983; 34: 145-60. 18. Haring H, Obermaier-Kusser B. Insulin receptor kinase defects in insulin-resistant tissues and their role in the pathogenesis of NIDDM. Diabetes Metab Rev 1989; 5: 431-41. 19. Taylor R, Agius L. The biochemistry of diabetes. Biochem J 1988; 350: 625-40. 20. Moller DE, Yokota A, Flier JS. Normal insulin receptor cDNA sequence in Pima Indians with NIDDM. Diabetes 1989; 38: 1496-500. 21. Gama A, Patterson AP, Kadowaki T, et al. The amino add sequence of the insulin receptor is normal in an insulin-resistant Pima Indian. J Clin Endocrinol Metab 1990; 70: 1155-61.
No regrets Decisions about access to abortion are often argued on grounds of safety. But abortion, for good reasons, is a highly emotional issue and therefore information on safety can be bent by the biases of those looking at the topic. After so much public, religious, and political debate, perhaps no-one can approach the analysis of the clinical outcome of abortion with an entirely open mind and a few people unashamedly look for the data they "want" to buttress their preconceptions. Initially, the debate tended to revolve around the physical safety of abortion. The low mortality rates from central and eastern Europe in the 1960s were said to be politically adjusted and western leaders in obstetrics claimed it was impossible to conduct abortions with a death rate of less than 1 in 10 000 operations. However, in the 1970s statistics from the USA and the UK unequivocally showed that firsttrimester vacuum aspiration abortion could be carried out with a mortality as low as 1 in 100 000 operations.! On July 30,1987, then President Ronald Reagan, in remarks at a briefmg for the Right to Life leaders, directed then Surgeon General C. Everett Koop to prepare a comprehensive report on the medical and psychological impact of abortion on women. The Surgeon General "met privately with 27 different groups which had philosophical, social, medical, or other professional, interests in the abortion issue".2 After extensive staff consultations with a range of specialists, Koop, a former paediatric surgeon who is personally opposed to abortion, declined to issue a report. He wrote a letter to the President on Jan 9, 1989, stating that "despite a diligent review..., the scientific studies do not provide conclusive data on the health effects of abortion on women"/’Koop’s scientific integrity had prevailed over an administration prepared to dissemble. On March 16, 1989, a congressional hearing3 was held to review the Surgeon General’s draft report, subsequently published in the Congressional Record.4 In view of the impasse regarding the psychological impact of abortion, the American Psychological Association appointed an expert review panel whose report was published last month in Science.s Clearly, the psychological responses after abortion are
1189
intrinsically more difficult to evaluate than mortality and morbidity statistics. Thus, the researchers limited their analysis to those papers with the most rigorous designs from the USA, supplemented by a major study from Denmark which used a uniform system not available in any population registration 6 other country. Overall, the panel found "legal abortion of an unwanted pregnancy in the first trimester does hazard for
not
women." even more from a clinical important, Perhaps their review noted that there is "little perspective, evidence of psychopathology" after abortion. The data permit some generalisations. Women who never wanted to become pregnant were less likely to report regret than women for whom pregnancy was "highly meaningful." Those who had negative feelings towards their partner, experienced opposition from their parents, or were highly ambivalent also experienced increased distress. If a woman mentioned a subsequent good relationship with her partner, she was more likely to experience regret a year after abortion. Women were more likely to have problems if they had attended a clinic accompanied by a male partner rather than on their own. Existing protocols have been based on the voluntary participation of study subjects and may have excluded those experiencing most stress. An ideal study would assess a women’s psychological status before pregnancy and follow her reactions afterwards. Koop has called for such a prospective study based on a national sample of women. Only two studies have attempted to compare the psychological responses after abortion and after birth. Athanasiou and colleagues, using the Minnesota Multiphasic Personality Inventory, found the two groups "startlingly similar".7 Zabin et al found that adolescents who chose to abort an unintended pregnancy had somewhat greater self-esteem than those who carried the pregnancy to term.8 The proven surgical safety of early abortion and the apparent lack of psychological sequelae cannot decide the ethics of terminating a pregnancy, but studies of the type reported in Science help remove illegitimate weapons from the political battlefield. There is one last category of data that, like the psychological consequences of abortion, is especially difficult to evaluate-the outcome of births to women who seek abortion but fail to obtain one and are compelled to carry the baby to term. The only comprehensive pair-matched study of "unwanted" and "wanted" children has now been followed for 24 years in Prague, Czechoslovakia.9 In the aggregate, the 220 children born to women twice denied abortion for the same pregnancy experienced a far more detrimental psychosocial development than did the 220 children born to women who had stopped taking contraception to conceive or had accepted an unplanned pregnancy. As young adults, they reported more psychological pose
a
psychological
most
disorders and more difficulties in partner relations, and also appeared more often in the alcohol, drug, and criminal registers. Any clinical procedure that is adopted on a large scale will be associated with some side-effects, occasionally severe. Just as therapeutic abortion has a measurable, if very small, mortality, so some women will be severely damaged psychologically. As Koop noted, these cases, whilst tragic, are "minuscule from a public health perspective".’o 1. Atash, HK, Mackay, HT, Binkin NJ, Hogue CJ. Legal abortion mortality in the United States: 1972 to 1982. Am J Obstet Gynecol 1987; 155: 605-12. CE. Letter to President Reagan, Jan 9, 1989. In: ref 3: 68-71. 3. Committee on Government Operations, House of Representatives. Medical and psychological impact of abortion. Hearing of March 16, 1989, 101st congress, 1st session, Washington, DC: US Government Printing Office, 1989. 4. Koop CE. Surgeon General’s Report on Abortion. Congressional Record,
2.
Koop
March 21, 1989. NE, David HP, Major BN, Roth SH, Russo NF, Wyatt GE. Psychological responses after abortion. Science 1990; 268: 41-44. 6. David HP, Rasmussen NK, Holst E. Postpartum and postabortion psychotic reactions. Fam Plan Perspect 1981; 13: 88-92. 7. Athanasiou R, Oppel W, Michelson L, Unger T, Yager M. Psychiatric sequelae to term birth and induced early and late abortion: a longitudinal study. Fam Plan Perspect 1973; 5: 227-31. 8. Zabin LS, Hirsch MB, Emerson MR. When urban adolescents choose abortion: effects on education, psychological status and subsequent pregnancy. Fam Plan Perspect 1989; 21: 248-55. 9. David HP, Dytrych Z, Metejcek Z, Schuller Z. Bom unwanted. Prague: Avicenum; New York: Springer, 1988. 10. Koop CE. In: Committee on Government Operations, House of Representatives tenth report, 101st Congress, 2nd session, Dec 11, 1989. House report 101-392: 14. Washington, DC: Government Printing Office, 1989. 5. Adler
PHAEOCHROMOCYTOMA STILL SURPRISES there is a commonly recognised cluster of symptoms associated with phaeochromocytoma,l the diagnosis is all too often missed and the consequences are likely to prove fatal: 85% of patients with this tumour who entered the Mayo Clinic between 1928 and 1977 were diagnosed only at necropsy.2 In this context the series lately reported by Sardesai and colleagues3 is instructive. These workers describe six patients who presented with sudden unexplained pulmonary oedema. None of them had an antecedent history of hypertension and five of them died. The diagnosis of phaeochromocytoma was established at necropsy, or by computed tomography and surgery in the survivor. In four of those who died there were multiple areas of focal myocardial necrosis and surrounding infiltration with acute inflammatory ’cells; the heart failure had been precipitated by catecholamine-induced myocarditis. A direct effect of catecholamines on the heart has been known for many years, both in patients receiving infusions to support the circulation4 and in those with phaeochromocytoma.5 This effect can occur in the absence of coronary atherosclerosis and is not related to the degree of hypertension. Blood pressure is normal or low in some patients with phaeochromocytoma owing to the secretion of catecholamines with predominantly p-adrenoreceptor stimulating effects. However, such patients are not exempt from cardiac lesions.6 Whilst early appearances suggest
Although
inflammatory infiltration, later changes comprise focal degeneration and fibrosis leading to the cardiomyopathy associated with these tumours.’ In laboratory animals the histological picture is similar in all species that have been
numbers of individuals, but several factors suggest strongly that insulin receptor mutations are not of great importance in this type of diabetes. First, there is little evidence for heritable defects in receptor function in NIDDM. Insulin-binding affinity appears normal, and receptor number is modulated only as an apparently reversible consequence of hyperinsulinaemia.17 Mild impairment of receptor tyrosine kinase activity in NIDDM and obesityll,18 may be an acquired defect reflecting regulation by other hormones. Second, it is not certain that all insulin-regulated processes in NIDDM show the uniformity of resistance to insulin that would be expected as a consequence of a primary defect in the receptor.19 Lack of uniformity in this regard would be compatible with defects distal to the receptor in signalling pathways. Third, individuals with even moderately severe insulin resistance due to receptor mutations do not necessarily display hyperglycaemia. 15 Their insulin resistance may be compensated by hyperinsulinaemia without development of diabetes. It appears that additional factors acting to intensify insulin resistance or impair insulin secretion would be required to cause diabetes. Fourth, the best available estimate of the frequency of mutant receptor alleles in the population (although for various reasons this could be an underestimate) suggests that as few as 1% of individuals who will get NIDDM might have an important mutation.15 Finally, in a few insulin resistant or diabetic Pima Indians who have been examined, the receptor sequence is normal.20,21 Thus it seems that receptor mutations may at best occur in only a small subset of cases of NIDDM, and then only as one of several factors contributing to the aetiology of the disease.
1. DeFronzo RA. The triumvirate: &bgr;-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988; 37: 667-87. 2. Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-607. 3. Taylor R. Aetiology of non-insulin dependent diabetes. Br Med Bull 1989; 45: 73-91. 4. Czech MP. The nature and regulation of the insulin receptor: structure and function. Ann Rev Physiol 1985; 47: 357-81. 5. Goldfine ID. The insulin receptor: molecular biology and transmembrane signalling. Endocr Rev 1987; 8: 235-55. 6. Zick Y. The insulin receptor: structure and function. Crit Rev Biochem Mol Biol 1989; 24: 217-69. 7. Rosen OM. After insulin binds. Science 1987; 237: 1452-58. 8. Housley MD, Siddle K. Molecular basis of insulin receptor function. Br Med Bull 1989; 45: 264-84. 9. Goldstein JL, Brown MS, Anderson RGW, Russell DW, Schneider WJ. Receptor mediated endocytosis: concepts emerging from the LDL receptor system. Annu Rev Cell Biol 1985; 1: 1-39. 10. Taylor SI. Receptor defects in patients with extreme insulin resistance. Diabetes Metab Rev 1985; 1: 171-202. 11. Reddy SSK, Kahn CR. Insulin resistance: a look at the role of insulin receptor kinase. Diabetic Med 1988; 5: 621-29. 12. Atkinson AB, Kennedy L, Andrews WJ, et al. Diverse endocrine presentations of the syndrome of acanthosis nigricans and insulin resistance. J R Coll Physicians Lond 1989; 23: 165-69. 13. Flier JS, Eastman RC, Minaker KL, Matteson D, Rowe JW. Acanthosis nigricans in obese women with hyperandrogenism: characterization of an insulin-resistance state distinct from the type A and B syndromes. Diabetes 1985; 34: 101-07. 14. Seino S, Seino M, Bell GI. Human insulin-receptor gene. Diabetes 1990; 39: 129-33.
15.
Taylor SI, Kadowaki T, Kadowaki H, Accili D, Cama A, McKeon C. Mutations in insulin receptor gene in insulin-resistant patients.
Diabetes Care 1990; 13: 257-79. 16. Taira M, Taira M, Hashimoto N, et al. Human diabetes associated with a deletion of the tyrosine kinase domain of the insulin receptor. Science 1989; 245: 63-66. 17. Flier JS. Insulin receptors and insulin resistance. Annu Rev Med 1983; 34: 145-60. 18. Haring H, Obermaier-Kusser B. Insulin receptor kinase defects in insulin-resistant tissues and their role in the pathogenesis of NIDDM. Diabetes Metab Rev 1989; 5: 431-41. 19. Taylor R, Agius L. The biochemistry of diabetes. Biochem J 1988; 350: 625-40. 20. Moller DE, Yokota A, Flier JS. Normal insulin receptor cDNA sequence in Pima Indians with NIDDM. Diabetes 1989; 38: 1496-500. 21. Gama A, Patterson AP, Kadowaki T, et al. The amino add sequence of the insulin receptor is normal in an insulin-resistant Pima Indian. J Clin Endocrinol Metab 1990; 70: 1155-61.
No regrets Decisions about access to abortion are often argued on grounds of safety. But abortion, for good reasons, is a highly emotional issue and therefore information on safety can be bent by the biases of those looking at the topic. After so much public, religious, and political debate, perhaps no-one can approach the analysis of the clinical outcome of abortion with an entirely open mind and a few people unashamedly look for the data they "want" to buttress their preconceptions. Initially, the debate tended to revolve around the physical safety of abortion. The low mortality rates from central and eastern Europe in the 1960s were said to be politically adjusted and western leaders in obstetrics claimed it was impossible to conduct abortions with a death rate of less than 1 in 10 000 operations. However, in the 1970s statistics from the USA and the UK unequivocally showed that firsttrimester vacuum aspiration abortion could be carried out with a mortality as low as 1 in 100 000 operations.! On July 30,1987, then President Ronald Reagan, in remarks at a briefmg for the Right to Life leaders, directed then Surgeon General C. Everett Koop to prepare a comprehensive report on the medical and psychological impact of abortion on women. The Surgeon General "met privately with 27 different groups which had philosophical, social, medical, or other professional, interests in the abortion issue".2 After extensive staff consultations with a range of specialists, Koop, a former paediatric surgeon who is personally opposed to abortion, declined to issue a report. He wrote a letter to the President on Jan 9, 1989, stating that "despite a diligent review..., the scientific studies do not provide conclusive data on the health effects of abortion on women"/’Koop’s scientific integrity had prevailed over an administration prepared to dissemble. On March 16, 1989, a congressional hearing3 was held to review the Surgeon General’s draft report, subsequently published in the Congressional Record.4 In view of the impasse regarding the psychological impact of abortion, the American Psychological Association appointed an expert review panel whose report was published last month in Science.s Clearly, the psychological responses after abortion are
1189
intrinsically more difficult to evaluate than mortality and morbidity statistics. Thus, the researchers limited their analysis to those papers with the most rigorous designs from the USA, supplemented by a major study from Denmark which used a uniform system not available in any population registration 6 other country. Overall, the panel found "legal abortion of an unwanted pregnancy in the first trimester does hazard for
not
women." even more from a clinical important, Perhaps their review noted that there is "little perspective, evidence of psychopathology" after abortion. The data permit some generalisations. Women who never wanted to become pregnant were less likely to report regret than women for whom pregnancy was "highly meaningful." Those who had negative feelings towards their partner, experienced opposition from their parents, or were highly ambivalent also experienced increased distress. If a woman mentioned a subsequent good relationship with her partner, she was more likely to experience regret a year after abortion. Women were more likely to have problems if they had attended a clinic accompanied by a male partner rather than on their own. Existing protocols have been based on the voluntary participation of study subjects and may have excluded those experiencing most stress. An ideal study would assess a women’s psychological status before pregnancy and follow her reactions afterwards. Koop has called for such a prospective study based on a national sample of women. Only two studies have attempted to compare the psychological responses after abortion and after birth. Athanasiou and colleagues, using the Minnesota Multiphasic Personality Inventory, found the two groups "startlingly similar".7 Zabin et al found that adolescents who chose to abort an unintended pregnancy had somewhat greater self-esteem than those who carried the pregnancy to term.8 The proven surgical safety of early abortion and the apparent lack of psychological sequelae cannot decide the ethics of terminating a pregnancy, but studies of the type reported in Science help remove illegitimate weapons from the political battlefield. There is one last category of data that, like the psychological consequences of abortion, is especially difficult to evaluate-the outcome of births to women who seek abortion but fail to obtain one and are compelled to carry the baby to term. The only comprehensive pair-matched study of "unwanted" and "wanted" children has now been followed for 24 years in Prague, Czechoslovakia.9 In the aggregate, the 220 children born to women twice denied abortion for the same pregnancy experienced a far more detrimental psychosocial development than did the 220 children born to women who had stopped taking contraception to conceive or had accepted an unplanned pregnancy. As young adults, they reported more psychological pose
a
psychological
most
disorders and more difficulties in partner relations, and also appeared more often in the alcohol, drug, and criminal registers. Any clinical procedure that is adopted on a large scale will be associated with some side-effects, occasionally severe. Just as therapeutic abortion has a measurable, if very small, mortality, so some women will be severely damaged psychologically. As Koop noted, these cases, whilst tragic, are "minuscule from a public health perspective".’o 1. Atash, HK, Mackay, HT, Binkin NJ, Hogue CJ. Legal abortion mortality in the United States: 1972 to 1982. Am J Obstet Gynecol 1987; 155: 605-12. CE. Letter to President Reagan, Jan 9, 1989. In: ref 3: 68-71. 3. Committee on Government Operations, House of Representatives. Medical and psychological impact of abortion. Hearing of March 16, 1989, 101st congress, 1st session, Washington, DC: US Government Printing Office, 1989. 4. Koop CE. Surgeon General’s Report on Abortion. Congressional Record,
2.
Koop
March 21, 1989. NE, David HP, Major BN, Roth SH, Russo NF, Wyatt GE. Psychological responses after abortion. Science 1990; 268: 41-44. 6. David HP, Rasmussen NK, Holst E. Postpartum and postabortion psychotic reactions. Fam Plan Perspect 1981; 13: 88-92. 7. Athanasiou R, Oppel W, Michelson L, Unger T, Yager M. Psychiatric sequelae to term birth and induced early and late abortion: a longitudinal study. Fam Plan Perspect 1973; 5: 227-31. 8. Zabin LS, Hirsch MB, Emerson MR. When urban adolescents choose abortion: effects on education, psychological status and subsequent pregnancy. Fam Plan Perspect 1989; 21: 248-55. 9. David HP, Dytrych Z, Metejcek Z, Schuller Z. Bom unwanted. Prague: Avicenum; New York: Springer, 1988. 10. Koop CE. In: Committee on Government Operations, House of Representatives tenth report, 101st Congress, 2nd session, Dec 11, 1989. House report 101-392: 14. Washington, DC: Government Printing Office, 1989. 5. Adler
PHAEOCHROMOCYTOMA STILL SURPRISES there is a commonly recognised cluster of symptoms associated with phaeochromocytoma,l the diagnosis is all too often missed and the consequences are likely to prove fatal: 85% of patients with this tumour who entered the Mayo Clinic between 1928 and 1977 were diagnosed only at necropsy.2 In this context the series lately reported by Sardesai and colleagues3 is instructive. These workers describe six patients who presented with sudden unexplained pulmonary oedema. None of them had an antecedent history of hypertension and five of them died. The diagnosis of phaeochromocytoma was established at necropsy, or by computed tomography and surgery in the survivor. In four of those who died there were multiple areas of focal myocardial necrosis and surrounding infiltration with acute inflammatory ’cells; the heart failure had been precipitated by catecholamine-induced myocarditis. A direct effect of catecholamines on the heart has been known for many years, both in patients receiving infusions to support the circulation4 and in those with phaeochromocytoma.5 This effect can occur in the absence of coronary atherosclerosis and is not related to the degree of hypertension. Blood pressure is normal or low in some patients with phaeochromocytoma owing to the secretion of catecholamines with predominantly p-adrenoreceptor stimulating effects. However, such patients are not exempt from cardiac lesions.6 Whilst early appearances suggest
Although
inflammatory infiltration, later changes comprise focal degeneration and fibrosis leading to the cardiomyopathy associated with these tumours.’ In laboratory animals the histological picture is similar in all species that have been