through the mechanisms of weight loss. Kiens and
Lithell have recently provided evidence that changes in the lipoprotein profile associated with endurance training are to a large extent explainable by increases in lipoprotein lipase in skeletal muscle tissue induced by training.' The question ofthe mechanism by which exercise provokes changes in concentrations of high density lipoprotein cholesterol remains unresolved. It may well be that exercise is no more effective than fat weight reduction alone. Our study examined the effect of low intensity exercise in women of normal weight without symptoms and found a beneficial effect on high density lipoprotein cholesterol concentration in the absence of a change in fatness. P R M JONES N G NORGAN
A HARDMAN A HUDSON
Loughborough University,
Loughborough LEt 1
reverse-namely, increased insulin secretion and hyperinsulinism.4 A serious omission in this paper is the criteria on which the detection of diabetes mellitus was made. The authors state that routine biochemical measurements were not made; therefore, we can only assume that diabetes mellitus was diagnosed because of symptoms. Yet it is insulin requiring diabetes that commonly presents clinically, while patients with non-insulin requiring diabetes may remain asymptomatic for many years. Thus a significant increase in the number of cases of clinically important yet asymptomatic non-insulin requiring diabetes in users of oral contraceptives could have been completely overlooked. We refute that this study excludes a relation between prolonged use of oral contraceptives and clinically important diabetes mellitus.
3TU
VICTOR WYNN JOHN C STEVENSON
I Wood PD, Stefanick ML, Dreon DM, et al. Changes in plasma lipids and lipoproteins in overweight men during weight loss through dieting as compared with exercise. N Engl J Med 1988;319: 1173-9. 2 Huttunen JK, Lansimies E, Voutilainen E, et al. Effect of moderate physical exercise on serum lipoproteins: a controlled clinical trial with special reference to serum high-density lipoproteins. Circulation 1979;60: 1220-9. 3 Farrell P'A, Barboriak J. TIhe time course of alterations in plasma lipid and lipoprotein concentrations during eight weeks of endurance training. Atherosclerosis 1980;37:231-8. 4 Stubbe 1, Hansson P, Gustafson A, Nilsson-Ehle P. Plasma lipoproteins and lipolytic enzyme activities during endurance training in sedentary men: changes in high-density lipoprotein subfractions and composition. Metabolism 1983;32: 1120-8. 5 Kiens B, Lithell H. Lipoprotein metabolism influenced by training-induced changes in human skeletal muscle. J Cltn Invest 1989;83:558-64.
Oral contraceptives and diabetes mellitus SIR,-Drs Philip C Hannaford and Clifford R Kay state categorically that use of the contraceptive pill is not associated with an increased risk of developing diabetes mellitus.' We wonder, however, if they can be so definite in their conclusion. The number of subjects whom they studied who used oral contraceptives for 10 years or more is quite small (about 850), but even in this small cohort the relative risk of diabetes mellitus was increased by almost 50% (not significant). This may mean that the study sample was too small to detect an effect that was actually present. Thus the authors may be making a type 2 statistical error. Furthermore, 66 cases of diabetes mellitus occurred in former users of oral contraceptives, but it is not stated if these were overrepresented in women with a long duration of use. Thus the authors should also present a table of standardised rates of diabetes mellitus with respect to duration of former use together with time since treatment was stopped. Most of the women in the cohort were initially of an age when insulin requiring diabetes might be expected but non-insulin requiring diabetes would be rare; more than 90% were aged less than 40 years and more than 60% were aged less than 30 years at recruitment.2 It is extraordinary that neither in this paper nor in their previous report' do the authors make any attempt to classify the type of diabetes. We would have no reason to suppose that use of oral contraceptives would cause insulin deficiency as their effect is to cause the
Wynn Institute for Metabolic Research, London NW8 9SQ 1 Hannaford PC, Kay CR. Oral contraceptives and diabetes mellitus. BrMedJ l989;299:1315-6. (25 November.) 2 Royal College of General Practitioners. Oral contraceptives and health. London: I'itman Medical, 1974. 3 Wingrave SJ, Kay CR, Vessey Ml'. Oral contraceptives and diabetes mellitus. BrrMedJ7 1979;i:23. 4 Wynn V, Adams PW, Godsland 1, et al. Comparison of effects of different combined oral-contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1979;i: 1045-9.
AUTHORS'REPLY,-When preparing our short report' we assumed that any diabetogenic effects of oral contraceptives would be seen mostly among current users as the adverse glucose tolerance effects in some users tends to reverse once they stop taking the contraceptive pill.)2 3Clearly, Professor Victor Wynn and Dr John C Stevenson feel that these metabolic changes have a more permanent influence. The table details the risk of developing diabetes mellitus by duration of ever use (former or current) of oral contraceptives; this analysis also allows for time since stopping taking the contraceptive pill. There was no evidence of an increased risk even among those who had used the contraceptive pill for at least 10 years. The Royal College of General Practitioners' oral contraception study is a prospective observational study of total reported morbidity and mortality. The participating general practitioners report any diagnoses made by themselves or by the specialist services. Deliberately, diagnostic criteria are not specified and routine biochemical measurements are not taken. Comparisons between women who do and do not use the contraceptive pill are valid provided that the doctors apply similar diagnostic criteria to both groups. We do not believe that there has been any differential reporting of diagnoses or screening of women for illness. Indeed, if such bias had occurred it would have had the effect of spuriously increasing rates of illness in users.' Our results include all reported cases of clinically recognisable diabetes mellitus, whether insulin requiring or non-insulin requiring. We were careful to state that ". . use of the pill is not associated with an increased risk of developing clinical signs of diabetes mellitus." It is impossible to know how many of the study cohort currently have undetected asymptomatic diabetes. Neither do we know whether asymptomatic diabetes
Duration of current use (months) 1-59
60-119
_s120
All ever use
0-39 (82)
0-35 (50) 0 90 0-63 to 1-28 174 034
0-27 (24) 0-69 0-44 to 1-09 79703
0 30 (11) 0 77 0 41 to 1 44 26524
0-32 (85) 0 81 0-60 to 1 10 280 261
*Indirectly standardised for age and parity at diagnosis, social class, and smoking history at recruitment; expressed as rates per thousand women years.
196
Royal College of General Practitioners, Manchester Research Unit, Manchester M20 OTR I Hannaford PC, Kay CR. Oral contraceptives and diabetes mellitus. BrMedJ 1989;299:1315-6. (25 November.) 2 Duffy TJ, Ray R. Oral contraceptive use: prospective follow-up of women with suspected glucose intolerance. Contraception 1984;30: 197-208. 3 Wynn V. Effect of duration of low-dose oral contraceptive administration on carbohydrate metabolism. Am J7 Obstet (Gnecol 1982;142:739-46. 4 Royal College of General Practitioners. Oral contraceptives and health. London: Pitman Medical, 1974. 5 Wynn V, Adams PW, Godsland I, et al. Comparison of effects of different combined oral-contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1979;i: 1045-9.
When risk factors have little meaning SIR,-The anonymous article on the difficult decision that has to be made when results of antenatal testing are abnormal usefully draws attention to difficulties encountered in applying antenatal risk factors.' In my experience many doctors, including a membership examiner, mistakenly believe that ammiocentesis should be favoured when the risk of Down's syndrome exceeds the risk of miscarriage from the procedure. This "decision rule" is illogical. Couples differ in their attitude to termination, and though some families are able to maximise the abilities of a handicapped child others buckle under the strain. Clearly the risks of chromosomal abnormality and miscarriage are relevant pieces of information (and should be read from tables and recorded in the notes). The couple have, however, to be helped to relate these risks to their individual circumstances rather than being encouraged to decide on the likelihood of two unequal outcomes. Many couples mistakenly believe that a normal amniocentesis result excludes the possibility of congenital abnormality; it is important they understand that a small risk remains. Routine antenatal screening is best discussed with the general practitioner undertaking shared care, who usually knows the couple and thus has an advantage over a hospital antenatal clinic. It is hoped that advances in screening for chromosomal abnormalities will make diagnosis more certain while reducing the risk of miscarriage. The pain of choosing between having a termination and caring for a handicapped child will, however, remain. P BINGHAM
1 Anonymous. When risk factors hase little meaning. Br Med 7 1989;299:1599-600. (23 December.)
0
194 267
PHILIP C HANNAFORD CLIFFORD R KAY
Coventry Health Authority, Coventry CV I 2GQ
Standardised rates of diabetes mellitus (ICD code 250) in non-users and ever users oforal contraceptives
Standardised rate* (No) Risk relative to never users 95% Confidence interval Period of observation (women vears)
is clinically important (unfortunately Professor Wynn and Dr Stevenson did not reference their statement that asymptomatic non-insulin requiring diabetes is clinically important). In the past Professor Wynn has expressed concern about the diabetogenic effect of the contraceptive pill." He now seems to imply that he is worried only about the risk of developing non-insulin requiring diabetes. We believe that our evidence supports the statement that users of the contraceptive pill have so far shown no increased risk of developing clinical diabetes. We hope that we shall be able to continue the study so that we can observe with increased power the experience of postmenopausal women.
General practitioner contract SIR,-I am the youngest partner of four in an entirely rural dispensing practice in the south west of England. I have just read through the revised
BMJ VOLUME 300
20 JANUARY 1990
Lithell have recently provided evidence that changes in the lipoprotein profile associated with endurance training are to a large extent explainable by increases in lipoprotein lipase in skeletal muscle tissue induced by training.' The question ofthe mechanism by which exercise provokes changes in concentrations of high density lipoprotein cholesterol remains unresolved. It may well be that exercise is no more effective than fat weight reduction alone. Our study examined the effect of low intensity exercise in women of normal weight without symptoms and found a beneficial effect on high density lipoprotein cholesterol concentration in the absence of a change in fatness. P R M JONES N G NORGAN
A HARDMAN A HUDSON
Loughborough University,
Loughborough LEt 1
reverse-namely, increased insulin secretion and hyperinsulinism.4 A serious omission in this paper is the criteria on which the detection of diabetes mellitus was made. The authors state that routine biochemical measurements were not made; therefore, we can only assume that diabetes mellitus was diagnosed because of symptoms. Yet it is insulin requiring diabetes that commonly presents clinically, while patients with non-insulin requiring diabetes may remain asymptomatic for many years. Thus a significant increase in the number of cases of clinically important yet asymptomatic non-insulin requiring diabetes in users of oral contraceptives could have been completely overlooked. We refute that this study excludes a relation between prolonged use of oral contraceptives and clinically important diabetes mellitus.
3TU
VICTOR WYNN JOHN C STEVENSON
I Wood PD, Stefanick ML, Dreon DM, et al. Changes in plasma lipids and lipoproteins in overweight men during weight loss through dieting as compared with exercise. N Engl J Med 1988;319: 1173-9. 2 Huttunen JK, Lansimies E, Voutilainen E, et al. Effect of moderate physical exercise on serum lipoproteins: a controlled clinical trial with special reference to serum high-density lipoproteins. Circulation 1979;60: 1220-9. 3 Farrell P'A, Barboriak J. TIhe time course of alterations in plasma lipid and lipoprotein concentrations during eight weeks of endurance training. Atherosclerosis 1980;37:231-8. 4 Stubbe 1, Hansson P, Gustafson A, Nilsson-Ehle P. Plasma lipoproteins and lipolytic enzyme activities during endurance training in sedentary men: changes in high-density lipoprotein subfractions and composition. Metabolism 1983;32: 1120-8. 5 Kiens B, Lithell H. Lipoprotein metabolism influenced by training-induced changes in human skeletal muscle. J Cltn Invest 1989;83:558-64.
Oral contraceptives and diabetes mellitus SIR,-Drs Philip C Hannaford and Clifford R Kay state categorically that use of the contraceptive pill is not associated with an increased risk of developing diabetes mellitus.' We wonder, however, if they can be so definite in their conclusion. The number of subjects whom they studied who used oral contraceptives for 10 years or more is quite small (about 850), but even in this small cohort the relative risk of diabetes mellitus was increased by almost 50% (not significant). This may mean that the study sample was too small to detect an effect that was actually present. Thus the authors may be making a type 2 statistical error. Furthermore, 66 cases of diabetes mellitus occurred in former users of oral contraceptives, but it is not stated if these were overrepresented in women with a long duration of use. Thus the authors should also present a table of standardised rates of diabetes mellitus with respect to duration of former use together with time since treatment was stopped. Most of the women in the cohort were initially of an age when insulin requiring diabetes might be expected but non-insulin requiring diabetes would be rare; more than 90% were aged less than 40 years and more than 60% were aged less than 30 years at recruitment.2 It is extraordinary that neither in this paper nor in their previous report' do the authors make any attempt to classify the type of diabetes. We would have no reason to suppose that use of oral contraceptives would cause insulin deficiency as their effect is to cause the
Wynn Institute for Metabolic Research, London NW8 9SQ 1 Hannaford PC, Kay CR. Oral contraceptives and diabetes mellitus. BrMedJ l989;299:1315-6. (25 November.) 2 Royal College of General Practitioners. Oral contraceptives and health. London: I'itman Medical, 1974. 3 Wingrave SJ, Kay CR, Vessey Ml'. Oral contraceptives and diabetes mellitus. BrrMedJ7 1979;i:23. 4 Wynn V, Adams PW, Godsland 1, et al. Comparison of effects of different combined oral-contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1979;i: 1045-9.
AUTHORS'REPLY,-When preparing our short report' we assumed that any diabetogenic effects of oral contraceptives would be seen mostly among current users as the adverse glucose tolerance effects in some users tends to reverse once they stop taking the contraceptive pill.)2 3Clearly, Professor Victor Wynn and Dr John C Stevenson feel that these metabolic changes have a more permanent influence. The table details the risk of developing diabetes mellitus by duration of ever use (former or current) of oral contraceptives; this analysis also allows for time since stopping taking the contraceptive pill. There was no evidence of an increased risk even among those who had used the contraceptive pill for at least 10 years. The Royal College of General Practitioners' oral contraception study is a prospective observational study of total reported morbidity and mortality. The participating general practitioners report any diagnoses made by themselves or by the specialist services. Deliberately, diagnostic criteria are not specified and routine biochemical measurements are not taken. Comparisons between women who do and do not use the contraceptive pill are valid provided that the doctors apply similar diagnostic criteria to both groups. We do not believe that there has been any differential reporting of diagnoses or screening of women for illness. Indeed, if such bias had occurred it would have had the effect of spuriously increasing rates of illness in users.' Our results include all reported cases of clinically recognisable diabetes mellitus, whether insulin requiring or non-insulin requiring. We were careful to state that ". . use of the pill is not associated with an increased risk of developing clinical signs of diabetes mellitus." It is impossible to know how many of the study cohort currently have undetected asymptomatic diabetes. Neither do we know whether asymptomatic diabetes
Duration of current use (months) 1-59
60-119
_s120
All ever use
0-39 (82)
0-35 (50) 0 90 0-63 to 1-28 174 034
0-27 (24) 0-69 0-44 to 1-09 79703
0 30 (11) 0 77 0 41 to 1 44 26524
0-32 (85) 0 81 0-60 to 1 10 280 261
*Indirectly standardised for age and parity at diagnosis, social class, and smoking history at recruitment; expressed as rates per thousand women years.
196
Royal College of General Practitioners, Manchester Research Unit, Manchester M20 OTR I Hannaford PC, Kay CR. Oral contraceptives and diabetes mellitus. BrMedJ 1989;299:1315-6. (25 November.) 2 Duffy TJ, Ray R. Oral contraceptive use: prospective follow-up of women with suspected glucose intolerance. Contraception 1984;30: 197-208. 3 Wynn V. Effect of duration of low-dose oral contraceptive administration on carbohydrate metabolism. Am J7 Obstet (Gnecol 1982;142:739-46. 4 Royal College of General Practitioners. Oral contraceptives and health. London: Pitman Medical, 1974. 5 Wynn V, Adams PW, Godsland I, et al. Comparison of effects of different combined oral-contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1979;i: 1045-9.
When risk factors have little meaning SIR,-The anonymous article on the difficult decision that has to be made when results of antenatal testing are abnormal usefully draws attention to difficulties encountered in applying antenatal risk factors.' In my experience many doctors, including a membership examiner, mistakenly believe that ammiocentesis should be favoured when the risk of Down's syndrome exceeds the risk of miscarriage from the procedure. This "decision rule" is illogical. Couples differ in their attitude to termination, and though some families are able to maximise the abilities of a handicapped child others buckle under the strain. Clearly the risks of chromosomal abnormality and miscarriage are relevant pieces of information (and should be read from tables and recorded in the notes). The couple have, however, to be helped to relate these risks to their individual circumstances rather than being encouraged to decide on the likelihood of two unequal outcomes. Many couples mistakenly believe that a normal amniocentesis result excludes the possibility of congenital abnormality; it is important they understand that a small risk remains. Routine antenatal screening is best discussed with the general practitioner undertaking shared care, who usually knows the couple and thus has an advantage over a hospital antenatal clinic. It is hoped that advances in screening for chromosomal abnormalities will make diagnosis more certain while reducing the risk of miscarriage. The pain of choosing between having a termination and caring for a handicapped child will, however, remain. P BINGHAM
1 Anonymous. When risk factors hase little meaning. Br Med 7 1989;299:1599-600. (23 December.)
0
194 267
PHILIP C HANNAFORD CLIFFORD R KAY
Coventry Health Authority, Coventry CV I 2GQ
Standardised rates of diabetes mellitus (ICD code 250) in non-users and ever users oforal contraceptives
Standardised rate* (No) Risk relative to never users 95% Confidence interval Period of observation (women vears)
is clinically important (unfortunately Professor Wynn and Dr Stevenson did not reference their statement that asymptomatic non-insulin requiring diabetes is clinically important). In the past Professor Wynn has expressed concern about the diabetogenic effect of the contraceptive pill." He now seems to imply that he is worried only about the risk of developing non-insulin requiring diabetes. We believe that our evidence supports the statement that users of the contraceptive pill have so far shown no increased risk of developing clinical diabetes. We hope that we shall be able to continue the study so that we can observe with increased power the experience of postmenopausal women.
General practitioner contract SIR,-I am the youngest partner of four in an entirely rural dispensing practice in the south west of England. I have just read through the revised
BMJ VOLUME 300
20 JANUARY 1990
