vitamin K and thus associated with childhood cancer, but in the other hospital there was no association between type of delivery and cancer, regardless of whether or not intramuscular vitamin K had been given. Consequently it is unlikely that type of delivery will explain the link between intramuscular vitamin K and childhood cancer. We note the response from D Kaiser and PA Hooper of Roche. As they indicate in their letter, the second vitamin K study was indeed funded by them. This funding was only agreed after they had submitted our proposed design for appropriate peer review. The exact design of the study was discussed at length with Roche before it was started and so it is difficult to interpret their statement that they believe this to be seriously flawed. Kaiser and Hooper also criticise the statistical methods. The data have been analysed in two different ways, and although possibly some of their criticisms may apply to the use of logistic regression, they do not apply to the Mantel-Haenszel test that we used. The fact that both methods produced almost identical results is a refutation of their claim of bias in the statistical techniques. The MantelHaenszel results were published in detail so that it could be seen that these were not unduly influenced by any one particular year. J&OLDING
Association already not only adhere to recognised standards of good manufacturing practice but also submit pack copy and advertising for expert approval. These two associations account for 95% of the food supplements sold in Britain. Professor John Garrow and Dr Mark Rayner are drawing attention to the irresponsible activities of a tiny minority. Over the past four years I have personally given dossiers of advertisements that are illegal under present British law to the Ministry, the Department of Health, and, indeed, John Garrow. No action of any consequence has been taken, and we are told that because of budgetary restraints future action is unlikely unless there is a danger to public health. Food legislation demands that claims be accurate, and safety assured. The laws are in place to take action where and when it is needed. There is no scientific reason why products that adhere to our safety guidelines and submit to our advertising controls should be taken off the market, and we are working closely with the European Commission to bring about this result. Anything less would be an unwarranted restriction of consumer freedom. MAURICEItANSSEN
(Health Food Manufacturers' Association, ames Ditton, OLT
Surre)KT7
RE.ENWOOD)
I Richards T. Vitamins face control worldwide. 491. (29 August.)
Institute of Child Health, Royal Hospital for Sick Children, Bristol BS2 8BJ 1 Handel J, Tripp JG. Vitamin K prophylaxis against haemorrhagic disease of the newborn in the United Kingdom. BMJ _C991;303: 1109. -W
Vitamins face control worldwide EDITOR,-The news item by Tessa Richards' does little to help present a balanced and accurate picture. The Health Food Manufacturers' Association has advised safe upper limits for nutritional supplements since 1985 and these are adhered to by more than 95 per cent of the supplements on sale in the United Kingdom. The European Commission's discussion paper of December 1991 on the subject states that "there are relatively few cases of proven harm arising from the consumption of these products"-this was a European overview. The fact is that the commission's proposals have not been finalised; that the British government has prepared a draft directive which seems perfectly reasonable in its approach to upper safe limits as being the criteria for judging their suitability as foods and that the restrictive proposals of the other member states have far more to do with protecting the monopolies of pharmacies. These shops traditionally supply such products and in France, Germany, and Italy are almost twice as numerous as in the United Kingdom. There is also a substantial legal difficulty in categorising food supplements as medicines at relatively low doses. Just what do you claim to prevent, treat, or cure with 200 mg of that extremely safe vitamin, E? That is 20 times the recommended daily allowance; yet the French are saying that more than one time is obviously medicinal. The Medicines Control Agency withdrew a licence from a 500 mg vitamin E product on the grounds that it was not a medicine. It would hardly be reasonable to ask the manufacturer to now pay a £12000 fee to obtain a licence on bureaucratically created grounds. The Ministry of Agriculture, Fisheries, and Food is currently spending £1 65 m on trying to establish optimal levels for antioxidant nutrients. It is likely that vitamins C and E will be well above any "Euro RDA," and 3 carotene does not even possess one. Members of the Proprietary Association of Great Britain and the Health Food Manufacturers'
BMJ
VOLUME
305
19 SEPTEMBER 1992
BMJ
1992;305:
EDITOR,-The article by Tessa Richards is misleading. The British health food industry is not, neither manufacturers nor retailers, in conflict with the European Commission. At a recent meeting of EC ministers the British government presented a position paper calling for product safety, on the basis of published scientific research, to be the only criterion for upper limits which may be placed on vitamins and minerals available for general sale. This proposal was accepted and supported by the commission but opposed by other member states. In many cases, those who oppose us do so from an apparent desire to protect entrenched commercial interests rather than consumer safety. With the support of the Ministry of Agriculture, Fisheries, and Food and the Department of Health our trade associations are now working hard to have the high standards of product safety, with freedom of choice, currently enjoyed by British consumers accepted by the rest of Europe. The health food industry, in common with many other industries, does have a small number of "cowboy" operators who make outrageous claims. It is perhaps significant that these claims are usually made through advertisements in the national press. These products are rarely seen in genuine health food stores. There, proprietors and staff-many of whom are professionally trained and hold recognised certificates and diplomas in health food retailing-have to meet their customers face to face. They simply could not survive commercially unless the honesty and credibility of their products and service was.beyond question. It is a pity that Professor Garrow and Tessa Richards make no atfempt to differentiate between "cowboys" and those who have a real concern for the welfare of consumers-on whose continued health and satisfaction we all ultimately depend. RICCHARD)MISTHIN N National Association of Health Stores,
L
Boston, Lincolnshire PE2 1 9HG 1 Richards T. Vitamins face control worldwide. BMJ 1992;305: 491. (29 August.)
EDITOR,-There has been much confusion about whether vitamin pills are dietary supplements or drugs. This confusion seems to stem from the fact that a specific nutritional product may be sold as a
licensed medicine, while an identical product is sold as a supplement. Faced with what seems to be a highly irregular situation, many people who are unaware of the reasons for it may logically assume that the unlicensed products are in some way escaping proper control through some loophole of the law, and therefore that the forthcoming directive of the European Commission, which proposes to set a limit below which a product is a food and above which it is a medicine, is perfectly logical and indeed good. What may not be understood is that in Britain the legal difference between a food or food supplement and the same food or supplement sold as a drug is essentially whether or not the manufacturer -makes a medical claim for it. Thus a product licence would have to be sought for oat bran if the makers went all the way in their advertisements and claimed that their products actually lower blood cholesterol. It is against the law in Britain to make a medical claim for a food supplement that is not licensed as a medicine. We suggest that Professor John Garrow, who was quoted in Tessa Richards's article,' should encourage the government to enforce this law more effectively rather than support an EC directive which could result in the disappearance of up to 95 per cent of vitamin products in this country. As a nutritionist I am sure he would not like to see this happen. The loss of the products will occur because most manufacturers say they do not have the extensive funds and facilities required for licence applications. The fact is that, as Dr Mark Rayner says, few nutritional products are suitable candidates for medicinal claims. This only proves that they are not medicines, and therefore that they should not be classified as such. There are other ways of controlling dosages sold over the counter to the public. LINDI LAZARIDES Society for the Promotion of Nutritional Therapy, Heathfield, East Sussex TN2 1 8AE 1 Richards T. Vitamins face control worldwide. BMJ 1992;305: 491. (29 August.)
EDITOR,-The implications of the European Commission's decision to consider introducing legislation banning the free sale of vitamins, minerals, and other known nutrients' are quite astonishing. The whole adult population of Europe is free to purchase, in almost every corner shop, one of the most habit forming and toxic drugs known to humans. Even when the advertising of tobacco is eventually banned, no one would seriously suggest that the commission should ban its free sale. Films showing violence and sadistic cruelty are a regular part of the fare broadcast by many of Europe's television stations. Despite growing evidence on the behavioural effects of that kind of visual diet, our legislative freedom to pay to watch such material is not likely to be restricted. Yet the innocent practice by vast numbers of people, of purchasing nutrients in tablet or capsule form, is likely to be virtually ended by decree of our European bureaucrats. Far from removing trade barriers, this will be a grave restriction on trade. Even if the dubious argument that these tableted and encapsulated nutrients have no effect whatsoever is accepted, it is surely people's freedom to waste their money as they think fit. Buying vitamin supplements is a much healthier way of using money than is drinking, smoking, betting, or other forms of legitimate entertainment that often have a high cost in human health. Arguments about the "danger" of swallowing these nutrients are risible. In the United States the reporting of side effects of drugs and nutrients is mandatory. Compared with an annual total of hundreds of deaths and many times that number
711
of people damaged as a result of taking medically prescribed drugs, there has not been one documented case of death due to nutrients and only a relatively small handful of cases reporting serious side effects. The cost to human health of excess salt consumption must be far greater. The most reactionary aspect of the proposed legislation is that American and British journals are publishing a large and growing number of refereed articles reporting the value for human health of vitamin and mineral intake, not only in food form but also in nutrient form. Will the NHS of the future be happy to have nutrients given only through prescribed and costly "drugs"? WALTIEF BARKER
Early Childhood Development Unit, University of Bristol, Bristol BS8 I HP 1 Richards T. Vitamins face control worldwide. BMJ 1992;305: 491. (29 August.)
Oestrogen replacement after oophorectomy EDITOR,-We are puzzled as to why C Harriet M Anderson and colleagues question whether oestradiol provided by transdermal patches will be as effective as that provided by implants in conferring long term benefits of oestrogen replacement therapy.' They raise this question solely on the basis of a small difference between the two routes of administration in suppressing gonadotrophin. Although this would suggest that the oestradiol dose delivered by the patches was lower than that delivered by the implant, there was actually no significant difference between the two treatments in concentrations of circulating oestradiol. It would therefore seem that delivered doses were actually similar. The authors imply that a difference in gonadotrophin suppression will lead to a different effect on the short term and long term sequelae of the menopause. This extrapolation is based on a study which purported to show a dose-response effect (but actually used arbitrary lines) on urinary excretion of calcium and creatinine, a crude and indirect assessment of bone turnover.2 It has already been shown that oestrogen sensitive tissues do not always respond in a dose dependent manner to increasing dosage; higher doses may reduce sensitivity to oestrogen, possibly because of down regulation of the receptor mechanism.3 In the study of Anderson et al the two methods of giving oestradiol had equivalent biological activity in terms of suppressing vasomotor symptoms. With regard to long terms effects, the 0-05 mg transdermal dose of oestradiol is effective in preventing postmenopausal bone loss.4 It is also effective in producing beneficial changes in lipid and lipoproteins' and in arterial pulsatility index," which suggest that it would be effective in reducing the risk of cardiovascular disease. Thus there is no good evidence that the long term benefits of transdermal oestradiol 0-05mg will be any less than those of oestradiol implants 50 mg. Both routes have the advantage of avoiding the hepatic first pass effect of steroids given orally, and the patches are easier to apply and discontinue. T'IM C HILLARD JOHN C STEVENSON SOVRA I J WHITCROFT MALCOLM I WHITEHEAD Wynn Institute for Metabolic Research, London NW8 95Q 1 Anderson CHM, Rain SK, Forsling ML, Wheeler MJ. Oestrogen replacement after oophorectomy: comparison of patches and implants. BMJ 1992;305:90-1. (11 July.) 2 Selby PL, Peacock M. Dose dependent response of symptoms, pituitary, and bone to transdermal oestrogen in postmenopausal women. BMJ 1986;293:1337-9. 3 Dyer GI, Young 0, Townsend PT, Collins WP, Whitehead MI, Jelowitz J. Dose-related changes in vaginal cytology after topical conjugated enquine oestrogens. BMJ 1982;284:789. 4 Stevenson JC, Cust MP, Ganger KF, Hillard TC, Lees B,
712
Whitehead MI. Effects of transdermal versus oral homrone replacement therapy on bone density in spine and proximal femur in postmenopausal women. Lattcet 1990;335:265-9. 5 Crook D, Cust IMP, Gangar KF, Wortlington M, Hillard TC, Stevenson JC, et al. Comparison of transderinal and oral estrogen/progestin hormone replacement therapy: eflects on serum lipids and lipoproteins, Amti 7 Obstet Gvnecol 1992;166: 950-5. 6 Gangar KF, Vyas S, Whitehead M, Crook D, Meire H, Campbell S. Pulsatilirt index in intemal carotid artery in relation to transdermal oestradiol and time since menopause. Lancet 1991;338:839-42.
EDITOR,-We agree with Harriet Anderson and colleagues that hormone concentrations are not routinely measured in patients receiving oestrogen replacement. ,o Although their study showed significantly lower gonadotrophin concentrations in the implant group, there was no statistically significant difference in the oestradiol levels in the two groups and both were equally effective in preventing hot flushes. As the beneficial effect of hormone replacement therapy correlates with oestradiol concentrations and not gonadotrophin concentrations, it should not cause any panic. A serum oestradiol concentration of > 120 pmol/l provides no further additional effect and may be related to side effects like endometrial hyperplasia2; in the study of Anderson et al oestradiol concentrations were much higher in both groups. Oestrogen probably acts through intermediate products on bone metabolism; these could be prostaglandin E2, calcitonin, or changes in ratio of insulin-like growth factor and growth hormone.' Although calcitriol seems to be a safe and effective treatment for osteoporosis,4 oestrogen replacement therapy is of value in preventing further bone loss and fractures and may benefit the cardiovascular system as well. As regards the cardiovascular system, while oral oestrogen results in a significant increase in plasma triglycerides and in all major lipoprotein factors, percutaneous administration exerts a weak effect on liver metabolism but substantially increases concentrations of high density lipoprotein cholesterol.6 Steingold et al confirmed that transdermal route may have less adverse hepatic effects.Chetkowski et al also showed efficacy of transdermal patches for biological effects.As implants and patches are equally good in maintaining oestradiol levels and suppressing menopausal symptoms and their beneficial effects on cardiovascular and bone metabolism, we see no reason in forcing implants on oophorectomised premenopausal or postmenopausal patients if they are keen to have patches. B W ELIOT
J B SHARMA I JIMASCARENHAS Acute Services Unit, Northampton General Hospital, Northampton NNl 5BD 1 Anderson CMH, Raju SK, Forsling ML, Wheeler MJ. Oestrogen replacement after oophorectomy: comparison of patches and implants. BMJ 1992;305:90-1. (11 July.) 2 Sarlet N, Reginster JY, Gaspard U. Determination of mineral serum oestradiol for prevention of postmenopausal bone loss. Calcif Tissue Int 1 989;44(suppl):S69. 3 Duursma SA, Raymakers JA, Boereboom FTJ, Scheven BAA. Estrogen and bone metabolism. Obstet Gvtnaecol Sues 1992; 47: 38-44. 4 Tilyard MW, Spears GFS, TIhomson J, Dovey S. Treatment of postmenopausal osteoporosis with calcitriol or calcium. NEnglJMed 1992;326:357-62. 5 Lufkin EG, Hodgson SF, Kotowicz MA, O'Fallon WM, Wekner HW, Riggs BL, et al. The use of transdermal estrogen treatment in osteoporosis. In: Christiansen C, Overgaard K, eds. Osteoporosis 1990. Copenhagen: Osteopress, 1990:1995-8. 6 Tepper R, Goldberger S, May JY, Luz IJ, Beyth Y. Hormonal replacement therapy in postmenopausal women and cardiovascular disease: an overview. Obstet 6snaecol Surv 1992; 47:426-31. 7 Steingold KA, Matt DW, Deziegler D. Comparison of transdermal to oral estradiol administration on hormonal and hepatic parameters in women with premature ovarian failure. I Clin Endocrinol Metab 199 1;73:275-8 1. 8 Chetkowski RJ, Meldrum DR, Steingold KA, Randle D, Lu, JK, Eggena P, es al. Biologic effects of transdermal estradiol. NEnglJ7Med 1986;314:1615-20.
EDIrFOR,-Harriet Anderson and colleagues state that premenopausal women undergoing prophylactic oophorectomy are given oestrogen replacement therapy to prevent menopausal symptoms.' It is unfortunate that they did not emphasise the real issues of long term skeletal and cardiovascular protection.2 It is well recognised that premature ovarianfailure appreciably increases the risk of death from myocardial causes.3 We question the ethics of delaying oestrogen replacement for seven days, thereby subjecting premenopausal women to miserable vasomotor symptoms. Was this really necessary? In their final sentence Anderson and colleagues cast doubts as to whether transdermal therapy "will be as effective as the implant in conferring the many long-term benefits of oestrogen replacement." This is inappropriate for two reasons. Firstly, there are no long term epidemiological data regarding skeletal and cardiovascular protection for implants. Most of the published epidemiological data relate to oral conjugated oestrogens.'5 Data do exist, however, showing comparable lipid changes and skeletal preservation of oral and transdermal therapy." Secondly, the dosages studied are not equivalent-a fact which is acknowledged in one of the studies quoted by Anderson and colleagues: Stanczyk et al stated that comparable oestradiol concentrations are obtained with 0 05 mg oestrogen patches and 25 mg implants.3 The authors state that the 0-05 mg patch can suppress gonadotrophin release after spontaneous menopause but not after oophorectomy. The papers cited do not confirm this: both studies found similar concentrations of follicle stimulating hormone and luteinising hormone after four weeks of oestrogen therapy.930 Indeed Chetkowski eg al, referring to spontaneously postmenopausal women treated with various doses of oral and transdermal". oestrogens, state: "even the largest doses of these medications did not lower the gonadotrophins to the levels observed in the premenopausal subjects." Anderson et al explain the recorded difference in gonadotrophin levels by "the higher sustained oestradiol concentrations in the implant group" yet their results state that the mean oestradiol concentrations did not differ significantly. There is no evidence that concentrations of follicle stimulating hormone and luteinising hormone in postmenopausal women taking hormone replacement therapy are of any value in determining efficacy of treatment. It seems inappropriate on the basis of this study to cast doubt on the efficacy of transdermal administration of oestrogen. Evidence already exists indicating a similar biological effect to comparable doses of conjugated oral oestrogens, for which there is an abundance of epidemiological evidence. BRIAN A REID KEVI N F GANGER
Department of Obstetrics and Gvnaecology, St Mary's Hospital Medical School, London W2 I PG I Anderson CHM, Raju SK, Forsling ML, Wheeler MJ.
2 3 4
5 6
7
8.
Oestrogen replacement after oophorectomy: comparison of patches and implants. BMJ 1992;305:90-1. (11 July.) Stevenson JC. Osteoporosis and cardiovascular disease in women: converging paths? Lantcet 1990;336:1 121-2. Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens CH. Menopause and the risk of coronary heart disease in women. N&EgglAMed 1987;316:1 105-10. Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, ct al. Postmenopausal estrogen therapy and cardiovascular disease. Ten year follow up from the Nurses' Health Study. NEnglJMed 1991;325:756-62. Paganini-Hill A, Ross RK, Gerkins VR, Henderson BE, Arthur M, Mack TM. Menopausal estrogen therapy and hip fractures. Ann Internz Med 1981;95:28-31. Stevenson JC, Cust MP, Gangar KF, Hillard TC, Lees B, Whitehead MI. Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women. Latncet 1990;336:265-9. Crook D, Cust MP, Gangar KF, Worthington M, Hillard TC, Stevenson JC, et al. Comparison of transdermal and oral estrogen-progestin replacement therapy: effects on serum lipids and lipoproteins. Am)I Obstet Gynecol 1992;166:950-5. Stanczvk FZ, Shoupe D, Nunez V, Macias-Gonzales P. A randomised comparison of nonoral estradiol delivery in
BMJ
VOLUME
305
19 SEPTEMBER 1992
Association already not only adhere to recognised standards of good manufacturing practice but also submit pack copy and advertising for expert approval. These two associations account for 95% of the food supplements sold in Britain. Professor John Garrow and Dr Mark Rayner are drawing attention to the irresponsible activities of a tiny minority. Over the past four years I have personally given dossiers of advertisements that are illegal under present British law to the Ministry, the Department of Health, and, indeed, John Garrow. No action of any consequence has been taken, and we are told that because of budgetary restraints future action is unlikely unless there is a danger to public health. Food legislation demands that claims be accurate, and safety assured. The laws are in place to take action where and when it is needed. There is no scientific reason why products that adhere to our safety guidelines and submit to our advertising controls should be taken off the market, and we are working closely with the European Commission to bring about this result. Anything less would be an unwarranted restriction of consumer freedom. MAURICEItANSSEN
(Health Food Manufacturers' Association, ames Ditton, OLT
Surre)KT7
RE.ENWOOD)
I Richards T. Vitamins face control worldwide. 491. (29 August.)
Institute of Child Health, Royal Hospital for Sick Children, Bristol BS2 8BJ 1 Handel J, Tripp JG. Vitamin K prophylaxis against haemorrhagic disease of the newborn in the United Kingdom. BMJ _C991;303: 1109. -W
Vitamins face control worldwide EDITOR,-The news item by Tessa Richards' does little to help present a balanced and accurate picture. The Health Food Manufacturers' Association has advised safe upper limits for nutritional supplements since 1985 and these are adhered to by more than 95 per cent of the supplements on sale in the United Kingdom. The European Commission's discussion paper of December 1991 on the subject states that "there are relatively few cases of proven harm arising from the consumption of these products"-this was a European overview. The fact is that the commission's proposals have not been finalised; that the British government has prepared a draft directive which seems perfectly reasonable in its approach to upper safe limits as being the criteria for judging their suitability as foods and that the restrictive proposals of the other member states have far more to do with protecting the monopolies of pharmacies. These shops traditionally supply such products and in France, Germany, and Italy are almost twice as numerous as in the United Kingdom. There is also a substantial legal difficulty in categorising food supplements as medicines at relatively low doses. Just what do you claim to prevent, treat, or cure with 200 mg of that extremely safe vitamin, E? That is 20 times the recommended daily allowance; yet the French are saying that more than one time is obviously medicinal. The Medicines Control Agency withdrew a licence from a 500 mg vitamin E product on the grounds that it was not a medicine. It would hardly be reasonable to ask the manufacturer to now pay a £12000 fee to obtain a licence on bureaucratically created grounds. The Ministry of Agriculture, Fisheries, and Food is currently spending £1 65 m on trying to establish optimal levels for antioxidant nutrients. It is likely that vitamins C and E will be well above any "Euro RDA," and 3 carotene does not even possess one. Members of the Proprietary Association of Great Britain and the Health Food Manufacturers'
BMJ
VOLUME
305
19 SEPTEMBER 1992
BMJ
1992;305:
EDITOR,-The article by Tessa Richards is misleading. The British health food industry is not, neither manufacturers nor retailers, in conflict with the European Commission. At a recent meeting of EC ministers the British government presented a position paper calling for product safety, on the basis of published scientific research, to be the only criterion for upper limits which may be placed on vitamins and minerals available for general sale. This proposal was accepted and supported by the commission but opposed by other member states. In many cases, those who oppose us do so from an apparent desire to protect entrenched commercial interests rather than consumer safety. With the support of the Ministry of Agriculture, Fisheries, and Food and the Department of Health our trade associations are now working hard to have the high standards of product safety, with freedom of choice, currently enjoyed by British consumers accepted by the rest of Europe. The health food industry, in common with many other industries, does have a small number of "cowboy" operators who make outrageous claims. It is perhaps significant that these claims are usually made through advertisements in the national press. These products are rarely seen in genuine health food stores. There, proprietors and staff-many of whom are professionally trained and hold recognised certificates and diplomas in health food retailing-have to meet their customers face to face. They simply could not survive commercially unless the honesty and credibility of their products and service was.beyond question. It is a pity that Professor Garrow and Tessa Richards make no atfempt to differentiate between "cowboys" and those who have a real concern for the welfare of consumers-on whose continued health and satisfaction we all ultimately depend. RICCHARD)MISTHIN N National Association of Health Stores,
L
Boston, Lincolnshire PE2 1 9HG 1 Richards T. Vitamins face control worldwide. BMJ 1992;305: 491. (29 August.)
EDITOR,-There has been much confusion about whether vitamin pills are dietary supplements or drugs. This confusion seems to stem from the fact that a specific nutritional product may be sold as a
licensed medicine, while an identical product is sold as a supplement. Faced with what seems to be a highly irregular situation, many people who are unaware of the reasons for it may logically assume that the unlicensed products are in some way escaping proper control through some loophole of the law, and therefore that the forthcoming directive of the European Commission, which proposes to set a limit below which a product is a food and above which it is a medicine, is perfectly logical and indeed good. What may not be understood is that in Britain the legal difference between a food or food supplement and the same food or supplement sold as a drug is essentially whether or not the manufacturer -makes a medical claim for it. Thus a product licence would have to be sought for oat bran if the makers went all the way in their advertisements and claimed that their products actually lower blood cholesterol. It is against the law in Britain to make a medical claim for a food supplement that is not licensed as a medicine. We suggest that Professor John Garrow, who was quoted in Tessa Richards's article,' should encourage the government to enforce this law more effectively rather than support an EC directive which could result in the disappearance of up to 95 per cent of vitamin products in this country. As a nutritionist I am sure he would not like to see this happen. The loss of the products will occur because most manufacturers say they do not have the extensive funds and facilities required for licence applications. The fact is that, as Dr Mark Rayner says, few nutritional products are suitable candidates for medicinal claims. This only proves that they are not medicines, and therefore that they should not be classified as such. There are other ways of controlling dosages sold over the counter to the public. LINDI LAZARIDES Society for the Promotion of Nutritional Therapy, Heathfield, East Sussex TN2 1 8AE 1 Richards T. Vitamins face control worldwide. BMJ 1992;305: 491. (29 August.)
EDITOR,-The implications of the European Commission's decision to consider introducing legislation banning the free sale of vitamins, minerals, and other known nutrients' are quite astonishing. The whole adult population of Europe is free to purchase, in almost every corner shop, one of the most habit forming and toxic drugs known to humans. Even when the advertising of tobacco is eventually banned, no one would seriously suggest that the commission should ban its free sale. Films showing violence and sadistic cruelty are a regular part of the fare broadcast by many of Europe's television stations. Despite growing evidence on the behavioural effects of that kind of visual diet, our legislative freedom to pay to watch such material is not likely to be restricted. Yet the innocent practice by vast numbers of people, of purchasing nutrients in tablet or capsule form, is likely to be virtually ended by decree of our European bureaucrats. Far from removing trade barriers, this will be a grave restriction on trade. Even if the dubious argument that these tableted and encapsulated nutrients have no effect whatsoever is accepted, it is surely people's freedom to waste their money as they think fit. Buying vitamin supplements is a much healthier way of using money than is drinking, smoking, betting, or other forms of legitimate entertainment that often have a high cost in human health. Arguments about the "danger" of swallowing these nutrients are risible. In the United States the reporting of side effects of drugs and nutrients is mandatory. Compared with an annual total of hundreds of deaths and many times that number
711
of people damaged as a result of taking medically prescribed drugs, there has not been one documented case of death due to nutrients and only a relatively small handful of cases reporting serious side effects. The cost to human health of excess salt consumption must be far greater. The most reactionary aspect of the proposed legislation is that American and British journals are publishing a large and growing number of refereed articles reporting the value for human health of vitamin and mineral intake, not only in food form but also in nutrient form. Will the NHS of the future be happy to have nutrients given only through prescribed and costly "drugs"? WALTIEF BARKER
Early Childhood Development Unit, University of Bristol, Bristol BS8 I HP 1 Richards T. Vitamins face control worldwide. BMJ 1992;305: 491. (29 August.)
Oestrogen replacement after oophorectomy EDITOR,-We are puzzled as to why C Harriet M Anderson and colleagues question whether oestradiol provided by transdermal patches will be as effective as that provided by implants in conferring long term benefits of oestrogen replacement therapy.' They raise this question solely on the basis of a small difference between the two routes of administration in suppressing gonadotrophin. Although this would suggest that the oestradiol dose delivered by the patches was lower than that delivered by the implant, there was actually no significant difference between the two treatments in concentrations of circulating oestradiol. It would therefore seem that delivered doses were actually similar. The authors imply that a difference in gonadotrophin suppression will lead to a different effect on the short term and long term sequelae of the menopause. This extrapolation is based on a study which purported to show a dose-response effect (but actually used arbitrary lines) on urinary excretion of calcium and creatinine, a crude and indirect assessment of bone turnover.2 It has already been shown that oestrogen sensitive tissues do not always respond in a dose dependent manner to increasing dosage; higher doses may reduce sensitivity to oestrogen, possibly because of down regulation of the receptor mechanism.3 In the study of Anderson et al the two methods of giving oestradiol had equivalent biological activity in terms of suppressing vasomotor symptoms. With regard to long terms effects, the 0-05 mg transdermal dose of oestradiol is effective in preventing postmenopausal bone loss.4 It is also effective in producing beneficial changes in lipid and lipoproteins' and in arterial pulsatility index," which suggest that it would be effective in reducing the risk of cardiovascular disease. Thus there is no good evidence that the long term benefits of transdermal oestradiol 0-05mg will be any less than those of oestradiol implants 50 mg. Both routes have the advantage of avoiding the hepatic first pass effect of steroids given orally, and the patches are easier to apply and discontinue. T'IM C HILLARD JOHN C STEVENSON SOVRA I J WHITCROFT MALCOLM I WHITEHEAD Wynn Institute for Metabolic Research, London NW8 95Q 1 Anderson CHM, Rain SK, Forsling ML, Wheeler MJ. Oestrogen replacement after oophorectomy: comparison of patches and implants. BMJ 1992;305:90-1. (11 July.) 2 Selby PL, Peacock M. Dose dependent response of symptoms, pituitary, and bone to transdermal oestrogen in postmenopausal women. BMJ 1986;293:1337-9. 3 Dyer GI, Young 0, Townsend PT, Collins WP, Whitehead MI, Jelowitz J. Dose-related changes in vaginal cytology after topical conjugated enquine oestrogens. BMJ 1982;284:789. 4 Stevenson JC, Cust MP, Ganger KF, Hillard TC, Lees B,
712
Whitehead MI. Effects of transdermal versus oral homrone replacement therapy on bone density in spine and proximal femur in postmenopausal women. Lattcet 1990;335:265-9. 5 Crook D, Cust IMP, Gangar KF, Wortlington M, Hillard TC, Stevenson JC, et al. Comparison of transderinal and oral estrogen/progestin hormone replacement therapy: eflects on serum lipids and lipoproteins, Amti 7 Obstet Gvnecol 1992;166: 950-5. 6 Gangar KF, Vyas S, Whitehead M, Crook D, Meire H, Campbell S. Pulsatilirt index in intemal carotid artery in relation to transdermal oestradiol and time since menopause. Lancet 1991;338:839-42.
EDITOR,-We agree with Harriet Anderson and colleagues that hormone concentrations are not routinely measured in patients receiving oestrogen replacement. ,o Although their study showed significantly lower gonadotrophin concentrations in the implant group, there was no statistically significant difference in the oestradiol levels in the two groups and both were equally effective in preventing hot flushes. As the beneficial effect of hormone replacement therapy correlates with oestradiol concentrations and not gonadotrophin concentrations, it should not cause any panic. A serum oestradiol concentration of > 120 pmol/l provides no further additional effect and may be related to side effects like endometrial hyperplasia2; in the study of Anderson et al oestradiol concentrations were much higher in both groups. Oestrogen probably acts through intermediate products on bone metabolism; these could be prostaglandin E2, calcitonin, or changes in ratio of insulin-like growth factor and growth hormone.' Although calcitriol seems to be a safe and effective treatment for osteoporosis,4 oestrogen replacement therapy is of value in preventing further bone loss and fractures and may benefit the cardiovascular system as well. As regards the cardiovascular system, while oral oestrogen results in a significant increase in plasma triglycerides and in all major lipoprotein factors, percutaneous administration exerts a weak effect on liver metabolism but substantially increases concentrations of high density lipoprotein cholesterol.6 Steingold et al confirmed that transdermal route may have less adverse hepatic effects.Chetkowski et al also showed efficacy of transdermal patches for biological effects.As implants and patches are equally good in maintaining oestradiol levels and suppressing menopausal symptoms and their beneficial effects on cardiovascular and bone metabolism, we see no reason in forcing implants on oophorectomised premenopausal or postmenopausal patients if they are keen to have patches. B W ELIOT
J B SHARMA I JIMASCARENHAS Acute Services Unit, Northampton General Hospital, Northampton NNl 5BD 1 Anderson CMH, Raju SK, Forsling ML, Wheeler MJ. Oestrogen replacement after oophorectomy: comparison of patches and implants. BMJ 1992;305:90-1. (11 July.) 2 Sarlet N, Reginster JY, Gaspard U. Determination of mineral serum oestradiol for prevention of postmenopausal bone loss. Calcif Tissue Int 1 989;44(suppl):S69. 3 Duursma SA, Raymakers JA, Boereboom FTJ, Scheven BAA. Estrogen and bone metabolism. Obstet Gvtnaecol Sues 1992; 47: 38-44. 4 Tilyard MW, Spears GFS, TIhomson J, Dovey S. Treatment of postmenopausal osteoporosis with calcitriol or calcium. NEnglJMed 1992;326:357-62. 5 Lufkin EG, Hodgson SF, Kotowicz MA, O'Fallon WM, Wekner HW, Riggs BL, et al. The use of transdermal estrogen treatment in osteoporosis. In: Christiansen C, Overgaard K, eds. Osteoporosis 1990. Copenhagen: Osteopress, 1990:1995-8. 6 Tepper R, Goldberger S, May JY, Luz IJ, Beyth Y. Hormonal replacement therapy in postmenopausal women and cardiovascular disease: an overview. Obstet 6snaecol Surv 1992; 47:426-31. 7 Steingold KA, Matt DW, Deziegler D. Comparison of transdermal to oral estradiol administration on hormonal and hepatic parameters in women with premature ovarian failure. I Clin Endocrinol Metab 199 1;73:275-8 1. 8 Chetkowski RJ, Meldrum DR, Steingold KA, Randle D, Lu, JK, Eggena P, es al. Biologic effects of transdermal estradiol. NEnglJ7Med 1986;314:1615-20.
EDIrFOR,-Harriet Anderson and colleagues state that premenopausal women undergoing prophylactic oophorectomy are given oestrogen replacement therapy to prevent menopausal symptoms.' It is unfortunate that they did not emphasise the real issues of long term skeletal and cardiovascular protection.2 It is well recognised that premature ovarianfailure appreciably increases the risk of death from myocardial causes.3 We question the ethics of delaying oestrogen replacement for seven days, thereby subjecting premenopausal women to miserable vasomotor symptoms. Was this really necessary? In their final sentence Anderson and colleagues cast doubts as to whether transdermal therapy "will be as effective as the implant in conferring the many long-term benefits of oestrogen replacement." This is inappropriate for two reasons. Firstly, there are no long term epidemiological data regarding skeletal and cardiovascular protection for implants. Most of the published epidemiological data relate to oral conjugated oestrogens.'5 Data do exist, however, showing comparable lipid changes and skeletal preservation of oral and transdermal therapy." Secondly, the dosages studied are not equivalent-a fact which is acknowledged in one of the studies quoted by Anderson and colleagues: Stanczyk et al stated that comparable oestradiol concentrations are obtained with 0 05 mg oestrogen patches and 25 mg implants.3 The authors state that the 0-05 mg patch can suppress gonadotrophin release after spontaneous menopause but not after oophorectomy. The papers cited do not confirm this: both studies found similar concentrations of follicle stimulating hormone and luteinising hormone after four weeks of oestrogen therapy.930 Indeed Chetkowski eg al, referring to spontaneously postmenopausal women treated with various doses of oral and transdermal". oestrogens, state: "even the largest doses of these medications did not lower the gonadotrophins to the levels observed in the premenopausal subjects." Anderson et al explain the recorded difference in gonadotrophin levels by "the higher sustained oestradiol concentrations in the implant group" yet their results state that the mean oestradiol concentrations did not differ significantly. There is no evidence that concentrations of follicle stimulating hormone and luteinising hormone in postmenopausal women taking hormone replacement therapy are of any value in determining efficacy of treatment. It seems inappropriate on the basis of this study to cast doubt on the efficacy of transdermal administration of oestrogen. Evidence already exists indicating a similar biological effect to comparable doses of conjugated oral oestrogens, for which there is an abundance of epidemiological evidence. BRIAN A REID KEVI N F GANGER
Department of Obstetrics and Gvnaecology, St Mary's Hospital Medical School, London W2 I PG I Anderson CHM, Raju SK, Forsling ML, Wheeler MJ.
2 3 4
5 6
7
8.
Oestrogen replacement after oophorectomy: comparison of patches and implants. BMJ 1992;305:90-1. (11 July.) Stevenson JC. Osteoporosis and cardiovascular disease in women: converging paths? Lantcet 1990;336:1 121-2. Colditz GA, Willett WC, Stampfer MJ, Rosner B, Speizer FE, Hennekens CH. Menopause and the risk of coronary heart disease in women. N&EgglAMed 1987;316:1 105-10. Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, ct al. Postmenopausal estrogen therapy and cardiovascular disease. Ten year follow up from the Nurses' Health Study. NEnglJMed 1991;325:756-62. Paganini-Hill A, Ross RK, Gerkins VR, Henderson BE, Arthur M, Mack TM. Menopausal estrogen therapy and hip fractures. Ann Internz Med 1981;95:28-31. Stevenson JC, Cust MP, Gangar KF, Hillard TC, Lees B, Whitehead MI. Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women. Latncet 1990;336:265-9. Crook D, Cust MP, Gangar KF, Worthington M, Hillard TC, Stevenson JC, et al. Comparison of transdermal and oral estrogen-progestin replacement therapy: effects on serum lipids and lipoproteins. Am)I Obstet Gynecol 1992;166:950-5. Stanczvk FZ, Shoupe D, Nunez V, Macias-Gonzales P. A randomised comparison of nonoral estradiol delivery in
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