332 EFFECTS OF LOW-ŒSTROGEN ORAL CONTRACEPTIVES
SIR,-Correspondents have raised several points about our paper.’ Dr Bye and his colleagues2and Dr Swyer3refer to thirteen studies of women taking norgestrel-containing oral contraceptives (o.c.) which, they maintain, show that these do not raise blood-pressure; in 11 studies, 30 p.g oestrogen preparations were used. However, most of the studies are little more than anecdotal as far as blood-pressure is concerned. In addition, with one possible exception, o.c. status was almost certainly known to those taking the pressures, and measurement bias is a very real possibility. A large study4 of the blood-pressure effects of high-cestrogen o.c. appeared to show little or no difference between users and non-users. One reason for this rather surprising result, in the light of subsequent studies,5 may have been that o.c. historires and blood-pressures were taken by the same person. Also, all but one of the studies cited2.3 were uncontrolled. Mean pressures during the early stages ofa longitudinal study in untreated subjects usually fall, 6, probably with increasing familiarity with the procedure. No such fall was seen by Bye and Elstein8 or, to any appreciable extent, by Korba.9 While this does not necessarily mean there was a hidden pressure-rising effect, it is not possible, without controls and without blind measurements, to be sure that 30 p.g cestrogen o.c. are without effect. Bergstein’s finding’" of a fall in pressure in hypertensive women switched from 50 g to 30 .g oestrogen o.c. is as likely to have been due to "regression to the mean"" coupled with familiarisation as to the change in o.c. In showing no pressure increases in women on 30 g o.c. the one controlled study 12 gave results very different from ours. However, these women were selected according to contraceptive practice while in our study there was no selection, blood-pressure being measured without reference to whether women were on o.c. or not. We found highly significant pressure differences between those on 30 g oestrogen o.c. and those not on o.c. Since the increase was at least the same in those on 30 µg as in those on 50 µg oestrogen o.c., it is reasonable to consider the possible role of the other active constituent in 30 µg oestrogen o.c., d-norgestrel. There is ample evidence that norgestrel in many respects is more potent than norethisterone. 13-11 Norethisterone acetate may contribute to the development of hypertension;16 this does not mean that norgestrel also does, but the blood-pressure effects of both compounds deserve further study. The metabolic studies cited by Bye et al.2 make it clear that progestagens are not converted to oestrogens to any biologically 1. Meade, T. W., and others Lancet, 1977, ii, 948. 2. Bye, P. G. T., Wiseman, R. A., Makin, E. J. B. ibid. p. 1085. 3. Swyer, G. I. M. ibid. p. 1086. 4. Kunin, C. M., and others Archs. intern. Med. 1969, 123, 362. 5. Weir, R. J. Am. Heart J. 1976, 92, 119. 6. The Framingham Study: sections 4 and 5 of publication no. (NIH) 74-618. U.S. Department of Health, Education, and Welfare, 1968. 7. National Center for Health Statistics: series 11, no. 4. U.S. Department of Health, Education, and Welfare, 1964. 8. Bye, P. G. T., Elstein, M. Br. med. J. 1973, ii, 389. 9. Korba, V. D. Cited by Bye et al. (ref. 2). 10. Bergstein, N. A. M. Clin. Ther. 1977, 1, 26. 11. Report of M.R.C. Working Party on Mild to Moderate Hypertension Br.
med. J. 1977, i, 1437. 12. Briggs, M., Briggs, M. Lancet, 1977, ii, 1233. 13. Gerhards, E., and others Acta endocr. 1971, 68, 219. 14. Swyer, G. I. M., Little, V. J. Reprod. Fert. 1968, suppl. 5, p. 63. 15. Brotherton, J. Sex Hormone Pharmacology. London, 1976. 16. Royal College of General Practitioners Lancet, 1977, i, 624.
RESULTS IN WOMEN ON
extent. If progestagens do raise blood-pressure we will have to look elsewhere for the explanation. Briggs and Briggs’2 state that 30 fLg oestrogen o.c. have little or no effect on haemostatic variables. Their own studies I) on this aspect were done on 5 women whose results were compared with the "laboratory normal reference range" (my italics). By contrast, we found substantially higher values of factor vn, factor x, and fibrinogen in those on 30 µg oestrogen o.c. than in women not on o.c. (though the values for those on 50
significant
µg oestrogen were even higher). We used "norethisterone" to indicate preparations containing the specified dose of either norethisterone or the acetate, and should have been explicit about this. For practical purposes, their actions 15,18 and metabolism can be considered the same; the acetate is effective at lower doses. All 3 or 4 mg preparations contain the acetate; in 1 mg preparations, norethisterone or the acetate may be used. The most precise comparison is- between high and low doses of the acetate, where the cestrogen is ethinylœstradiol. Our findings, excluding the 9 women on mestranol/norethisterone pills, are summarised in the table; our general conclusions are not affected. Both our study and those referred to by Dr Poller and Miss Thomson19 theoretically permit conclusions about progestagen to be drawn’theirs with 0.35 mg norethisterone in the absence of oestrogen, ours in the presence of oestrogen (the usual situation in oral contraception). The two sets of data can be compared. There could hardly be a greater difference between the suggestion of Poller et al. 20 of a tendency towards reduced coa-
gulability, and ours of precisely the opposite. Our conclusions were cautious, and we recommended further studies, preferably longitudinal; until such results are available, the blood-pressure effects of 30 µg oestrogen o.c. should remain an open question. In addition to the data already discussed, it seems possible that norethisterone acetate leads to a rise in blood-cholesterol.2’ The case for trying to distinguish the effects of progestagens from those of oestrogens is growing in strength. Suggestions that 30 µg oestrogen o.c. have no metabolic effects, at present, unwarranted. M.R.C.-D.H.S.S. Epidemiology and Medical Care Unit, Northwick Park Hospital, Harrow, Middlesex HA1 3UJ
T. W. MEADE
CLASSIFICATION OF OSTEOGENESIS IMPERFECTA BY DENTAL CHARACTERISTICS
SIR,—Osteogenesis imperfecta (0.1.) is a heritable disorder of connective tissue characterised by bone fragility, blue scleras, specific dental abnormalities, and hearing impairment.’ Considerable variation in expression has been noted and several types of the disorder may exist.1.2 An adequate classification of the types has not been reported. We have studied the clinical and radiological characteristics of the dentition of 39 individuals from 8 families who on the basis of bone disease had 0.1. of the tarda form. The disorder 17. Bnggs, M. H., Briggs, M. Curr. med. Res. Opinion, 1976, 3, 618. 18. Martindale: the Extra Pharmacopoeia. London, 1977. 19. Poller, L., Thomson, J. M. Lancet, 1977, ii, 1085. 20. Poller, L., Thomson, J. M., Thomas, P. W. Br. med. J. 1972, iv, 391. 21. Wynn, V., and others. Second International Norgestrel Symposium (Excerpta med. int Congr. Ser. 1974, no. 344); p. 47. 1. McKusick, V. A. Heritable Disorders of Connective Tissue; p. 390. St. Louis, 1972. 2. Bauze, R. J., Smith, R., Frances, M. J. O. J. Bone Jt Surg. 1975, 57B, 1.
50 µg CESTROGEN
O.C.
SIR,-Correspondents have raised several points about our paper.’ Dr Bye and his colleagues2and Dr Swyer3refer to thirteen studies of women taking norgestrel-containing oral contraceptives (o.c.) which, they maintain, show that these do not raise blood-pressure; in 11 studies, 30 p.g oestrogen preparations were used. However, most of the studies are little more than anecdotal as far as blood-pressure is concerned. In addition, with one possible exception, o.c. status was almost certainly known to those taking the pressures, and measurement bias is a very real possibility. A large study4 of the blood-pressure effects of high-cestrogen o.c. appeared to show little or no difference between users and non-users. One reason for this rather surprising result, in the light of subsequent studies,5 may have been that o.c. historires and blood-pressures were taken by the same person. Also, all but one of the studies cited2.3 were uncontrolled. Mean pressures during the early stages ofa longitudinal study in untreated subjects usually fall, 6, probably with increasing familiarity with the procedure. No such fall was seen by Bye and Elstein8 or, to any appreciable extent, by Korba.9 While this does not necessarily mean there was a hidden pressure-rising effect, it is not possible, without controls and without blind measurements, to be sure that 30 p.g cestrogen o.c. are without effect. Bergstein’s finding’" of a fall in pressure in hypertensive women switched from 50 g to 30 .g oestrogen o.c. is as likely to have been due to "regression to the mean"" coupled with familiarisation as to the change in o.c. In showing no pressure increases in women on 30 g o.c. the one controlled study 12 gave results very different from ours. However, these women were selected according to contraceptive practice while in our study there was no selection, blood-pressure being measured without reference to whether women were on o.c. or not. We found highly significant pressure differences between those on 30 g oestrogen o.c. and those not on o.c. Since the increase was at least the same in those on 30 µg as in those on 50 µg oestrogen o.c., it is reasonable to consider the possible role of the other active constituent in 30 µg oestrogen o.c., d-norgestrel. There is ample evidence that norgestrel in many respects is more potent than norethisterone. 13-11 Norethisterone acetate may contribute to the development of hypertension;16 this does not mean that norgestrel also does, but the blood-pressure effects of both compounds deserve further study. The metabolic studies cited by Bye et al.2 make it clear that progestagens are not converted to oestrogens to any biologically 1. Meade, T. W., and others Lancet, 1977, ii, 948. 2. Bye, P. G. T., Wiseman, R. A., Makin, E. J. B. ibid. p. 1085. 3. Swyer, G. I. M. ibid. p. 1086. 4. Kunin, C. M., and others Archs. intern. Med. 1969, 123, 362. 5. Weir, R. J. Am. Heart J. 1976, 92, 119. 6. The Framingham Study: sections 4 and 5 of publication no. (NIH) 74-618. U.S. Department of Health, Education, and Welfare, 1968. 7. National Center for Health Statistics: series 11, no. 4. U.S. Department of Health, Education, and Welfare, 1964. 8. Bye, P. G. T., Elstein, M. Br. med. J. 1973, ii, 389. 9. Korba, V. D. Cited by Bye et al. (ref. 2). 10. Bergstein, N. A. M. Clin. Ther. 1977, 1, 26. 11. Report of M.R.C. Working Party on Mild to Moderate Hypertension Br.
med. J. 1977, i, 1437. 12. Briggs, M., Briggs, M. Lancet, 1977, ii, 1233. 13. Gerhards, E., and others Acta endocr. 1971, 68, 219. 14. Swyer, G. I. M., Little, V. J. Reprod. Fert. 1968, suppl. 5, p. 63. 15. Brotherton, J. Sex Hormone Pharmacology. London, 1976. 16. Royal College of General Practitioners Lancet, 1977, i, 624.
RESULTS IN WOMEN ON
extent. If progestagens do raise blood-pressure we will have to look elsewhere for the explanation. Briggs and Briggs’2 state that 30 fLg oestrogen o.c. have little or no effect on haemostatic variables. Their own studies I) on this aspect were done on 5 women whose results were compared with the "laboratory normal reference range" (my italics). By contrast, we found substantially higher values of factor vn, factor x, and fibrinogen in those on 30 µg oestrogen o.c. than in women not on o.c. (though the values for those on 50
significant
µg oestrogen were even higher). We used "norethisterone" to indicate preparations containing the specified dose of either norethisterone or the acetate, and should have been explicit about this. For practical purposes, their actions 15,18 and metabolism can be considered the same; the acetate is effective at lower doses. All 3 or 4 mg preparations contain the acetate; in 1 mg preparations, norethisterone or the acetate may be used. The most precise comparison is- between high and low doses of the acetate, where the cestrogen is ethinylœstradiol. Our findings, excluding the 9 women on mestranol/norethisterone pills, are summarised in the table; our general conclusions are not affected. Both our study and those referred to by Dr Poller and Miss Thomson19 theoretically permit conclusions about progestagen to be drawn’theirs with 0.35 mg norethisterone in the absence of oestrogen, ours in the presence of oestrogen (the usual situation in oral contraception). The two sets of data can be compared. There could hardly be a greater difference between the suggestion of Poller et al. 20 of a tendency towards reduced coa-
gulability, and ours of precisely the opposite. Our conclusions were cautious, and we recommended further studies, preferably longitudinal; until such results are available, the blood-pressure effects of 30 µg oestrogen o.c. should remain an open question. In addition to the data already discussed, it seems possible that norethisterone acetate leads to a rise in blood-cholesterol.2’ The case for trying to distinguish the effects of progestagens from those of oestrogens is growing in strength. Suggestions that 30 µg oestrogen o.c. have no metabolic effects, at present, unwarranted. M.R.C.-D.H.S.S. Epidemiology and Medical Care Unit, Northwick Park Hospital, Harrow, Middlesex HA1 3UJ
T. W. MEADE
CLASSIFICATION OF OSTEOGENESIS IMPERFECTA BY DENTAL CHARACTERISTICS
SIR,—Osteogenesis imperfecta (0.1.) is a heritable disorder of connective tissue characterised by bone fragility, blue scleras, specific dental abnormalities, and hearing impairment.’ Considerable variation in expression has been noted and several types of the disorder may exist.1.2 An adequate classification of the types has not been reported. We have studied the clinical and radiological characteristics of the dentition of 39 individuals from 8 families who on the basis of bone disease had 0.1. of the tarda form. The disorder 17. Bnggs, M. H., Briggs, M. Curr. med. Res. Opinion, 1976, 3, 618. 18. Martindale: the Extra Pharmacopoeia. London, 1977. 19. Poller, L., Thomson, J. M. Lancet, 1977, ii, 1085. 20. Poller, L., Thomson, J. M., Thomas, P. W. Br. med. J. 1972, iv, 391. 21. Wynn, V., and others. Second International Norgestrel Symposium (Excerpta med. int Congr. Ser. 1974, no. 344); p. 47. 1. McKusick, V. A. Heritable Disorders of Connective Tissue; p. 390. St. Louis, 1972. 2. Bauze, R. J., Smith, R., Frances, M. J. O. J. Bone Jt Surg. 1975, 57B, 1.
50 µg CESTROGEN
O.C.
