746 that produced by oral micronised restradiol-17. It is thought to be caused by oxidation of cestradiol, mainly in the gut.3 These data, which form part of a larger study of oestrogen production and metabolism in postmenopausal women, are reported here to emphasise that biochemical differences between certain hormone preparations may be more apparent than real. Moreover, since the steroids may also be interconverted in endometrial tissue itself"the adjectives "natural" and "synthetic", when applied to preparations used for treatment of postmenopausal women, are often more ambiguous than helpful. J. D. HUTTON M. A. F. MURRAY Departments of Obstetrics and Gynæcology H. S. JACOBS and Chemical Pathology, R. W. BEARD St. Mary’s Hospital Medical School, V. H. T. JAMES London W2
defence for the misclassification of the other matters we shift to firmer and his colleagues suggest that, in Professor Doll ground. women on hormone replacement therapy, there may be a substantially increased risk of endometrial cancer. We have given reasons for doubting a causal association. We will add two more: inevitably the American series excluded 30-40%’ of women on H.R.T.-namely, those who had lost their uterus. Thus, the non-hysterectomy group emerged with a spuriously high risk ratio. Further, between 1950 and 1970 the American mortality from endometrial cancer fell from 9.1 to 4 per 100 OOO,Z though H.R.T. was gaining ground over that period. We agree that the risks must, as always, be weighed against the benefits : on both we need more information.-ED.L.
*,* We
oestrone
can
offer
sulphate.
no
But
on
ADVERTISING ŒSTROGENS
SIR,-Certain pharmaceutical firms have started was disturbing to see restrone sulphate singled out example of a synthetic restrogen in your editorial (March 12, p. 577). This material is the most abundant form of oestrogen so far recognised in the peripheral plasma of non-
SIR,-It
as an
pregnant women6-8 where its concentration is some five times that of (estradiol-17p and fifteen times that of restrone.8 After ovariectomy its concentration, although reduced,, remains much greater than that of oestrone or oestradiol 9 It is unlikely that our understanding of the possible hazards of oestrogen therapy will be improved without due consideration of the available biochemical evidence. Division of Steroid Endocrinology, Department of Chemical Pathology, School of Medicine, Leeds LS2 9L9
GRAHAM MULLEY J. R. A. MITCHELL
Yen, S. S. C., Martin, P. L., Burnier, A. M., Czekala, M. O., Greany, J. R., Callantine, R. J. clin. Endocr. Metab. 1975, 40, 518. 3. Ryan, K. J. Engel, L. L. Endocrinology, 1953, 52, 287. 4. Tseng, L. Gurpide, E. ibid. 1973, 93, 245. 5. Buirchell, B. J., Hähnel, R. J. Steroid Biochem. 1975, 6, 1489. 6. Brown, J. B., Smyth, B. J. J. Reprod. Fertil. 1971, 24, 142. 7. Loriaux, D. L., Ruder, H. J., Lipsett, M. B. Steroids, 1971, 18, 463. 8. Hawkins, R. A., Oaksey, R. E. J. Endocr. 1974, 60, 3. 9. Oakey, R. E., Hawkins, R. A. Br. med. J. 1976, i, 1071. 10. Mulley, G., Mitchell, J. R. A. Lancet, 1976, i, 1397. 11. Gordon, H. The Management of the Menopause and Post-Menopausal Years. Lancaster, 1976. 12. Aksel, S., Schomberg, D. W., Tyrey, L., Hammond, C. B. Am. J. Obstet. Gynec. 1976, 126, 165. 2.
to the manufacturers, however, are not difficult to spot: treatment to one patient costs 10 a year, and there are over
efits R. E. OAKEY
SiR,—You state that menopausal symptoms are "obviously due to oestrogen deprivation". This widely accepted theory does not withstand critical scrutiny,t°and recent publications cast further doubt on the oestrogen-deficiency concept. In a study of postmenopausal women, Gordonll found no correlation between hot flushes and oestrogen status as assessed by vaginal cytology. He suggested that the assumption that vasomotor side-effects of the menopause are hormone-dependent might be wrong. Aksel et al2found that neither declining oestrogen nor rising gonadotrophin values had any direct correlation with the onset of hot flushes in young women after oophorectomy. These workers concluded that the cause of the hot flush remains to be elucidated. Your editorial also mentions the National Health Service clinics which are now providing hormone-replacement therapy. We find it astonishing that oestrogens are being given increasingly to menopausal women, since the rationale of this treatment is highly questionable and the superiority of oestrogen over placebo has not been convincingly established. There is an urgent need to investigate the pathophysiology of hot flushes and to initiate a prospective, large-scale, doubleblind controlled trial comparing oestrogen with a control preparation. Department of Medicine, General Hospital, Nottingham NG1 6HA
an ener-
getic campaign to alter our view of postmenopausal women, Using film-shows, glossy handouts, and lavish hospitality they are trying to persuade doctors that being a woman and over 50 is a disease, susceptible to "treatment" with exogenous oestrogens. Advertising copy is illustrated by a picture of a smiling middle-aged photographic model. We are asked to believe that she is taking cestrogens while the frowning elderly model beside her is not-a technique formerly reserved for selling washing-powder. The advertisements dwell on osteoporosis, with the explicit statement that long-term oestrogen administration to symptom-free women will prevent this condition. This suggestion is dubious. The benefits to the patient of long-term cestrogen administration are not proven. The benfive million postmenopausal women in Britain. This high-powered sales campaign is disturbing because carcinogenic effects of prolonged unopposed oestrogen stimulation are theoretically possible3-1 and have been suggested in dinical trial.6-* Advertising material ignores this, or suggests that reports of the association with endometrial cancer (discussed in your editorial of March 12, p. 577) and breast cancer are scientifically unsound. Each firm implies that its own product has a special reason to be "safe", either because it is "natural" (i.e., prepared from horse’s urine) or because it is "naturally occurring" (i.e., artificially synthesised to the formula of one of the human oestrogens). I am concerned that we are speedily being indoctrinated by the commercial machine, while no-one has a vested interest in spelling out the dangers of long-term use_of oestrogens. Department of Obstetrics and Gynæcology, Eastern General Hospital, Edinburgh
JAMES OWEN DRIFE
WHOOPING-COUGH VACCINATION p. 234) states that the risks of whooping-cough vaccination exceed its efficacy. His conclusion rests heavily on the apparent failure of whoopingcough mortality in Scotland to depart from the level predicted by the pre-vaccination trend. The pattern in the Province of Ontario has been strikingly different from that reported by Professor Stewart. The accompanying figure, an extension of one published in 1961,9 shows the trend of mortality from whooping-cough over a period of
SIR,-Professor Stewart (Jan. 29,
1.
Gambrell,
R. D. in Consensus
on
Menopause Research; p. 153. Lancaster,
1976.
Cramer, D. W., et al. Gynec. Oncol. 1974, 2, 130. Sherman, B. M., Korenman, S. G. Cancer, 1974, 33, 1306. MacMahon, B., Cole, P. Rec. Results Cancer Res. 1972, 39, 185. Drife, J. O., McClelland, D. B. L., Pryde, A., Roberts, M. M., Smith, I.I. Br. med. J. 1976, ii, 503. 6. Smith, D. C., Prentice, R., Thompson, D. J., Herrmann, W. L. New Engl. 2. 3. 4. 5.
J. Med. 1975, 293, 1164. 7. 8. 9.
Ziel, H. K., Fmkle, W. D. ibid. 1975, 293, 1167. Hoover, R., Gray, L. A., Cole, P., MacMahon, B. ibid. 1976, 295, 401. Buck, C. Can. J. publ. Hlth, 1961, 52, 352.
defence for the misclassification of the other matters we shift to firmer and his colleagues suggest that, in Professor Doll ground. women on hormone replacement therapy, there may be a substantially increased risk of endometrial cancer. We have given reasons for doubting a causal association. We will add two more: inevitably the American series excluded 30-40%’ of women on H.R.T.-namely, those who had lost their uterus. Thus, the non-hysterectomy group emerged with a spuriously high risk ratio. Further, between 1950 and 1970 the American mortality from endometrial cancer fell from 9.1 to 4 per 100 OOO,Z though H.R.T. was gaining ground over that period. We agree that the risks must, as always, be weighed against the benefits : on both we need more information.-ED.L.
*,* We
oestrone
can
offer
sulphate.
no
But
on
ADVERTISING ŒSTROGENS
SIR,-Certain pharmaceutical firms have started was disturbing to see restrone sulphate singled out example of a synthetic restrogen in your editorial (March 12, p. 577). This material is the most abundant form of oestrogen so far recognised in the peripheral plasma of non-
SIR,-It
as an
pregnant women6-8 where its concentration is some five times that of (estradiol-17p and fifteen times that of restrone.8 After ovariectomy its concentration, although reduced,, remains much greater than that of oestrone or oestradiol 9 It is unlikely that our understanding of the possible hazards of oestrogen therapy will be improved without due consideration of the available biochemical evidence. Division of Steroid Endocrinology, Department of Chemical Pathology, School of Medicine, Leeds LS2 9L9
GRAHAM MULLEY J. R. A. MITCHELL
Yen, S. S. C., Martin, P. L., Burnier, A. M., Czekala, M. O., Greany, J. R., Callantine, R. J. clin. Endocr. Metab. 1975, 40, 518. 3. Ryan, K. J. Engel, L. L. Endocrinology, 1953, 52, 287. 4. Tseng, L. Gurpide, E. ibid. 1973, 93, 245. 5. Buirchell, B. J., Hähnel, R. J. Steroid Biochem. 1975, 6, 1489. 6. Brown, J. B., Smyth, B. J. J. Reprod. Fertil. 1971, 24, 142. 7. Loriaux, D. L., Ruder, H. J., Lipsett, M. B. Steroids, 1971, 18, 463. 8. Hawkins, R. A., Oaksey, R. E. J. Endocr. 1974, 60, 3. 9. Oakey, R. E., Hawkins, R. A. Br. med. J. 1976, i, 1071. 10. Mulley, G., Mitchell, J. R. A. Lancet, 1976, i, 1397. 11. Gordon, H. The Management of the Menopause and Post-Menopausal Years. Lancaster, 1976. 12. Aksel, S., Schomberg, D. W., Tyrey, L., Hammond, C. B. Am. J. Obstet. Gynec. 1976, 126, 165. 2.
to the manufacturers, however, are not difficult to spot: treatment to one patient costs 10 a year, and there are over
efits R. E. OAKEY
SiR,—You state that menopausal symptoms are "obviously due to oestrogen deprivation". This widely accepted theory does not withstand critical scrutiny,t°and recent publications cast further doubt on the oestrogen-deficiency concept. In a study of postmenopausal women, Gordonll found no correlation between hot flushes and oestrogen status as assessed by vaginal cytology. He suggested that the assumption that vasomotor side-effects of the menopause are hormone-dependent might be wrong. Aksel et al2found that neither declining oestrogen nor rising gonadotrophin values had any direct correlation with the onset of hot flushes in young women after oophorectomy. These workers concluded that the cause of the hot flush remains to be elucidated. Your editorial also mentions the National Health Service clinics which are now providing hormone-replacement therapy. We find it astonishing that oestrogens are being given increasingly to menopausal women, since the rationale of this treatment is highly questionable and the superiority of oestrogen over placebo has not been convincingly established. There is an urgent need to investigate the pathophysiology of hot flushes and to initiate a prospective, large-scale, doubleblind controlled trial comparing oestrogen with a control preparation. Department of Medicine, General Hospital, Nottingham NG1 6HA
an ener-
getic campaign to alter our view of postmenopausal women, Using film-shows, glossy handouts, and lavish hospitality they are trying to persuade doctors that being a woman and over 50 is a disease, susceptible to "treatment" with exogenous oestrogens. Advertising copy is illustrated by a picture of a smiling middle-aged photographic model. We are asked to believe that she is taking cestrogens while the frowning elderly model beside her is not-a technique formerly reserved for selling washing-powder. The advertisements dwell on osteoporosis, with the explicit statement that long-term oestrogen administration to symptom-free women will prevent this condition. This suggestion is dubious. The benefits to the patient of long-term cestrogen administration are not proven. The benfive million postmenopausal women in Britain. This high-powered sales campaign is disturbing because carcinogenic effects of prolonged unopposed oestrogen stimulation are theoretically possible3-1 and have been suggested in dinical trial.6-* Advertising material ignores this, or suggests that reports of the association with endometrial cancer (discussed in your editorial of March 12, p. 577) and breast cancer are scientifically unsound. Each firm implies that its own product has a special reason to be "safe", either because it is "natural" (i.e., prepared from horse’s urine) or because it is "naturally occurring" (i.e., artificially synthesised to the formula of one of the human oestrogens). I am concerned that we are speedily being indoctrinated by the commercial machine, while no-one has a vested interest in spelling out the dangers of long-term use_of oestrogens. Department of Obstetrics and Gynæcology, Eastern General Hospital, Edinburgh
JAMES OWEN DRIFE
WHOOPING-COUGH VACCINATION p. 234) states that the risks of whooping-cough vaccination exceed its efficacy. His conclusion rests heavily on the apparent failure of whoopingcough mortality in Scotland to depart from the level predicted by the pre-vaccination trend. The pattern in the Province of Ontario has been strikingly different from that reported by Professor Stewart. The accompanying figure, an extension of one published in 1961,9 shows the trend of mortality from whooping-cough over a period of
SIR,-Professor Stewart (Jan. 29,
1.
Gambrell,
R. D. in Consensus
on
Menopause Research; p. 153. Lancaster,
1976.
Cramer, D. W., et al. Gynec. Oncol. 1974, 2, 130. Sherman, B. M., Korenman, S. G. Cancer, 1974, 33, 1306. MacMahon, B., Cole, P. Rec. Results Cancer Res. 1972, 39, 185. Drife, J. O., McClelland, D. B. L., Pryde, A., Roberts, M. M., Smith, I.I. Br. med. J. 1976, ii, 503. 6. Smith, D. C., Prentice, R., Thompson, D. J., Herrmann, W. L. New Engl. 2. 3. 4. 5.
J. Med. 1975, 293, 1164. 7. 8. 9.
Ziel, H. K., Fmkle, W. D. ibid. 1975, 293, 1167. Hoover, R., Gray, L. A., Cole, P., MacMahon, B. ibid. 1976, 295, 401. Buck, C. Can. J. publ. Hlth, 1961, 52, 352.
