603 ations have not yet been sought. It would also be interesting if islands of non-participating endometrium were isolated and examined for the presence or absence of progesterone receptors. Both these studies could be done without any advance in receptor technology. In the absence of progesterone receptors, the relative incidence of carcinoma would depend on the amount of circulating cestrogen, and so carcinoma would be commoner with sequential preparations than with combined type pills. Of the 21 cases of endometrial carcinoma occurring in young women on oral contraception reported to a special registry in the United States by 1975,2 16 had occurred with sequential pills, at a time when these constituted only 8% of oral contraceptives in use. We have reported this case for two reasons. Firstly, to emphasise the importance of thoroughly investigating intermenstrual bleeding irrespective of age, menstrual regularity or mode of contraception, and secondly because we believe it is necessary to re-examine the management of endometrial carcinoma in relatively young women. High-dose progestagen therapy has been reported to be effective in anovulatory infertile women with highly differentiated endometrial carcinoma,’s and disappearance of carcinoma-in-situ has been noted after induction of ovulation and pregnancy.16 For the reasons given above, it would be unwise to anticipate similar good results with high-dose progestagen therapy for early carcinomas in women who have not lacked endogenous progesterone or exogenous progestagen. In these women surgery seems to be the only rational form of treatment.
King George V Memorial Hospital, Sydney, New South Wales, Australia
R. P. S. JANSEN P. M. ELLIOTT
SKIN ABSORTION OF 8-HYDROXYQUINOUNES
SIR,-The subacute myelo-optic neuropathy (s.M.o.N.) catastrophe focused our interest on the absorption of 8-hydroxyquinolines. These drugs were introduced 60 years ago, and for a long time they were regarded as harmless and were thought not to be absorbed. The optic neuritis appearing after the treatment of acrodermatitis enteropathica’ and the S.M.O.N. syndrome2 changed this attitude. The 8-hydroxyquinolines are absorbed from the gut, and they give toxic effects. The 8-hydroxyquinolines are widely used in dermatology. However, no studies have been published on their absorption from the skin. Electron-capture gas chromatgraphy after extractive alkylation has made the compounds amenable for detection below 20 ng/ml in serum or urine.3 Four patients with widespread dermatitis were treated with an ointment containing 3% clioquinol (’Locacorten-Vioform’ ointment). A body area of 40% was treated with 15-20 g of the ointment twice daily. The serum concentration increased to 0.8-1.2 ILglml within four hours of application, remained constant during treatment, and fell on the second day thereafter. No clioquinol could be detected in serum on the fifth day -
after treatment. In one patient the urinary excretion of cliowas measured. The daily excretion during treatment was 15-20 mg/day, >95% being excreted as conjugated metabolites. Thus our skin treatment gave about the same urinary excretion as from a daily oral dose of 0·25gg (one tablet) of clioqumo1.4 We estimated that 3-4% of the applied clioquinol was absorbed.
quinol
15. Kolstad,P. Acta obstet gynœcol. stand. 1972, suppl. 19, 38. 16 Kistner, R. W., Gore, H., Hertig, A. T. Am. J Obstet. Gynec. 1964, 1011 1 Berggren, L., Hansson, O. Lancet, 1966, i, 52. 2 Hansson, O. Läkartidningen, 1976, 73, 2351. 3. Hartvig, P , Fagerlund, C Unpublished. 4 Berggren, L., Hansson, O. Clin. Pharmac. Ther.
1968, 9, 67.
95,
Short-term treatment of the skin with 8-hydroxyquinolines is probably not dangerous, but care is needed when large areas of the skin are treated for a long time. Department of Dermatology and Hospital Pharmacy, University Hospital, S-750 14 Uppsala, Sweden
TORKEL FISCHER PER HARTVIG
CLOMIPHENE, ANENCEPHALY, AND SPINA BIFIDA
SIR,-Sporadic reports of births of infants with anencephaly and/or spina bifida (A.S.B.) to women who had been treated with clomiphene’-’ raised the possibility that the drug had caused the malformation; an alternative speculation is that in such cases the subfertility (the indication for the treatment) is caused by unrecognised spontaneous abortion itself caused in part by A. S.B.1 67 Workers who doubt that the relationship is causal have noted the low rates of malformation among prospectively sampled pregnancies preceded by clomiphene therapy.’9 However, such prospective studies may not be able to discriminate between the two hypotheses because patients are self-selected for clomiphene therapy, and it is difficult to estimate in what proportion of them subfertility is an index of A.s.B. proneness. Hence it is not easy to see how to estimate the expected number of A.S.B. cases on the null hypothesis that the drug ,
does not cause the malformation. Nevin and Harley have reviewed the prior pregnancies of women ascertained because they have had an A.S.B. infant after clomiphene therapy. Since the authors of the relevant papers did not emphasise the significance of the outcome of these pregnancies, 3 it seems reasonable to take them as an unselected sample of such pregnancies. The outcomes of the 7 prior pregnancies which were not preceded by clomiphene treatment were 3 normal live births, 2 spontaneous abortions, and 2 anencephalics. If these women were randomly chosen (rather than selectively A.S.B. prone), a maximum value for the probability of an A.s.B. case in each of these prior pregnancies might be 0.008. Now the probability of 0 or 1 A.S.B. births among 5 pregnancies is 0.9994; in other words, the probability of 2 or more A.S.B. cases in 5 unselected pregnancies is 0-0006. This calculation does not prove that clomiphene never causes A.s.B., but it does show that those women who bear A.S.B. babies after clomiphene therapy also have an unusually high probability of doing so before-higher apparently than the recurrence-rates usually cited for A.S.B. One of the women who gave birth to an A.S.B. infant both before and after clomiphene treatment had an imperfectly controlled Stein-Leventhal syndrome.3 Perhaps the hormone imbalance associated with this syndrome is teratogenic. It would be interesting to know the incidence of malformations among births to women treated for this syndrome. It would also be interesting to know the incidence of A.S.B. among the prior pregnancies of all women tfeated with clomiphene: it is just possible that, far from causing A.S.B., clomiphene may, to some ’extent, protect against it. Galton
Laboratory, Department of Human Genetics and Biometry, University College London, London NW1 2HE
W.
H. JAMES
H. G. Lancet, 1973, i, 1256. Sandler, B. ibid. 1973, ii, 379. 3. Barrett, C., Hakim, C. ibid. p. 916. 4. Field, B., Kerr, C. ibid. 1974, ii, 1511. 5. Nevin, N. C., Harley, J. M. G. Ulster med. J. 1976, 45, 59. 6. James, W. H. Lancet, 1973, ii, 916. 7. James, W. H. ibid. 1974, ii, 1512. 8. Goldfarb, A. F., Morales, A., Rakoff, A. E., Protos, P. Obstet. Gynec. 1968, 31, 342. 9. Hack, M., Brish, M., Serr, D. M., Insler, V., Salomy, M., Lunenfeld, B. J. Am. med. Ass. 1972, 220, 1329. 1. 2.
Dyson, J. L., Kohler,
King George V Memorial Hospital, Sydney, New South Wales, Australia
R. P. S. JANSEN P. M. ELLIOTT
SKIN ABSORTION OF 8-HYDROXYQUINOUNES
SIR,-The subacute myelo-optic neuropathy (s.M.o.N.) catastrophe focused our interest on the absorption of 8-hydroxyquinolines. These drugs were introduced 60 years ago, and for a long time they were regarded as harmless and were thought not to be absorbed. The optic neuritis appearing after the treatment of acrodermatitis enteropathica’ and the S.M.O.N. syndrome2 changed this attitude. The 8-hydroxyquinolines are absorbed from the gut, and they give toxic effects. The 8-hydroxyquinolines are widely used in dermatology. However, no studies have been published on their absorption from the skin. Electron-capture gas chromatgraphy after extractive alkylation has made the compounds amenable for detection below 20 ng/ml in serum or urine.3 Four patients with widespread dermatitis were treated with an ointment containing 3% clioquinol (’Locacorten-Vioform’ ointment). A body area of 40% was treated with 15-20 g of the ointment twice daily. The serum concentration increased to 0.8-1.2 ILglml within four hours of application, remained constant during treatment, and fell on the second day thereafter. No clioquinol could be detected in serum on the fifth day -
after treatment. In one patient the urinary excretion of cliowas measured. The daily excretion during treatment was 15-20 mg/day, >95% being excreted as conjugated metabolites. Thus our skin treatment gave about the same urinary excretion as from a daily oral dose of 0·25gg (one tablet) of clioqumo1.4 We estimated that 3-4% of the applied clioquinol was absorbed.
quinol
15. Kolstad,P. Acta obstet gynœcol. stand. 1972, suppl. 19, 38. 16 Kistner, R. W., Gore, H., Hertig, A. T. Am. J Obstet. Gynec. 1964, 1011 1 Berggren, L., Hansson, O. Lancet, 1966, i, 52. 2 Hansson, O. Läkartidningen, 1976, 73, 2351. 3. Hartvig, P , Fagerlund, C Unpublished. 4 Berggren, L., Hansson, O. Clin. Pharmac. Ther.
1968, 9, 67.
95,
Short-term treatment of the skin with 8-hydroxyquinolines is probably not dangerous, but care is needed when large areas of the skin are treated for a long time. Department of Dermatology and Hospital Pharmacy, University Hospital, S-750 14 Uppsala, Sweden
TORKEL FISCHER PER HARTVIG
CLOMIPHENE, ANENCEPHALY, AND SPINA BIFIDA
SIR,-Sporadic reports of births of infants with anencephaly and/or spina bifida (A.S.B.) to women who had been treated with clomiphene’-’ raised the possibility that the drug had caused the malformation; an alternative speculation is that in such cases the subfertility (the indication for the treatment) is caused by unrecognised spontaneous abortion itself caused in part by A. S.B.1 67 Workers who doubt that the relationship is causal have noted the low rates of malformation among prospectively sampled pregnancies preceded by clomiphene therapy.’9 However, such prospective studies may not be able to discriminate between the two hypotheses because patients are self-selected for clomiphene therapy, and it is difficult to estimate in what proportion of them subfertility is an index of A.s.B. proneness. Hence it is not easy to see how to estimate the expected number of A.S.B. cases on the null hypothesis that the drug ,
does not cause the malformation. Nevin and Harley have reviewed the prior pregnancies of women ascertained because they have had an A.S.B. infant after clomiphene therapy. Since the authors of the relevant papers did not emphasise the significance of the outcome of these pregnancies, 3 it seems reasonable to take them as an unselected sample of such pregnancies. The outcomes of the 7 prior pregnancies which were not preceded by clomiphene treatment were 3 normal live births, 2 spontaneous abortions, and 2 anencephalics. If these women were randomly chosen (rather than selectively A.S.B. prone), a maximum value for the probability of an A.s.B. case in each of these prior pregnancies might be 0.008. Now the probability of 0 or 1 A.S.B. births among 5 pregnancies is 0.9994; in other words, the probability of 2 or more A.S.B. cases in 5 unselected pregnancies is 0-0006. This calculation does not prove that clomiphene never causes A.s.B., but it does show that those women who bear A.S.B. babies after clomiphene therapy also have an unusually high probability of doing so before-higher apparently than the recurrence-rates usually cited for A.S.B. One of the women who gave birth to an A.S.B. infant both before and after clomiphene treatment had an imperfectly controlled Stein-Leventhal syndrome.3 Perhaps the hormone imbalance associated with this syndrome is teratogenic. It would be interesting to know the incidence of malformations among births to women treated for this syndrome. It would also be interesting to know the incidence of A.S.B. among the prior pregnancies of all women tfeated with clomiphene: it is just possible that, far from causing A.S.B., clomiphene may, to some ’extent, protect against it. Galton
Laboratory, Department of Human Genetics and Biometry, University College London, London NW1 2HE
W.
H. JAMES
H. G. Lancet, 1973, i, 1256. Sandler, B. ibid. 1973, ii, 379. 3. Barrett, C., Hakim, C. ibid. p. 916. 4. Field, B., Kerr, C. ibid. 1974, ii, 1511. 5. Nevin, N. C., Harley, J. M. G. Ulster med. J. 1976, 45, 59. 6. James, W. H. Lancet, 1973, ii, 916. 7. James, W. H. ibid. 1974, ii, 1512. 8. Goldfarb, A. F., Morales, A., Rakoff, A. E., Protos, P. Obstet. Gynec. 1968, 31, 342. 9. Hack, M., Brish, M., Serr, D. M., Insler, V., Salomy, M., Lunenfeld, B. J. Am. med. Ass. 1972, 220, 1329. 1. 2.
Dyson, J. L., Kohler,
