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EFFECTS OF ORAL CONTRACEPTIVES ON THE FETUS
1258 got pregnant in the first place. What proportion of unwanted pregnancies are due to bad luck (viz., to " method failure "), to plain ignorance, to drunkenness or other drug " abuse, and to carelessness ? And what is meant by carelessness " ? Is it reasonable to view an unwanted pregnancy as a plea for help or attention or affection ?
questions because the answers are not obvious. are answered, it is difficult to establish the which unwanted pregnancy and the psychogenic
I ask these
antiandrogenic properties-e.g., cyproterone acetate.1,2 Even inhibitors of enzymes essential for the
biosynthesis
of &Dgr;4-3-ketosteroids-e.g., 17p-hydroxy-4,4,17oc-trimethyl1 cx-cyano-5-androstene-3-one-caused only moderate feminisation of the external genitals; a vagina was never formed.3 Norethindrone, however, is not antiandrogenic in the classic test models in rats and mice, and we are not aware of any
Yet, until they extent to
illness fnntintrMit
nnnn
it
are
rfnllv nrpupntnhli-
Galton Laboratory, Department of Human Genetics and Biometry, University College London.
WILLIAM H.
JAMES.
SEMEN EXAMINATIONS AFTER VASECTOMY
SIR,-Following vasectomy, the Simon Population Trust and the Medical Defence Union recommend that two consecutive semen examinations demonstrating azoospermia are sufficient before contraceptive precautions can be discarded without the risk of pregnancy. We wish to report that two men, whose vasectomies were confirmed by the pathologist, had two azoospermic semen analyses followed by the finding of spermatozoa in the third specimens examined 3 months and 4 months after operation. We are aware of the variation in the length of time after vasectomy before azoospermia is attained, and also of the relationship between azoospermia and the number of ejaculations. Most of our patients have negative semen samples 3 months after operation, but as well as the two patients mentioned we have two who have scanty sperm 9 months after operation. These men have no evidence of vasal duplication and vasectomy was confirmed histologically in both. Opinion varies as to whether recanalisationor missed double vasis the commoner cause of failure of vasectomy when the original operation has been confirmed histologically. We believe it important to draw attention to the variable time before azoospermia occurs, and to note that spermatozoa can be demonstrated in a third specimen of semen after two previous consecutive azoospermia samples. In our clinic we insist upon three consecutively negative semen specimens before declaring a patient sterile. Liverpool Regional Urological Centre, Sefton General Hospital, Liverpool 15.
J. G. TEMPLE R. M. JAMESON.
EFFECTS OF ORAL CONTRACEPTIVES ON THE FETUS
SIR,-Professor Gardner and his colleagues (Sept. 26, 667) describe the case of a phenotypic female infant with normal external genitalia but with testes and the XY The mother had taken large chromosomal pattern. of an oral quantities contraceptive in an attempt to induce p.
abortion as soon as she realised she was pregnant. We believe it is unlikely that the hormone preparation was responsible for the feminisation.
Firstly, numerous experiments have shown that norethindrone, even in extreme doses, has no influence on male sexual differentiation. It has, on the contrary, a distinct virilising effect on female fetuses (see accompanying figure). Secondly, in experiments with progestational compounds laboratory animals, pronounced feminisation, including formation of a vagina in genetic male fetuses, has so far only been seen after administration of compounds with on
1. 2.
Hanley, G. H. Lancet, 1968, ii, 207. Watt, G. T. Br. med. J. 1969, iv, 443.
Sagittal sections of rat fetuses after norethindrone treatment of the mother (3 mg. daily) from the 17th to the 21st day of pregnancy: (a) heavily virilised female fetus from a treated mother; (b) normal male fetus from the same mother. (Hsmatoxylin and eosin; x 13, reduced by about a third.)
evidence that this steroid inhibits one of the enzymes involved in the biosynthesis of androgens. Thirdly, the appearances of the patient’s genital tract make it unlikely that the feminisation was mediated by norethindrone since:
(a) Compounds with specific feminising properties do not influence testicular differentiation. The infant, however, showed an embryonal testicular pattern of primitive seminiferous cords. (b) The retrogression of mullerian elements in male fetuses influenced by androgens or antiandrogens, but is controlled by an as yet unknown testicular factor.’,s Even if norethindrone had feminising properties, the presence of uterus and tubes cannot be attributed to medication. cannot be
Professor Gardner and his colleagues do not discuss whether the oestrogen component of the contraceptive might have caused the malformations. As long as 30 years ago, experiments on laboratory animals revealed that certain structures of the genital tract can be feminised by oestrogens in extremely high doses. Up to 100 mg. of oestradiol dipropionate was administered daily to rats and mice in the appropriate stage of pregnancy; but doses up to 1 mg. of this steroid had no substantial influence on the differentiation of the male fetuses.s It should be mentioned that, in earlier years, extremely large doses of oestrogen were used in attempts to prevent threatened or habitual abortion. To our knowledge, no malformations were reported corresponding to those described.’-10 The abnormality in sexual differentiation was therefore in all probability unconnected with the abuse of the oral contraceptive. The most likely explanation, 1.
Neumann, F., von Berswordt-Wallrabe, R., Elger, W., Steinbeck, H., Hahn, J. D., Kramer, M. Rec. Prog. Hormone Res. 1970, 26,
2.
Neumann, F., Elger, W., Steinbeck,
337.
H. Proc. R. Soc. B, 1970, 259, 179. 3. Bongiovanni, A. M., Eberlein, W. R., Goldman, A. S., Neu, M. Rec. Prog. Hormone Res. 1967, 23, 375. 4. Jost, A. Archs Anat. microsc. Morph. exp. 1947, 36, 271. 5. Jost, A. C. r. Ass. Anat. 1947, 34, 255. 6. Greene, R. R., Burrill, M. W., Ivy, A. C. Am. J. Anat. 1940, 67 305. 7. 8. 9. 10.
Karnaky, K. J. Sth. Med. J. 1942, 35, 838. Kaufmann, C., Weber, M., Zander, J. Dt. med. Wschr.1959, 84, 347. Plotz, J., Darup, E. Zbl. Gynák. 1949, 71, 867. Smith, O. W. Am. J. Obstet. Gynec. 1948, 56, 821.
1259
mentioned by Professor Gardner and his colleagues, is that this
was a case
of
"
naturally " occurring XY
pure
gonadal dysgenesis. F. NEUMANN W. ELGER H. STEINBECK.
Schering AG, 1 Berlin, 65.
STEROID ABNORMALITIES AND LUNG CANCER
SIR,-Dr. Johns suggests (Nov. 28, p. 1139) that the abnormalities in steroid excretion in lung-cancer patients that I have reported (Aug. 29, p. 441) may be due to the effect of anxiety about the diagnosis and also possibly due to sleep disturbances. I cannot exclude these possibilities in this investigation with any degree of certainty, but I can do so with regard to the results from our previous work.1 In this we found no significant difference between lung-
patients and sick controls with chest diseases in the excretion of the total 17-hydroxycorticosteroids (17-OHc.s.) and of the total 17-oxosteroids in seven consecutive 24-hour collections from the day of admission. Therefore, the lungcancer patients were probably no more anxious about their illness nor had more disturbed sleep than the controls. Since the patients in this investigation and in the more recent one were from the same wards of the same hospitals, and were investigated soon after admission before a diagnosis was established, it is reasonable to assume that the patients in the second investigation are comparable to those of the first. Therefore the raised 17-OHc.s. levels found in the early-morning urine specimens appear to be due mainly to disturbed diurnal variation. It would be interesting to know whether the balance between paradoxical (rapid-eye-movement) sleep and orthodox sleep is disturbed in these patients. cancer
Southern General Hospital, Glasgow S.W.1.
L. G. S. RAO.
ELECTIONS TO COUNCIL OF THE ROYAL COLLEGE OF SURGEONS SIR,-There must be many who are grateful to the Moynihan Club for their continued stand on the controversial topic of adequate provincial representation at the Royal College of Surgeons of England (Nov. 28, p. 1133). There are certainly many who regret the rapidly diminishing prestige of this College in the provinces, and the sad lack of awareness by Council of the serious state of affairs outside London. Until recently adequate representation was not thought too serious a matter since the College had a very minor political role, but despite recent Presidential protestations to the contrary it is now apparent that this is no longer the case. At the last annual general meeting we were assured that the College could have no political role, and almost in the same breath we were also told that specialist registration was essential, in Council’s opinion, as a prelude to entry into a European medical community. I do not suggest that such opinions may not be very proper for Council if they have taken adequate steps to assess that this is the majority opinion of Fellows (which they have not), but surely it is nothing less than equivocation to suggest that such a role is non-political. If, in this sorry story, there is one fact which stands out bright and clear, it is that the yearning for faith in the non-political role is financial in origin, with the fear of loss of status as a recognised charity at the heart of the problem. It is all too easy to be only destructively critical, but there are suggestions voiced at all provincial discussions on 1.
Kissen, D. M., Rao, L. G. S. Ann. N.Y. Acad. Sci. 1969, 164, 476.
never been adequately answered by Council. 1. Regional representation together with facilities for the expression of specialist opinion by coopted representatives of the specialist bodies on appropriate committees. The regional representative must be backed by a regional committee which should be the mechanism by which he can
these matters which have
seek the views of those he represents. Commonwealth Fellows need representation but on a less full scale than do Fellows working in Britain. The often heard argument that many outstanding potential members of Council will find no place on Council is just as easily levelled at the present system as against this alternative. 2. The existing very long tenure of office, usually amounting to sixteen years, should be abbreviated to eight or ten years with an insistence that at least a substantial part of this period should fall within the active working life of the candidate for Council. 3. Finally, could not the academic faculties of the College, rather than the College itself, become the officially registered charities, allowing the College Council to face up to the role which is being offered outside the purely educational field ? The alternative must be the evolution of some focal point for surgical opinion outside the College, which few would wish to see but which many now feel to be
increasingly likely. MICHAEL ROBERTS.
PROSPECTS IN SURGICAL RESEARCH
SIR,-Mr. Anscombe’s letter (Nov. 28, p. 1133) on behalf of the Moynihan Chirurgical Club is one more sign of a coming struggle for power, if not for glory, in the Council of the R.C.S. The case for democratic regional representation is irrefutable. But what are these special, urgent regional interests which are not being currently represented and which take precedence over the appointment of younger men to the Council for shorter periods ? For to decentralise officially now, some may think, would open the door to future chaos and other regional interestsAfter Manchester, what then ? Khartoum, Karachi, Hong-Kong ?
Perhaps
even
a
surgical Avignon
some-
where in Africa ? Many voters will want to know how an increased regional representation will alter Council policies, and indeed, whether these regional members, once voted in, will discharge their duties any more effectively. They would be obliged to state their policies if regional representation is to become a major point of debate. Sir Arthur Keith used to say, after many years of service, that the only president who took any interest in the future of young surgeons was Lord Moynihan, and it was during Moynihan’s presidency that Sir Arthur pushed through the Buckston Browne Farm affair. Are his successors bent on carrying on the tradition ? In an editorial (Nov. 21, p. 1072) on migration of doctors, Sir, you stated, " The prospect of the graduate must be brightened." Will more regional representation do anything about that ? Will the regional members bolster up a policy of postgraduate training involving preoccupation with a fellowship which, had it been operating in former times, would have rendered John Hunter himself unemployable ? What guarantee do we have that the regional members will serve any better the interests of their younger colleagues and the future of surgery ? Take surgeons appointed to the Medical Research Council during the past twenty years. On this Council, metropolitan and provincial members have had equal opportunity to look after metropolitan and provincial surgical interests. But have they ? The accompanying graph reveals the
questions because the answers are not obvious. are answered, it is difficult to establish the which unwanted pregnancy and the psychogenic
I ask these
antiandrogenic properties-e.g., cyproterone acetate.1,2 Even inhibitors of enzymes essential for the
biosynthesis
of &Dgr;4-3-ketosteroids-e.g., 17p-hydroxy-4,4,17oc-trimethyl1 cx-cyano-5-androstene-3-one-caused only moderate feminisation of the external genitals; a vagina was never formed.3 Norethindrone, however, is not antiandrogenic in the classic test models in rats and mice, and we are not aware of any
Yet, until they extent to
illness fnntintrMit
nnnn
it
are
rfnllv nrpupntnhli-
Galton Laboratory, Department of Human Genetics and Biometry, University College London.
WILLIAM H.
JAMES.
SEMEN EXAMINATIONS AFTER VASECTOMY
SIR,-Following vasectomy, the Simon Population Trust and the Medical Defence Union recommend that two consecutive semen examinations demonstrating azoospermia are sufficient before contraceptive precautions can be discarded without the risk of pregnancy. We wish to report that two men, whose vasectomies were confirmed by the pathologist, had two azoospermic semen analyses followed by the finding of spermatozoa in the third specimens examined 3 months and 4 months after operation. We are aware of the variation in the length of time after vasectomy before azoospermia is attained, and also of the relationship between azoospermia and the number of ejaculations. Most of our patients have negative semen samples 3 months after operation, but as well as the two patients mentioned we have two who have scanty sperm 9 months after operation. These men have no evidence of vasal duplication and vasectomy was confirmed histologically in both. Opinion varies as to whether recanalisationor missed double vasis the commoner cause of failure of vasectomy when the original operation has been confirmed histologically. We believe it important to draw attention to the variable time before azoospermia occurs, and to note that spermatozoa can be demonstrated in a third specimen of semen after two previous consecutive azoospermia samples. In our clinic we insist upon three consecutively negative semen specimens before declaring a patient sterile. Liverpool Regional Urological Centre, Sefton General Hospital, Liverpool 15.
J. G. TEMPLE R. M. JAMESON.
EFFECTS OF ORAL CONTRACEPTIVES ON THE FETUS
SIR,-Professor Gardner and his colleagues (Sept. 26, 667) describe the case of a phenotypic female infant with normal external genitalia but with testes and the XY The mother had taken large chromosomal pattern. of an oral quantities contraceptive in an attempt to induce p.
abortion as soon as she realised she was pregnant. We believe it is unlikely that the hormone preparation was responsible for the feminisation.
Firstly, numerous experiments have shown that norethindrone, even in extreme doses, has no influence on male sexual differentiation. It has, on the contrary, a distinct virilising effect on female fetuses (see accompanying figure). Secondly, in experiments with progestational compounds laboratory animals, pronounced feminisation, including formation of a vagina in genetic male fetuses, has so far only been seen after administration of compounds with on
1. 2.
Hanley, G. H. Lancet, 1968, ii, 207. Watt, G. T. Br. med. J. 1969, iv, 443.
Sagittal sections of rat fetuses after norethindrone treatment of the mother (3 mg. daily) from the 17th to the 21st day of pregnancy: (a) heavily virilised female fetus from a treated mother; (b) normal male fetus from the same mother. (Hsmatoxylin and eosin; x 13, reduced by about a third.)
evidence that this steroid inhibits one of the enzymes involved in the biosynthesis of androgens. Thirdly, the appearances of the patient’s genital tract make it unlikely that the feminisation was mediated by norethindrone since:
(a) Compounds with specific feminising properties do not influence testicular differentiation. The infant, however, showed an embryonal testicular pattern of primitive seminiferous cords. (b) The retrogression of mullerian elements in male fetuses influenced by androgens or antiandrogens, but is controlled by an as yet unknown testicular factor.’,s Even if norethindrone had feminising properties, the presence of uterus and tubes cannot be attributed to medication. cannot be
Professor Gardner and his colleagues do not discuss whether the oestrogen component of the contraceptive might have caused the malformations. As long as 30 years ago, experiments on laboratory animals revealed that certain structures of the genital tract can be feminised by oestrogens in extremely high doses. Up to 100 mg. of oestradiol dipropionate was administered daily to rats and mice in the appropriate stage of pregnancy; but doses up to 1 mg. of this steroid had no substantial influence on the differentiation of the male fetuses.s It should be mentioned that, in earlier years, extremely large doses of oestrogen were used in attempts to prevent threatened or habitual abortion. To our knowledge, no malformations were reported corresponding to those described.’-10 The abnormality in sexual differentiation was therefore in all probability unconnected with the abuse of the oral contraceptive. The most likely explanation, 1.
Neumann, F., von Berswordt-Wallrabe, R., Elger, W., Steinbeck, H., Hahn, J. D., Kramer, M. Rec. Prog. Hormone Res. 1970, 26,
2.
Neumann, F., Elger, W., Steinbeck,
337.
H. Proc. R. Soc. B, 1970, 259, 179. 3. Bongiovanni, A. M., Eberlein, W. R., Goldman, A. S., Neu, M. Rec. Prog. Hormone Res. 1967, 23, 375. 4. Jost, A. Archs Anat. microsc. Morph. exp. 1947, 36, 271. 5. Jost, A. C. r. Ass. Anat. 1947, 34, 255. 6. Greene, R. R., Burrill, M. W., Ivy, A. C. Am. J. Anat. 1940, 67 305. 7. 8. 9. 10.
Karnaky, K. J. Sth. Med. J. 1942, 35, 838. Kaufmann, C., Weber, M., Zander, J. Dt. med. Wschr.1959, 84, 347. Plotz, J., Darup, E. Zbl. Gynák. 1949, 71, 867. Smith, O. W. Am. J. Obstet. Gynec. 1948, 56, 821.
1259
mentioned by Professor Gardner and his colleagues, is that this
was a case
of
"
naturally " occurring XY
pure
gonadal dysgenesis. F. NEUMANN W. ELGER H. STEINBECK.
Schering AG, 1 Berlin, 65.
STEROID ABNORMALITIES AND LUNG CANCER
SIR,-Dr. Johns suggests (Nov. 28, p. 1139) that the abnormalities in steroid excretion in lung-cancer patients that I have reported (Aug. 29, p. 441) may be due to the effect of anxiety about the diagnosis and also possibly due to sleep disturbances. I cannot exclude these possibilities in this investigation with any degree of certainty, but I can do so with regard to the results from our previous work.1 In this we found no significant difference between lung-
patients and sick controls with chest diseases in the excretion of the total 17-hydroxycorticosteroids (17-OHc.s.) and of the total 17-oxosteroids in seven consecutive 24-hour collections from the day of admission. Therefore, the lungcancer patients were probably no more anxious about their illness nor had more disturbed sleep than the controls. Since the patients in this investigation and in the more recent one were from the same wards of the same hospitals, and were investigated soon after admission before a diagnosis was established, it is reasonable to assume that the patients in the second investigation are comparable to those of the first. Therefore the raised 17-OHc.s. levels found in the early-morning urine specimens appear to be due mainly to disturbed diurnal variation. It would be interesting to know whether the balance between paradoxical (rapid-eye-movement) sleep and orthodox sleep is disturbed in these patients. cancer
Southern General Hospital, Glasgow S.W.1.
L. G. S. RAO.
ELECTIONS TO COUNCIL OF THE ROYAL COLLEGE OF SURGEONS SIR,-There must be many who are grateful to the Moynihan Club for their continued stand on the controversial topic of adequate provincial representation at the Royal College of Surgeons of England (Nov. 28, p. 1133). There are certainly many who regret the rapidly diminishing prestige of this College in the provinces, and the sad lack of awareness by Council of the serious state of affairs outside London. Until recently adequate representation was not thought too serious a matter since the College had a very minor political role, but despite recent Presidential protestations to the contrary it is now apparent that this is no longer the case. At the last annual general meeting we were assured that the College could have no political role, and almost in the same breath we were also told that specialist registration was essential, in Council’s opinion, as a prelude to entry into a European medical community. I do not suggest that such opinions may not be very proper for Council if they have taken adequate steps to assess that this is the majority opinion of Fellows (which they have not), but surely it is nothing less than equivocation to suggest that such a role is non-political. If, in this sorry story, there is one fact which stands out bright and clear, it is that the yearning for faith in the non-political role is financial in origin, with the fear of loss of status as a recognised charity at the heart of the problem. It is all too easy to be only destructively critical, but there are suggestions voiced at all provincial discussions on 1.
Kissen, D. M., Rao, L. G. S. Ann. N.Y. Acad. Sci. 1969, 164, 476.
never been adequately answered by Council. 1. Regional representation together with facilities for the expression of specialist opinion by coopted representatives of the specialist bodies on appropriate committees. The regional representative must be backed by a regional committee which should be the mechanism by which he can
these matters which have
seek the views of those he represents. Commonwealth Fellows need representation but on a less full scale than do Fellows working in Britain. The often heard argument that many outstanding potential members of Council will find no place on Council is just as easily levelled at the present system as against this alternative. 2. The existing very long tenure of office, usually amounting to sixteen years, should be abbreviated to eight or ten years with an insistence that at least a substantial part of this period should fall within the active working life of the candidate for Council. 3. Finally, could not the academic faculties of the College, rather than the College itself, become the officially registered charities, allowing the College Council to face up to the role which is being offered outside the purely educational field ? The alternative must be the evolution of some focal point for surgical opinion outside the College, which few would wish to see but which many now feel to be
increasingly likely. MICHAEL ROBERTS.
PROSPECTS IN SURGICAL RESEARCH
SIR,-Mr. Anscombe’s letter (Nov. 28, p. 1133) on behalf of the Moynihan Chirurgical Club is one more sign of a coming struggle for power, if not for glory, in the Council of the R.C.S. The case for democratic regional representation is irrefutable. But what are these special, urgent regional interests which are not being currently represented and which take precedence over the appointment of younger men to the Council for shorter periods ? For to decentralise officially now, some may think, would open the door to future chaos and other regional interestsAfter Manchester, what then ? Khartoum, Karachi, Hong-Kong ?
Perhaps
even
a
surgical Avignon
some-
where in Africa ? Many voters will want to know how an increased regional representation will alter Council policies, and indeed, whether these regional members, once voted in, will discharge their duties any more effectively. They would be obliged to state their policies if regional representation is to become a major point of debate. Sir Arthur Keith used to say, after many years of service, that the only president who took any interest in the future of young surgeons was Lord Moynihan, and it was during Moynihan’s presidency that Sir Arthur pushed through the Buckston Browne Farm affair. Are his successors bent on carrying on the tradition ? In an editorial (Nov. 21, p. 1072) on migration of doctors, Sir, you stated, " The prospect of the graduate must be brightened." Will more regional representation do anything about that ? Will the regional members bolster up a policy of postgraduate training involving preoccupation with a fellowship which, had it been operating in former times, would have rendered John Hunter himself unemployable ? What guarantee do we have that the regional members will serve any better the interests of their younger colleagues and the future of surgery ? Take surgeons appointed to the Medical Research Council during the past twenty years. On this Council, metropolitan and provincial members have had equal opportunity to look after metropolitan and provincial surgical interests. But have they ? The accompanying graph reveals the