1134
H.B.v. infections
in late pregnancy or early post but to reserve partum, judgment on the treatment of infants of HBsAg carrier mothers until prospective investigations in related populations establish the size of the risk. There is one further, and wider,
possible application of anti-HBs I.G. Infection may be acquired by sexual or close household contacts of either- acute hepatitis-B cases or HBsAg carriers.22 A trial in the U.S.A. among spouses of acute-hepatitis-B patients showed that high-titre anti-HBs I.G. conferred protection, but the attackrate of the control group was unexpectedly high.23 Any decision to give anti-HBs I.G. to similarly exposed spouses must depend on both availability of the material and assessments of the risk of infection.
DAMAGING ACTION the conflict between Government and doctors in the National Health Service must come from a compromise on two questions: what is a fair interpretation of the Government’s pay policy as it affects the juniors’ immediate prospects?; and how can their working conditions, notably the long hours on duty and on call, be improved? The pay policy must, in the national interest, be preserved; and the junior doctors declare that they have no wish to breach it, though their claim for clinical-assistant sessional rates (11.50 for 3yhours) for time over 80 hours a week looks a certain policy-buster. How much money can be provided, within the policy, for overtime payments? The Government’s figure of £12 million a year is challenged by the juniors, largely because not all those who have been entitled to retrospective overtime money have, for one reason or another, been granted it or claimed it in the past. Thus, say the juniors’ representatives, the Review Body’s pricing is faulty. Sir Ernest Woodroofe, chairman of the Review Body, has stated that he and his colleagues did take such factors into account, but he has suggested that misunderstandings may be removed by discussions between the Office of Manpower Economics, which serves the Review Body, and the B.M.A.’s statistical adviser. In the House of Commons last Monday, Mrs Barbara Castle, Secretary of State for Social Services, announced that the B.M.A. had accepted this proposal, and technical discussions would take place immediately. She repeated her assurance that it would be possible, under the pay policy, to begin to introduce new contracts for junior hospital doctors on a basis which would ensure "no detriment." Mrs Castle added that she was willing to enter into immediate talks with the juniors and with consultants’ representatives to see how far it would be possible to establish a maximum of 80 hours a week for junior staff. Such a timetable could not be introduced unless the consultants concurred and unless juniors in posts which did not entail long hours were willing to share the burden with those in other jobs. Neither the new audit on overtime nor the burden-sharing proposal will produce immediate happiness among A
SOLUTION to
junior hospital
22. Heathcote, J., Sherlock, S. Lancet, 1973, i, 1468. 23. Redeker, A. G., Mosley, J. W., Gocke, D. J., McKee, A. P., Engl.J. Med. 1975, 293, 1055.
Pollack, W. New
those juniors who are now applying sanctions by means of a 40-hour week and the treatment of emergencies only; but there is room here for continued negotiations and very soon, we trust, for the withdrawal of industrial action by the juniors. At the moment, they receive much public sympathy in their stand, but disasters to patients may befall at any hour during the disruptions and sympathy may turn to bitterness. Some N.H.S. consultants are now in industrial action against the Government’s plans for the separation of private and N.H.S. practice. The Council of the B.M.A. had recommended that, from Dec. 1, senior hospital doctors "should be advised to limit their work to caring for emergencies and to the care of patients already receiving inpatient treatment" and that the Central Committee for Hospital Medical Services be empowered to collect from consultants and other senior grades their undated resignations from the N.H.S. A statement issued on Nov. 26 by the Presidents and Deans of the Royal Colleges and Faculties deplored "the refusal of the Government, despite the profession’s earnest and explicit entreaties, to display any willingness to consult the profession in a meaningful way on these proposals"; but the Presidents and Deans could not associate themselves with those members of the profession who proposed to limit their services to the treatment of emergencies. The Presidents and Deans shared their colleagues’ concern, which they knew to be sincere, at the effect of the proposed actions on the care of patients; and, for the Colleges and Faculties, "this concern must... override all other considerations." Sir Rodney Smith, President of the Royal College of Surgeons of England, was due to meet the Prime Minister last Wednesday to emphasise these views. If the consultants fight the Government to the uttermost, with mass resignations from the N.H.S., then the Service may never recover. One widely held view is put by a distinguished orthopaedic surgeon:’ "If we can win this fight now we have some hope of picking up and eventually mending some of the inevitably broken pieces. But there will be no hope at all for patients or ourselves if we are squeezed into becoming acquiescent pawns of the D.H.S.S.". A renowned neurologist and dean sees it another way:2 "Under no circumstances could 1, or many of my colleagues in Newcastle, both senior and junior, subscribe to a course of action which, however indirectly, will damage patients, though I shall do what little I can to oppose each misguided Government directive in every way possible Industrial action by any group of doctors is intolerable; if taken by consultants it is unforgivable if it involves any withdrawal of clinical responsibility for patient care." Though The Lancet shares Professor Walton’s opinion of industrial action by doctors, we do not wish the Government to stand foursquare on its proposals for phasing-out of paybeds and licensing of private hospitals. If the Government cannot relent to the point of referring the issue to the Royal Commission, then let it give ground in the talks on the consultative document. The best course would be to concentrate for the moment on the investigation of methods for the elimination of the injustices (some, more real than others) in the borderland between private and N.H.S. practice. The Government should also make it more ...
1. Fairbank, T. J. Times, Dec. 2. 2. Walton, J. N. ibid. Nov. 28.
1135
plain to the consultants that it is not pressing ahead with legislation for the separation of private practice largely because the unions are baying at its heels.
DANGERS IN ETERNAL YOUTH A LEADER in June’ discussed the advantage and disadvantages of continuous oestrogen replacement in postmenopausal women.’ Of the advantages there can be little doubt-and some say that this therapy is a woman’s
disadvantages are nebulous: the and metabolic of cardiovascular effects are essendangers until so tially unproven; too, very lately, was the potenfor an increased incidence of cancer. Now an investial tigation from the Kaiser Medical Center in Los Angeles provides disturbing evidence that the risk of cancer in at least one site-the endometrium-may be substantially enhanced by continuous use of the so-called natural restrogens, the principle component of which is a sulphate conjugate of cestrone. Using the immense records of the Kaiser Foundation Health Plan, Ziel and Finkle2 compared 94 patients with endometrial cancer with twice that number of control women matched for several critical factors. Of the patients, 57% had received conjugated oestrogens; of the controls, only 15%. An elaborate statistical exercise revealed a "risk ratio" of 7.6 for takers versus non-takers, and the conclusions were not grossly altered when possible associated factors such as parity, excessive weight, and age at menopause were taken into account. This investigation provides the first fully acceptable evidence of a risk in long-term cestrogen replacement. The question then arises, is the risk equal with all restrogen preparations, or is it specific to those containing oestrone? Other evidence may point to the second possibility. Siiteri and his colleagues3 have noted that in patients with endometrial cancer there is excess peripheral conversion of androstenedione to oestrone, and they hypothesise that this may be causally related to the tumour. The difficulty with this suggestion is that the actual circulating levels of restrone do not seem to differ between patients and controls. Clearly other investigations similar to those of the Kaiser group are essential to establish whether alternative cestrogen preparations are associated with a similar risk. Meanwhile, in the absence of clearcut information on other potential dangers, the only possible recommendation is that all candidates for long-term cestrogen replacement should have a hysterectomy-not a very attractive prospect if the eventual aim is treatment of entire populations.
right.
In contrast, the
NEW DRUG TREATMENT FOR CUSHING’S
DISEASE
Cushing’s syndrome is the generic term used to describe the clinical and biochemical abnormalities resulting from a chronic excess of glucocorticoids. Cushing’s disease is the commonest variety of this syndrome, pro1. Lancet, 1975, i, 1282. 2. Ziel, H. K., Finkle, W. D. New Engl.J. Med. Dec. 4, 1975. 3 Suteri, P. K., Schwarz, B. E., McDonald, P. C. Gynec. Oncol. 1974, 2,
228.
duced by inappropriately high corticotrophin (A.C.T.H.) secretion from the anterior pituitary. Although pituitary tumours are common in Cushing’s disease, being radiologically detectable in up to 15% of patients at the time of diagnosis and arising subsequently in further patients if treatment is directed primarily to the adrenals, there is some evidence for an underlying abnormality of the central nervous system. Patients with Cushing’s disease lose their normal sleep-related A.C.T.H., growth-hormone (G.H.),land prolactin (PRL)3 secretory patterns, which remain abnormal after the adrenal overactivity has been corrected. Electroencephalographic recordings show a striking diminution in stage 3 and 4 sleep and in rapid eye movements.12 There is evidence that serotoninergic mechanisms in the central nervous system are involved in slow-wave sleep4 and in the stimulation of G.H.s and PRL secretion,6 though no work has been reported on the role of serotonin in the nocturnal surges of these hormones. In normal volunteers serotonin antagonists have been shown to block hypoglycaemia-induced cortisol secretion.’ Thus it seems likely, from work in man as well as in animals, that serotonin is involved in the control of A.C.T.H. secretion, possibly by the mediation of corticotrophin-releasing factor synthesised in the
hypothalamus. Krieger et al. have studied
the effect of cyproheptain three patients with function dine pituitary/adrenal Cushing’s disease. Cyproheptadine is one of the most potent antihistamines, and it also has anticholinergic and pronounced antiserotonin actions. Administration of this drug in a dose of 24 mg daily for three to six months was associated with prompt and sustained clinical and biochemical remission of the disease. Cortisolsecretion rate and urinary corticosteroid excretion returned to normal, but the abnormality in circadian periodicity of plasma-cortisol concentrations persisted and A.C.T.H. levels remained raised in one of the two patients tested. Although the urinary corticosteroid response to low doses of dexamethasone (2 mg per day) became normal, a paradoxical rise followed 8 mg per day. Normal amounts of stage 3 and 4 sleep were restored in the one patient studied. Cessation of treatment in one patient was followed by relapse. The claim of Dr Krieger and her colleagues that the effects obtained with cyproheptadine were due to its antiserotonin action seems a reasonable one although its antihistamine and anticholinergic actions cannot be ruled out. In view of the efficacy of cyproheptadine and its apparent lack of toxicity this drug does seem to offer a rational and promising approach to the treatment of Cushing’s disease. But before the drug is adopted as a routine treatment for Cushing’s disease, important questions must be answered. Will remission be maintained if treatment is prolonged, and sustained when prolonged treatment is withdrawn? Will growth of the causal pituitary tumour be suppressed or continue if cyproheptadine is used alone or after bilateral adrenalectomy? Will troublesome side-effects arise after prolonged therapy? on
1. Krieger, D. T., Glick, S. M. Am. J. Med. 1972, 52, 25. 2. Krieger, D. T., Glick, S. M.J. clin. Endocr. Metab. 1974, 39, 986. 3. Krieger, D. T., Howanitz, P. J., Frantz, A G. ibid. (in the press). 4. Jouvet, M. Science, 1969, 163, 32. 5. Brown, G. M., Chambers, J. W., Feldman, J. Proc. Soc. Neurosci. 1973, p. 404. 6. Macindoe, J. H., Turkington, R. M.J. clin. Invest. 1973, 52, 1972. 7. Plonk, J. W., Bivens, C. H., Feldman, J. M. J. clin. Endocr. Metab. 1974, 8.
38, 836. Krieger, D. T., Amorosa, L., Linick,
F. New
Engl. J. Med. 1975, 293,
893.
H.B.v. infections
in late pregnancy or early post but to reserve partum, judgment on the treatment of infants of HBsAg carrier mothers until prospective investigations in related populations establish the size of the risk. There is one further, and wider,
possible application of anti-HBs I.G. Infection may be acquired by sexual or close household contacts of either- acute hepatitis-B cases or HBsAg carriers.22 A trial in the U.S.A. among spouses of acute-hepatitis-B patients showed that high-titre anti-HBs I.G. conferred protection, but the attackrate of the control group was unexpectedly high.23 Any decision to give anti-HBs I.G. to similarly exposed spouses must depend on both availability of the material and assessments of the risk of infection.
DAMAGING ACTION the conflict between Government and doctors in the National Health Service must come from a compromise on two questions: what is a fair interpretation of the Government’s pay policy as it affects the juniors’ immediate prospects?; and how can their working conditions, notably the long hours on duty and on call, be improved? The pay policy must, in the national interest, be preserved; and the junior doctors declare that they have no wish to breach it, though their claim for clinical-assistant sessional rates (11.50 for 3yhours) for time over 80 hours a week looks a certain policy-buster. How much money can be provided, within the policy, for overtime payments? The Government’s figure of £12 million a year is challenged by the juniors, largely because not all those who have been entitled to retrospective overtime money have, for one reason or another, been granted it or claimed it in the past. Thus, say the juniors’ representatives, the Review Body’s pricing is faulty. Sir Ernest Woodroofe, chairman of the Review Body, has stated that he and his colleagues did take such factors into account, but he has suggested that misunderstandings may be removed by discussions between the Office of Manpower Economics, which serves the Review Body, and the B.M.A.’s statistical adviser. In the House of Commons last Monday, Mrs Barbara Castle, Secretary of State for Social Services, announced that the B.M.A. had accepted this proposal, and technical discussions would take place immediately. She repeated her assurance that it would be possible, under the pay policy, to begin to introduce new contracts for junior hospital doctors on a basis which would ensure "no detriment." Mrs Castle added that she was willing to enter into immediate talks with the juniors and with consultants’ representatives to see how far it would be possible to establish a maximum of 80 hours a week for junior staff. Such a timetable could not be introduced unless the consultants concurred and unless juniors in posts which did not entail long hours were willing to share the burden with those in other jobs. Neither the new audit on overtime nor the burden-sharing proposal will produce immediate happiness among A
SOLUTION to
junior hospital
22. Heathcote, J., Sherlock, S. Lancet, 1973, i, 1468. 23. Redeker, A. G., Mosley, J. W., Gocke, D. J., McKee, A. P., Engl.J. Med. 1975, 293, 1055.
Pollack, W. New
those juniors who are now applying sanctions by means of a 40-hour week and the treatment of emergencies only; but there is room here for continued negotiations and very soon, we trust, for the withdrawal of industrial action by the juniors. At the moment, they receive much public sympathy in their stand, but disasters to patients may befall at any hour during the disruptions and sympathy may turn to bitterness. Some N.H.S. consultants are now in industrial action against the Government’s plans for the separation of private and N.H.S. practice. The Council of the B.M.A. had recommended that, from Dec. 1, senior hospital doctors "should be advised to limit their work to caring for emergencies and to the care of patients already receiving inpatient treatment" and that the Central Committee for Hospital Medical Services be empowered to collect from consultants and other senior grades their undated resignations from the N.H.S. A statement issued on Nov. 26 by the Presidents and Deans of the Royal Colleges and Faculties deplored "the refusal of the Government, despite the profession’s earnest and explicit entreaties, to display any willingness to consult the profession in a meaningful way on these proposals"; but the Presidents and Deans could not associate themselves with those members of the profession who proposed to limit their services to the treatment of emergencies. The Presidents and Deans shared their colleagues’ concern, which they knew to be sincere, at the effect of the proposed actions on the care of patients; and, for the Colleges and Faculties, "this concern must... override all other considerations." Sir Rodney Smith, President of the Royal College of Surgeons of England, was due to meet the Prime Minister last Wednesday to emphasise these views. If the consultants fight the Government to the uttermost, with mass resignations from the N.H.S., then the Service may never recover. One widely held view is put by a distinguished orthopaedic surgeon:’ "If we can win this fight now we have some hope of picking up and eventually mending some of the inevitably broken pieces. But there will be no hope at all for patients or ourselves if we are squeezed into becoming acquiescent pawns of the D.H.S.S.". A renowned neurologist and dean sees it another way:2 "Under no circumstances could 1, or many of my colleagues in Newcastle, both senior and junior, subscribe to a course of action which, however indirectly, will damage patients, though I shall do what little I can to oppose each misguided Government directive in every way possible Industrial action by any group of doctors is intolerable; if taken by consultants it is unforgivable if it involves any withdrawal of clinical responsibility for patient care." Though The Lancet shares Professor Walton’s opinion of industrial action by doctors, we do not wish the Government to stand foursquare on its proposals for phasing-out of paybeds and licensing of private hospitals. If the Government cannot relent to the point of referring the issue to the Royal Commission, then let it give ground in the talks on the consultative document. The best course would be to concentrate for the moment on the investigation of methods for the elimination of the injustices (some, more real than others) in the borderland between private and N.H.S. practice. The Government should also make it more ...
1. Fairbank, T. J. Times, Dec. 2. 2. Walton, J. N. ibid. Nov. 28.
1135
plain to the consultants that it is not pressing ahead with legislation for the separation of private practice largely because the unions are baying at its heels.
DANGERS IN ETERNAL YOUTH A LEADER in June’ discussed the advantage and disadvantages of continuous oestrogen replacement in postmenopausal women.’ Of the advantages there can be little doubt-and some say that this therapy is a woman’s
disadvantages are nebulous: the and metabolic of cardiovascular effects are essendangers until so tially unproven; too, very lately, was the potenfor an increased incidence of cancer. Now an investial tigation from the Kaiser Medical Center in Los Angeles provides disturbing evidence that the risk of cancer in at least one site-the endometrium-may be substantially enhanced by continuous use of the so-called natural restrogens, the principle component of which is a sulphate conjugate of cestrone. Using the immense records of the Kaiser Foundation Health Plan, Ziel and Finkle2 compared 94 patients with endometrial cancer with twice that number of control women matched for several critical factors. Of the patients, 57% had received conjugated oestrogens; of the controls, only 15%. An elaborate statistical exercise revealed a "risk ratio" of 7.6 for takers versus non-takers, and the conclusions were not grossly altered when possible associated factors such as parity, excessive weight, and age at menopause were taken into account. This investigation provides the first fully acceptable evidence of a risk in long-term cestrogen replacement. The question then arises, is the risk equal with all restrogen preparations, or is it specific to those containing oestrone? Other evidence may point to the second possibility. Siiteri and his colleagues3 have noted that in patients with endometrial cancer there is excess peripheral conversion of androstenedione to oestrone, and they hypothesise that this may be causally related to the tumour. The difficulty with this suggestion is that the actual circulating levels of restrone do not seem to differ between patients and controls. Clearly other investigations similar to those of the Kaiser group are essential to establish whether alternative cestrogen preparations are associated with a similar risk. Meanwhile, in the absence of clearcut information on other potential dangers, the only possible recommendation is that all candidates for long-term cestrogen replacement should have a hysterectomy-not a very attractive prospect if the eventual aim is treatment of entire populations.
right.
In contrast, the
NEW DRUG TREATMENT FOR CUSHING’S
DISEASE
Cushing’s syndrome is the generic term used to describe the clinical and biochemical abnormalities resulting from a chronic excess of glucocorticoids. Cushing’s disease is the commonest variety of this syndrome, pro1. Lancet, 1975, i, 1282. 2. Ziel, H. K., Finkle, W. D. New Engl.J. Med. Dec. 4, 1975. 3 Suteri, P. K., Schwarz, B. E., McDonald, P. C. Gynec. Oncol. 1974, 2,
228.
duced by inappropriately high corticotrophin (A.C.T.H.) secretion from the anterior pituitary. Although pituitary tumours are common in Cushing’s disease, being radiologically detectable in up to 15% of patients at the time of diagnosis and arising subsequently in further patients if treatment is directed primarily to the adrenals, there is some evidence for an underlying abnormality of the central nervous system. Patients with Cushing’s disease lose their normal sleep-related A.C.T.H., growth-hormone (G.H.),land prolactin (PRL)3 secretory patterns, which remain abnormal after the adrenal overactivity has been corrected. Electroencephalographic recordings show a striking diminution in stage 3 and 4 sleep and in rapid eye movements.12 There is evidence that serotoninergic mechanisms in the central nervous system are involved in slow-wave sleep4 and in the stimulation of G.H.s and PRL secretion,6 though no work has been reported on the role of serotonin in the nocturnal surges of these hormones. In normal volunteers serotonin antagonists have been shown to block hypoglycaemia-induced cortisol secretion.’ Thus it seems likely, from work in man as well as in animals, that serotonin is involved in the control of A.C.T.H. secretion, possibly by the mediation of corticotrophin-releasing factor synthesised in the
hypothalamus. Krieger et al. have studied
the effect of cyproheptain three patients with function dine pituitary/adrenal Cushing’s disease. Cyproheptadine is one of the most potent antihistamines, and it also has anticholinergic and pronounced antiserotonin actions. Administration of this drug in a dose of 24 mg daily for three to six months was associated with prompt and sustained clinical and biochemical remission of the disease. Cortisolsecretion rate and urinary corticosteroid excretion returned to normal, but the abnormality in circadian periodicity of plasma-cortisol concentrations persisted and A.C.T.H. levels remained raised in one of the two patients tested. Although the urinary corticosteroid response to low doses of dexamethasone (2 mg per day) became normal, a paradoxical rise followed 8 mg per day. Normal amounts of stage 3 and 4 sleep were restored in the one patient studied. Cessation of treatment in one patient was followed by relapse. The claim of Dr Krieger and her colleagues that the effects obtained with cyproheptadine were due to its antiserotonin action seems a reasonable one although its antihistamine and anticholinergic actions cannot be ruled out. In view of the efficacy of cyproheptadine and its apparent lack of toxicity this drug does seem to offer a rational and promising approach to the treatment of Cushing’s disease. But before the drug is adopted as a routine treatment for Cushing’s disease, important questions must be answered. Will remission be maintained if treatment is prolonged, and sustained when prolonged treatment is withdrawn? Will growth of the causal pituitary tumour be suppressed or continue if cyproheptadine is used alone or after bilateral adrenalectomy? Will troublesome side-effects arise after prolonged therapy? on
1. Krieger, D. T., Glick, S. M. Am. J. Med. 1972, 52, 25. 2. Krieger, D. T., Glick, S. M.J. clin. Endocr. Metab. 1974, 39, 986. 3. Krieger, D. T., Howanitz, P. J., Frantz, A G. ibid. (in the press). 4. Jouvet, M. Science, 1969, 163, 32. 5. Brown, G. M., Chambers, J. W., Feldman, J. Proc. Soc. Neurosci. 1973, p. 404. 6. Macindoe, J. H., Turkington, R. M.J. clin. Invest. 1973, 52, 1972. 7. Plonk, J. W., Bivens, C. H., Feldman, J. M. J. clin. Endocr. Metab. 1974, 8.
38, 836. Krieger, D. T., Amorosa, L., Linick,
F. New
Engl. J. Med. 1975, 293,
893.
