hepatocellular carcinoma, and indeed this tumour occurs about 200 times more frequently in such patients than in the general population.'416 Niederau et al found that patients receiving treatment before cirrhosis appeared did not develop hepatocellular carcinoma later. '4 The case is, therefore, convincing. Individual people with the genetic predisposition to develop hereditary haemochromatosis seem to be relatively common (at least in white populations), and early venesection treatment prevents progression of hepatic disease to cirrhosis and may consequently prevent the complication of hepatocellular carcinoma. We should therefore aim at diagnosing hereditary haemochromatosis as early as possible, and screening for this condition would probably benefit more patients than many tests done routinely on blood taken from patients in hospital. Consultant Physician, Royal Infirmary, Edinburgh EH3 9YW
NIALL D C FINLAYSON
1 Weintraub LR, Edwards CQ, Krikker M, eds. Hemochromatosis. Proceedings of the first
international conference of the New York Academy of Sciences. Ann NY Acad Sci 1988;526: 1-370.
2 Refsum SB, Schreiner BBI. Regulation of iron balance by absorption and excretion. A critical review and new hypothesis. ScandJ Gastroenierol 1984;19:867-74. 3 Lombard M, Bomford AB, Poison RJ, Bellingham AJ, Williams R. Differential expression of transferrin receptor in duodenal mucosa in iron overload. Gastroenterology 1990;98:976-84. 4 Sheldon JH. Haemochromatosis. London: Oxford University Press, 1935. 5 Simon M, Bourel M, Genetet B, Fauchet R. Idiopathic haemochromatosis. Demonstration of recessive transmission and earlv detection by family HLA typing. N EnglJ Med 1977;297:101721. 6 Mohler DN, Wheby MS. Hemochromatosis heterozygotes may have significant iron overload when they also have hereditary spherocytosis. AmJI Med Sci 1986;292:320-4. 7 Barron R, Grace ND, Sherwood G, Powell LW. Iron overload complicating sideroblastic anaemia-Is the gene for hemochromatosis responsible? Gastroenterology 1989;96:1204-6. 8 Simon M, Alexandre JL, Bourel M, LeMarec B, Scordia C. Heredity of idiopathic haemochromatosis: a study of 106 families. Clin Genet 1977;1:327-41. 9 Olsson KS, Ritter B, Rosen U, Heedman PA, Staugard F. Prevalence of iron overload in central Sweden. Acta Med Scand 1983;213:145-50. 10 Edwards CQ, Griffen LM, Goldgar D, Drummond C, Skolnick MH, Kushner JP. Prevalence of hemochromatosis among 11 065 presumably healthy blood donors. N EnglJ Med 1988;318: 1355-62. 11 Escobar GJ, Heyman MB, Smith WB, Thaler MM. Primary hemochromatosis in childhood. Pediatrics 1987;80:549-54. 12 Powell LW, Bassett ML, Axelsen E, Ferluga J, Halliday JW. Is all genetic (hereditary) hemochromatosis HLA-associated? Ann NY Acad Sci 1988;526:23-33. 13 Askari AD, Muir WA, Rosner IA, Moskowitz RW, McLaren GD, Braun WE. Arthritis of hemochromatosis. Clinical spectrum, relation to histocompatibility antigens, and effectiveness of early phlebotomy. Amj Med 1983;75:957-65. 14 Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G. Survival and causes of death in cirrhotic and in non-cirrhotic patients with primary hemochromatosis. N EnglJ'Med 1985;313:1256-62. 15 Bassett ML, Halliday JW, Bryant S, Dent 0, Powell LW. Screening for hemochromatosis. Ann NYAcad Sci 1988;526:274-89. 16 Bradbear RA, Bain C, Siskind V, et al. Cohort study of internal malignancy in genetic hemochromatosis and other chronic non-alcoholic liver diseases. JNCI 1985;75:81-4.
Sleep disorders in children These problems are underrecognised and undertreated Over the past 10 to 15 years the specialty of sleep disorders medicine has become very popular (and commercially successful) in North America, where many sleep disorders centres now exist. The European Sleep Society was founded in 1972, and the British Sleep Society was established just last year. These developments, however, have been concerned overwhelmingly with sleep disorders in adults. Of the 450 papers presented at the annual meeting of the Association of Professional Sleep Societies in the United States last year just 18 concerned children and a further seven were about adolescents. Medical textbooks underestimate the range of sleep disorders. The official classification of sleep and arousal disorders has as its main categories insomnias, causes of daytime sleepiness, disorders of the sleep/wake cycle, and episodic disorders occurring in or made worse by sleep (parasomnias).' Additional problems encountered particularly in children include bedtime fears and bed wetting. The phrase "sleep disorder" implies a problem to the child or the parents; sleep behaviours-such as snoring, head banging, teeth grinding, or restless sleep-do not necessarily constitute a problem, though they might be part of a disorder. Sleep disorders in children may be clinically important in various ways. Chronic lack of sleep will affect the daytime behaviour and performance of the child -and often of other members of the family. This problem seems to be particularly common in mentally handicapped children.2 Parasomnias are often frightening and the cause of much concern to parents. They may also be a source of diagnostic confusion: nonepileptic parasomnias may be misdiagnosed as epilepsy, and non-convulsive forms of epilepsy in particular are sometimes misconstrued as "nightmares."3 Sleep disorders may complicate various physical illnesses or be a side effect of treatment,4 and they may also be part of psychological conditions such as emotional upset or overactivity.5 Most sleep disorders in early childhood are "developmental" in the sense that the child will grow out of them BMJ VOLUME 301
18-25 AUGUST 1990
spontaneously, although in the meantime much distress may be caused. Parents often suffer from being given conflicting advice. When their anxieties are based on lack of information about what is normal, explanation and reassurance can help. A range of more specific treatments is available, however, once the child's exact type of sleep problem has been ascertained, including the timing and circumstances in which it occurs. For the very common and distressing problems of settling and night wakening in a toddler the first step is to obtain an exact account of what happens from the parents and their reactions as the basis of a programme of retraining the child into acceptable sleep habits.6 This behavioural approach is usually effective-in contrast with the use of hypnotic drugs; these should be used only as a temporary measure in a crisis.7 In other cases irregular daily patterns of sleeping or waking may be corrected by appropriate advice.8 Every dramatic episode at night should not be called a "nightmare." It is natural and helpful for parents to console a child who wakes up frightened in a real nightmare. By contrast, parents should resist trying to awaken and comfort a child in a night terror or an agitated sleep walking episode (in both of which the child remains asleep) as waking may well increase the child's disturbance. The most appropriate response is to help the child to settle when the acute episode dies down or if the child awakens at the end of it. The cycle of night terrors occurring at regular times can often be broken over the course of a week by waking the child before each episode is due and keeping him or her awake for a few minutes.' Nocturnal epileptic attacks are far less common than other types of sleep disturbance. They may be suspected if the episode includes stiffening or jerking or if the child wakes at the start of the episode and reports strange sensations, perhaps followed by impairment of consciousness. In these circumstances full electroencephalographic evaluation is required; and if epilepsy is confirmed further investigations 351
may be needed as well as treatment with antiepileptic drugs in most cases. Loud snoring, snuffling, or choking during sleep, especially combined with nocturnal enuresis and very restless sleep, suggest obstructive sleep apnoea, for which adenotonsillectomy may be beneficial.'0 Additional effective measures, depending on the problem, include making the environment safe to avoid accidental injury during sleep walking and preventing night time fears and nightmares caused by disturbing stories or television programmes before the child goes to bed. Signs to suggest that a sleep disorder is more than developmental and that further investigation is required include very frequent occurrence, onset in or persistence into late childhood, appearance after a traumatic event, and other evidence of psychological disturbance. In these circumstances psychological help may well be needed. In the case of undiagnosed parasomnia video recordings to identify the precise nature of the attacks can be valuable, preferably accompanied by electroencephalographic monitoring.3 The help available for children with sleep disorders and their parents could be improved if doctors were taught more about sleep problems and if protocols for taking the history paid more attention to sleep. Guidelines for teaching medical students about sleep disorders have been published in the United States," but there has been no comparable development in Britain. Many important research issues need to be explored. For example, how can the quality of children's sleep be judged? What are the effects of poor quality sleep on
daytime learning and behaviour? What types of sleep disturbance mean that the child is psychologically disturbed? How do the severe sleep disorders in children with a mental handicap come about, and how can they be treated? What sleep problems complicate serious illne-ss and how might their effects be minimised? Answers to such questions would be valuable to general practitioners, paediatricians, and to others concerned with the health and welfare of children. GREGORY STORES
Clinical Reader, University of Oxford, Section of Child and Adolescent Psychiatry, Park Hospital for Children, Oxford OX3 7LQ 1 Association of Sleep Disorders Centers. Diagnostic classification of sleep and arousal disorders. Sleep 1979;2:1-137. 2 Clements J, Wing L, Dunn G. Sleep problems in handicapped children: a preliminary study. J C(hild Psochol Psvchiatry 1986;27:399-407. 3 Stores G. Confusions concerning sleep disorders and the epilepsies in children and adolescents. Br J Psschiatrv (in press). 4 Wooten V. Medical causes of insomnia. In: Kryger MH, Roth T, Dement WC, eds. Principles and practice of'sleep medicine. Philadelphia: Saunders, 1989:456-75. 5 Simonds JF, Parraga H. Sleep behaviors and disorders in children and adolescents evalttated in psychiatric clinics. Developmental and Behavioral Pediatrics 1984;5:6-10. 6 Dotuglas J, Richman N. Msy child won't sleep. Harmondsworth: Penguin, 1984. 7 Simonoff E, Stores G. Controlled trial of trimeprazine tartrate for night waking. Arch l)is Child
1987;62:253-7. 8 Ferber R. Solve sour child's sleep problems. London: Dorling Kinderslcv, 1989. 9 I-ask B. Novel and non-toxic treatment for night terrors. BrMedj 1988;297:592. 10 Stradling JR, Thomas G, Warle ARH W'illiams P, Freeland A. Effect of adenotonsillectomy on noctural hypoxaemia, sleep disturbance, and svmptoms in snoring children. I.ancet 1990;335: 249-53. 11 Medical School Curriculum Task Force. The Medical School Curriculum Consensus Workshop: consensus document. Sleep 1988;1 1:566-70.
Medical termination of pregnancy Combined with prostaglandin R U 486 is effective The uterine progesterone receptor was discovered in 1970,' 2 and before long it was recognised as a suitable molecular target for an antigestagen. In 1982 Philibert and colleagues at Roussel-Uclaf reported the synthesis of RU 38486, "an antiglucocorticoid with a new mechanism of antihormone activity."3 The first two numerals were soon dropped, and the term RU 486 is now more often used than the approved name, mifepristone (17[3-hydroxy-1 1[3(dimethylaminophenyl)17a-(1-propynyl)estra-4,9-dien-3-one). It has been termed a "designer drug," the first in a new class of compounds that compete with progesterone for its specific receptors and so antagonise its action. It is a derivative of norethisterone, the main change to the molecule being the dimethylaminophenol group at the specific position and spatial orientation (11I) that has proved to be of great importance for antihormonal function.' It binds with high affinity to the progesterone receptor in target organs, including the endometrium. Depending on the model studied it has virtually no agonist activity and also almost no effect on oestrogen receptors in the uterus or mineralocorticoid receptors in the kidney.4 As the glucocorticoid and progesterone receptors have a very similar structure' RU 486 also has antiglucocorticoid activity, but this is negligible in short term use at the prescribed dose.5 The pre-embryo reaches the uterus within a few days and implants in the endometrium about seven to eight days after fertilisation.6 When the pregnancy proceeds (and most often it does not) human chorionic gonadotrophin almost immediately is detectable, and this prevents regression of the corpus luteum. Continued secretion of progesterone from the ovary -and its reception at the endometrium -are essential for the 352
maintenance of early pregnancy. By the seventh week of pregnancy, however, enucleation of the corpus luteum no longer leads to failure of the pregnancy.7 Thereafter sufficient progesterone is produced by the placenta, and this probably explains the diminishing effectiveness of mifepristone with or without prostaglandins in terminating pregnancies beyond the 49th day. The pharmacokinetics and metabolism of mifepristone have been studied in detail.' 8 Its bioavailability after oral absorption is of the order of 70%. The peak concentration in the plasma is achieved in one to two hours; and though the half life is 12 to 24 hours, the drug's complex metabolism ensures a high plasma concentration for several days after a single oral dose greater than 25 mg. Mifepristone is distributed more slowly after parenteral administration and is also more active. The vaginal route is ineffective. ' The effects of mifepristone vary with the phase of the menstrual cycle.49 Given during the first three days of the follicular phase there is no change in the events of the normal cycle apart from a small inhibition of early production of oestradiol.9 But when given throughout follicular development in small doses such as 25 mg a day'0 or even as low as 10 mg a day" the drug inhibits ovulation and lengthens the cycle by about seven days. This observation, confirming the role of progesterone in the processes of follicle maturation, the luteinising htormone surge, and ovulation, suggests a basis for an oestrogen free systemic contraceptive. ' 5 12 13 If given shortly after ovulation the drug will inhibit the formation of the corpus luteum. But given in the mid-luteal phase there seems to be little or no luteolytic effect. '4 '5 There BMJ VOLUME 301
18-25 AUGUST 1990
NIALL D C FINLAYSON
1 Weintraub LR, Edwards CQ, Krikker M, eds. Hemochromatosis. Proceedings of the first
international conference of the New York Academy of Sciences. Ann NY Acad Sci 1988;526: 1-370.
2 Refsum SB, Schreiner BBI. Regulation of iron balance by absorption and excretion. A critical review and new hypothesis. ScandJ Gastroenierol 1984;19:867-74. 3 Lombard M, Bomford AB, Poison RJ, Bellingham AJ, Williams R. Differential expression of transferrin receptor in duodenal mucosa in iron overload. Gastroenterology 1990;98:976-84. 4 Sheldon JH. Haemochromatosis. London: Oxford University Press, 1935. 5 Simon M, Bourel M, Genetet B, Fauchet R. Idiopathic haemochromatosis. Demonstration of recessive transmission and earlv detection by family HLA typing. N EnglJ Med 1977;297:101721. 6 Mohler DN, Wheby MS. Hemochromatosis heterozygotes may have significant iron overload when they also have hereditary spherocytosis. AmJI Med Sci 1986;292:320-4. 7 Barron R, Grace ND, Sherwood G, Powell LW. Iron overload complicating sideroblastic anaemia-Is the gene for hemochromatosis responsible? Gastroenterology 1989;96:1204-6. 8 Simon M, Alexandre JL, Bourel M, LeMarec B, Scordia C. Heredity of idiopathic haemochromatosis: a study of 106 families. Clin Genet 1977;1:327-41. 9 Olsson KS, Ritter B, Rosen U, Heedman PA, Staugard F. Prevalence of iron overload in central Sweden. Acta Med Scand 1983;213:145-50. 10 Edwards CQ, Griffen LM, Goldgar D, Drummond C, Skolnick MH, Kushner JP. Prevalence of hemochromatosis among 11 065 presumably healthy blood donors. N EnglJ Med 1988;318: 1355-62. 11 Escobar GJ, Heyman MB, Smith WB, Thaler MM. Primary hemochromatosis in childhood. Pediatrics 1987;80:549-54. 12 Powell LW, Bassett ML, Axelsen E, Ferluga J, Halliday JW. Is all genetic (hereditary) hemochromatosis HLA-associated? Ann NY Acad Sci 1988;526:23-33. 13 Askari AD, Muir WA, Rosner IA, Moskowitz RW, McLaren GD, Braun WE. Arthritis of hemochromatosis. Clinical spectrum, relation to histocompatibility antigens, and effectiveness of early phlebotomy. Amj Med 1983;75:957-65. 14 Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G. Survival and causes of death in cirrhotic and in non-cirrhotic patients with primary hemochromatosis. N EnglJ'Med 1985;313:1256-62. 15 Bassett ML, Halliday JW, Bryant S, Dent 0, Powell LW. Screening for hemochromatosis. Ann NYAcad Sci 1988;526:274-89. 16 Bradbear RA, Bain C, Siskind V, et al. Cohort study of internal malignancy in genetic hemochromatosis and other chronic non-alcoholic liver diseases. JNCI 1985;75:81-4.
Sleep disorders in children These problems are underrecognised and undertreated Over the past 10 to 15 years the specialty of sleep disorders medicine has become very popular (and commercially successful) in North America, where many sleep disorders centres now exist. The European Sleep Society was founded in 1972, and the British Sleep Society was established just last year. These developments, however, have been concerned overwhelmingly with sleep disorders in adults. Of the 450 papers presented at the annual meeting of the Association of Professional Sleep Societies in the United States last year just 18 concerned children and a further seven were about adolescents. Medical textbooks underestimate the range of sleep disorders. The official classification of sleep and arousal disorders has as its main categories insomnias, causes of daytime sleepiness, disorders of the sleep/wake cycle, and episodic disorders occurring in or made worse by sleep (parasomnias).' Additional problems encountered particularly in children include bedtime fears and bed wetting. The phrase "sleep disorder" implies a problem to the child or the parents; sleep behaviours-such as snoring, head banging, teeth grinding, or restless sleep-do not necessarily constitute a problem, though they might be part of a disorder. Sleep disorders in children may be clinically important in various ways. Chronic lack of sleep will affect the daytime behaviour and performance of the child -and often of other members of the family. This problem seems to be particularly common in mentally handicapped children.2 Parasomnias are often frightening and the cause of much concern to parents. They may also be a source of diagnostic confusion: nonepileptic parasomnias may be misdiagnosed as epilepsy, and non-convulsive forms of epilepsy in particular are sometimes misconstrued as "nightmares."3 Sleep disorders may complicate various physical illnesses or be a side effect of treatment,4 and they may also be part of psychological conditions such as emotional upset or overactivity.5 Most sleep disorders in early childhood are "developmental" in the sense that the child will grow out of them BMJ VOLUME 301
18-25 AUGUST 1990
spontaneously, although in the meantime much distress may be caused. Parents often suffer from being given conflicting advice. When their anxieties are based on lack of information about what is normal, explanation and reassurance can help. A range of more specific treatments is available, however, once the child's exact type of sleep problem has been ascertained, including the timing and circumstances in which it occurs. For the very common and distressing problems of settling and night wakening in a toddler the first step is to obtain an exact account of what happens from the parents and their reactions as the basis of a programme of retraining the child into acceptable sleep habits.6 This behavioural approach is usually effective-in contrast with the use of hypnotic drugs; these should be used only as a temporary measure in a crisis.7 In other cases irregular daily patterns of sleeping or waking may be corrected by appropriate advice.8 Every dramatic episode at night should not be called a "nightmare." It is natural and helpful for parents to console a child who wakes up frightened in a real nightmare. By contrast, parents should resist trying to awaken and comfort a child in a night terror or an agitated sleep walking episode (in both of which the child remains asleep) as waking may well increase the child's disturbance. The most appropriate response is to help the child to settle when the acute episode dies down or if the child awakens at the end of it. The cycle of night terrors occurring at regular times can often be broken over the course of a week by waking the child before each episode is due and keeping him or her awake for a few minutes.' Nocturnal epileptic attacks are far less common than other types of sleep disturbance. They may be suspected if the episode includes stiffening or jerking or if the child wakes at the start of the episode and reports strange sensations, perhaps followed by impairment of consciousness. In these circumstances full electroencephalographic evaluation is required; and if epilepsy is confirmed further investigations 351
may be needed as well as treatment with antiepileptic drugs in most cases. Loud snoring, snuffling, or choking during sleep, especially combined with nocturnal enuresis and very restless sleep, suggest obstructive sleep apnoea, for which adenotonsillectomy may be beneficial.'0 Additional effective measures, depending on the problem, include making the environment safe to avoid accidental injury during sleep walking and preventing night time fears and nightmares caused by disturbing stories or television programmes before the child goes to bed. Signs to suggest that a sleep disorder is more than developmental and that further investigation is required include very frequent occurrence, onset in or persistence into late childhood, appearance after a traumatic event, and other evidence of psychological disturbance. In these circumstances psychological help may well be needed. In the case of undiagnosed parasomnia video recordings to identify the precise nature of the attacks can be valuable, preferably accompanied by electroencephalographic monitoring.3 The help available for children with sleep disorders and their parents could be improved if doctors were taught more about sleep problems and if protocols for taking the history paid more attention to sleep. Guidelines for teaching medical students about sleep disorders have been published in the United States," but there has been no comparable development in Britain. Many important research issues need to be explored. For example, how can the quality of children's sleep be judged? What are the effects of poor quality sleep on
daytime learning and behaviour? What types of sleep disturbance mean that the child is psychologically disturbed? How do the severe sleep disorders in children with a mental handicap come about, and how can they be treated? What sleep problems complicate serious illne-ss and how might their effects be minimised? Answers to such questions would be valuable to general practitioners, paediatricians, and to others concerned with the health and welfare of children. GREGORY STORES
Clinical Reader, University of Oxford, Section of Child and Adolescent Psychiatry, Park Hospital for Children, Oxford OX3 7LQ 1 Association of Sleep Disorders Centers. Diagnostic classification of sleep and arousal disorders. Sleep 1979;2:1-137. 2 Clements J, Wing L, Dunn G. Sleep problems in handicapped children: a preliminary study. J C(hild Psochol Psvchiatry 1986;27:399-407. 3 Stores G. Confusions concerning sleep disorders and the epilepsies in children and adolescents. Br J Psschiatrv (in press). 4 Wooten V. Medical causes of insomnia. In: Kryger MH, Roth T, Dement WC, eds. Principles and practice of'sleep medicine. Philadelphia: Saunders, 1989:456-75. 5 Simonds JF, Parraga H. Sleep behaviors and disorders in children and adolescents evalttated in psychiatric clinics. Developmental and Behavioral Pediatrics 1984;5:6-10. 6 Dotuglas J, Richman N. Msy child won't sleep. Harmondsworth: Penguin, 1984. 7 Simonoff E, Stores G. Controlled trial of trimeprazine tartrate for night waking. Arch l)is Child
1987;62:253-7. 8 Ferber R. Solve sour child's sleep problems. London: Dorling Kinderslcv, 1989. 9 I-ask B. Novel and non-toxic treatment for night terrors. BrMedj 1988;297:592. 10 Stradling JR, Thomas G, Warle ARH W'illiams P, Freeland A. Effect of adenotonsillectomy on noctural hypoxaemia, sleep disturbance, and svmptoms in snoring children. I.ancet 1990;335: 249-53. 11 Medical School Curriculum Task Force. The Medical School Curriculum Consensus Workshop: consensus document. Sleep 1988;1 1:566-70.
Medical termination of pregnancy Combined with prostaglandin R U 486 is effective The uterine progesterone receptor was discovered in 1970,' 2 and before long it was recognised as a suitable molecular target for an antigestagen. In 1982 Philibert and colleagues at Roussel-Uclaf reported the synthesis of RU 38486, "an antiglucocorticoid with a new mechanism of antihormone activity."3 The first two numerals were soon dropped, and the term RU 486 is now more often used than the approved name, mifepristone (17[3-hydroxy-1 1[3(dimethylaminophenyl)17a-(1-propynyl)estra-4,9-dien-3-one). It has been termed a "designer drug," the first in a new class of compounds that compete with progesterone for its specific receptors and so antagonise its action. It is a derivative of norethisterone, the main change to the molecule being the dimethylaminophenol group at the specific position and spatial orientation (11I) that has proved to be of great importance for antihormonal function.' It binds with high affinity to the progesterone receptor in target organs, including the endometrium. Depending on the model studied it has virtually no agonist activity and also almost no effect on oestrogen receptors in the uterus or mineralocorticoid receptors in the kidney.4 As the glucocorticoid and progesterone receptors have a very similar structure' RU 486 also has antiglucocorticoid activity, but this is negligible in short term use at the prescribed dose.5 The pre-embryo reaches the uterus within a few days and implants in the endometrium about seven to eight days after fertilisation.6 When the pregnancy proceeds (and most often it does not) human chorionic gonadotrophin almost immediately is detectable, and this prevents regression of the corpus luteum. Continued secretion of progesterone from the ovary -and its reception at the endometrium -are essential for the 352
maintenance of early pregnancy. By the seventh week of pregnancy, however, enucleation of the corpus luteum no longer leads to failure of the pregnancy.7 Thereafter sufficient progesterone is produced by the placenta, and this probably explains the diminishing effectiveness of mifepristone with or without prostaglandins in terminating pregnancies beyond the 49th day. The pharmacokinetics and metabolism of mifepristone have been studied in detail.' 8 Its bioavailability after oral absorption is of the order of 70%. The peak concentration in the plasma is achieved in one to two hours; and though the half life is 12 to 24 hours, the drug's complex metabolism ensures a high plasma concentration for several days after a single oral dose greater than 25 mg. Mifepristone is distributed more slowly after parenteral administration and is also more active. The vaginal route is ineffective. ' The effects of mifepristone vary with the phase of the menstrual cycle.49 Given during the first three days of the follicular phase there is no change in the events of the normal cycle apart from a small inhibition of early production of oestradiol.9 But when given throughout follicular development in small doses such as 25 mg a day'0 or even as low as 10 mg a day" the drug inhibits ovulation and lengthens the cycle by about seven days. This observation, confirming the role of progesterone in the processes of follicle maturation, the luteinising htormone surge, and ovulation, suggests a basis for an oestrogen free systemic contraceptive. ' 5 12 13 If given shortly after ovulation the drug will inhibit the formation of the corpus luteum. But given in the mid-luteal phase there seems to be little or no luteolytic effect. '4 '5 There BMJ VOLUME 301
18-25 AUGUST 1990
