LONDON, SATURDAY 20 DECEMBER 1975

MEDICAL JOURNAL Bromocriptine -a changing scene Ergot, known to man since ancient times, is a product of the fungus Claviceps purpurea that grows on rye and grain. A symposium' at the Royal College of Physicians last May reviewed the pharmacology and clinical uses of the older as well as the more recently introduced ergot compounds. All the ergot alkaloids are derivatives of lysergic acid: the best known are the oxytocic ergometrine and the mixed ao-adrenergic agonist and antagonist ergometrine compounds. Nevertheless, the first group of ergot compounds isolated by Barger, Carr, and Dale in 1906, and called ergotoxine,2 is a mixture of ergot alkaloids: ergocornine, ergocristine, and ergokryptine. The inhibition of lactation by ergot was described by Dodart3 in 1676. When in 1954 Shelesnyak found that ergotoxine affected endometrial function in the rat4 he began the unravelling of a subtle endocrine relationship in reproduction. He suggested that ergotoxine inhibited release of prolactin from the pituitary,5 and this was later confirmed.6 In the rat prolactin stimulates the corpus luteum to secrete progesterone, which in turn prepares the endometrium for implantation ofthe fertilised ovum. Ergotoxine prevents implantation by suppressing prolactin sectetion; this effect may be reversed by the administration of either prolactin or progesterone.4 Having confirmed Shelesnyak's findings, Fluckiger embarked on a specific search for an ergot alkaloid that would inhibit prolactin release without the oxytocic and cardiovascular effects associated with the parent ergotoxine compounds, since he believed that such a drug would have great therapeutic importance. Bromocriptine (2-brom-oc-ergokryptine, CB154), the compound that was developed,' 7suppresses prolactin secretion by a direct action on the pituitary.8 In man prolactin suppression does not block implantation of the ovum, and bromocriptine is therefore not contraceptive as it is in the rat: on the contrary it is frequently effective in restoring normal gonadal function in both hypogonodal men and women with hyperprolactinaemia.9 -1 Irrespective of the cause of the raised prolactin levels, the only patients in this group who do not respond seem to be the minority who are shown to be truly deficient in gonadotrophins. There is now increasing evidence that in hyperprolactinaemia the hypogonadism is at least in part due to a prolactin-induced blockade of the action of the gonadotrophins on the gonads."1-13 When prolactin levels are lowered with bromocriptine the gonadotrophins can exert their normal effects and thus gonadal function returns to normal. Some of the patients with hyperprolactinaemia also have galactorrhoea, and it too ceases with this treatment, usually using doses of 7-5 to 15 mg daily. C) BRITISH MEDICAL JOURNAL 1975. All reproduction rights reserved.

Levodopa has been used to lower prolactin levels, but its action does not last long enough; bromocriptine has a much longer action and is therefore more effective. Since bromocriptine has been shown not to be teratogenic it has been used recently in restoring fertility. Its place has still finally to be defined, but it appears to be effective not only in patients with hyperprolactinaemia but also in some with normal prolactin levels, as described by M 0 Thorner et al,14 at p 694 of this issue. There is, however, some danger in restoring fertility in women with small pituitary tumours, since such lesions may rapidly enlarge, with visual impairment, during pregnancy. Arguably the tumour should be irradiated before pregnancy to reduce these risks,14 but there is no general agreement on the best management. Bromocriptine is also used for suppression of puerperal lactation,' 15 16 and will probably become the treatment of choice: it is effective, has few side effects, and does not affect the blood clotting system.1 In both disease and health bromocriptine's clinical efficiency in lowering prolactin levels is unsurpassed. Not only has it fulfilled the purpose for which it was developed but it has also helped in our understanding of how prolactin secretion is controlled. Only three years ago bromocriptine was showntobe a specific dopamine receptor-agonist with a prolonged action." At that time secretion of the hypothalamic prolactin-releaseinhibiting factor (PIF) was thought to be under dopaminergic control. Subsequently Schally and colleagues found that one of their hypothalamic extracts with the most potent PIF activity was devoid of the expected polypeptide content but instead contained only dopamine and noradrenaline,'8 and further that dopamine itself could act at the receptors in the pituitary cell. This discovery prompted the suggestion that dopamine might be one of the physiologically important PIFs.'9 The mode of action of bromocriptine in lowering prolactin levels both in patients with hyperprolactinaemia and post partum then became clear: it acts predominantly on the pituitary cells by activating dopamine receptors, as a functional analogue of PIF. Bromocriptine also stimulates other dopaminergic receptors apart from those of the prolactin-secreting cells. Its long action, its direct action on the dopamine receptors, and its lack of agonist activity on the other receptors make it a specific research tool as well as a very useful drug. Acromegalic patients have a paradoxical response to the administration of dopaminergic agonists. In normal people growth hormone (GH) levels rise after administration of a dopamine agonist, while in NO 5998 PAGE 667

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most patients with acromegaly GH levels fall.20 21 Again, levodopa was shown to have too short an action, and single doses of bromocriptine in acromegalic patients were found to lower GH levels.22 Patients have been treated successfually for up to nine months in the reports published so far.23-25 Higher doses are required than have been used for hyperprolactinaemia, usually between 20 and 60 mg per day. The results of this medical treatment are encouraging: many patients have clinical, biochemical, and metabolic improvement. Since surgery and radiotherapy are often ineffective in reversing these manifestations bromocriptine will be a major therapeutic advance if its current promise is upheld. Another obvious indication for bromocriptine is in treating Parkinsonism. There are theoretical advantages in the use of a dopamine agonist which, unlike levodopa, does not require to be metabolised to the active compound by dopaminergic neurones. All the reports indicate that bromocriptine may be superior to levodopa, though the results are not as dramatic as might have been expected on theoretical grounds.2 26-28 The side effects of bromocriptine are important. They may be divided into those which occur at the start of treatment and those found when patients are established on high doses. Any patient given a sufficiently large initial dose may develop nausea, vomiting, and postural hypotension. Micturition syncope has also been described. Normal people are the most sensitive to these initiating side effects; patients with hyperprolactinaemia and acromegaly less so; and finally the most resistant are women immediately post partum, in whom side effects are virtually unknown. Side effects may, however, usually be avoided if a really small dose is given at the start of treatment and then increased very slowly. Preferably treatment should be started in the evening, the dose being taken with food when going to bed. The other side effects, found during continuous therapy, are rare when the daily dose is less than 20 mg: they include mild constipation, muzziness, nasal congestion, cramps in the legs at night, and dystonic reactions in the Parkinsonian patients. Cardiac dysrhythmias have also occurred occasionally when high doses were given. Probably in the future new ergot derivatives with even more specific effects will be found. Bromocriptine is likely to be the first of a new class of therapeutic agents-the dopamine receptor agonists-for which further indications will be found as the role of dopamine in the peripheral autonomic nervous system is delineated.29 1 Symposium Ergot Compounds-The Changing Scene, Proceedings to be published in Postgraduate Medical_Journal. 2 Barger, G, Carr, F H, and Dale, H, British 1906, 2, 1792. 3 Dodart, M,J_ournal des Savants, 1676, p 76. 4 Shelesnyak, M C, Recent Progress in Hormone Research, 1957, 13, 269. 5 Shelesnyak, M C, Acta Endocrinologica, 1958, 27, 99. 6 Zeilmaker, G H, and Carlsen, R A, Acta Endocrinologica, 1962, 41, 321. 7 Fluckiger, E, and Wagner, H R, Experientia, 1968, 24, 1130. 8 Pasteels, J L, et al, Annales d'Endocrinologie (Paris), 1971, 32, 188. 9 Besser, G M, et al, British Medical_Journal, 1972, 3, 669. 10 Del Pozo, E, et al, Journal of Clinical Endocrinology and Metabolism, 1974, 39, 18. 1 Thorner, M 0, et al, British Medical Journal, 1974, 2, 419. 12 McNatty, K P, Sawers, R S, and McNeilly, A S, Nature, 1974, 250, 653. 13 Zarate, A, et al, American Journal of Obstetrics and Gynecology, 1972, 112, 1130. 14 Thorner, M 0, et al, British Medical3Journal, 1975, 4, 694. 16 Varga, L, et al, British Medical_Journal, 1972, 2, 743. 16 Rolland, R, and Schellekens, L A, Journal of Obstetrics and Gynaecology of the British Commonwealth, 1973, 80, 945. 17 Hokfelt, T, and Fuxe, K, Neuroendocrinology, 1972, 9, 100. 18 Schally, A V, et al, Federation Proceedings, 1974, 33, 237. 1 Takahara, J, Arimura, A, and Schally, A V, Endocrinology, 1974, 95, 462. 20 Liuzzi, A, et al, J7ournal of Clinical Endocrinology and Metabolism, 1972, 35, 941.

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Camanni, F, et al, Journal of Clinical Endocrinology and Metabolism, 1975, 40, 363. Liuzzi, A, et al, Journal of Clinical Endocrinology and Metabolism, 1974, 38, 910.

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Thorner, M 0, et al, British Medical_Journal, 1975, 1, 299. Chiodini, P G, et al,Journal of Clinical Endocrinology and Metabolism, 1975,

40, 705. Thorner, M 0, et al, Abstract 125, Proceedings of 75th Annual Meeting of the Endocrine Society, 1975. 26 Calne, D B, et al, British Medical Journal, 1974, 4, 442. 27 Calne, D B, et al, Lancet, 1974, 2, 1355. 28 Teychenne, P S, et al, Lancet, 1975, 2, 473. 29 Thorner, M 0, Lancet, 1975, 1, 662. 25

Acute appendicitis in pregnancy "The mortality of appendicitis complicating pregnancy and the puerperium is the mortality of delay," wrote Bablerl in 1908, when he found a 49% mortality among 103 pregnant women with perforated appendicitis. We now have the means to salvage many more patients-in 1967-9 in England and Wales2 only two women died from acute appendicitis during pregnancy-but we still make too many late diagnoses and see some gravely ill patients. From 1950 to 1973 the incidence of gangrene and perforation of the appendix in pregnant women in Oxford3 was twice that among the non-pregnant, while in the same series two out of four fetal deaths occurred in mothers who had been treated conservatively in hospital for two and a half and for three days. Similar figures were reported from Melbourne4 in 1972, where the incidence of perforation in the last trimester was five times that in the first. The clinical picture of acute appendicitis is in fact little changed in the first three or four months of pregnancy. It is especially in the last trimester and the puerperium that difficulties arise and delay in diagnosis may occur. What can be done to improve the situation ? There may be an understandable tendency for obstetricians to look for obstetric causes when acute abdominal pain occurs in their patients, but they must not overlook the fairly uncommon but dangerous surgical complications of pregnancy and the puerperium. A report from Aberdeen on some difficult cases appear .at page 691 of this issue. The symptoms and signs of acute appendicitis (and other surgical emergencies) are considerably modified during late pregnancy and the puerperium. Parker,5 in a paper which should be read by all obstetricians and general surgeons, identified these differences. There may be a classical shift of pain, but often pain is only vaguely localised. Tenderness will be found over the appendix, but it is likely to be higher than usual and may be situated under the right costal margin or out in the right flank. In particular, muscle guarding tends to be slight or wholly absent, and this may mislead the examiner into underestimating the significance of local tenderness. The umeful sign of altered tenderness described by Alders6 will help to differentiate uterine from extrauterine lesions, and the "heel-stamping" sign7 may alert the examiner to the presence of peritoneal irritation. Acute pyelitis may be a problem in differential diagnosis, but it is unwise to accept (as too often happens) that a few pus cells in the urine confirm a diagnosis of pyelitis. The Aberdeen paper stresses that anything more than intermittent mild colicky lower abdominal pain is abnormal in the puerperium. In these diagnostic difficulties there is a natural unwillingnass to risk disturbing the pregnancy or the involuting uterus by

Editorial: Bromocriptine--a changing scene.

LONDON, SATURDAY 20 DECEMBER 1975 MEDICAL JOURNAL Bromocriptine -a changing scene Ergot, known to man since ancient times, is a product of the fungus...
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