BRITISH MEDICAL JOURNAL

LONDON, SATURDAY 10 MARCH 1979

Sex differences in duodenal ulcer In Victorian Britain peptic ulcers were mostly confined to young women and were predominantly gastric. Duodenal ulcers were probably not being substantially underdiagnosed and we can conclude reasonably confidently that duodenal ulcer is a twentieth-century malady. The dominance of duodenal ulcer in men is now obvious in most Western communities, but the male to female ratio appears to have varied steadily throughout the earlier part of this century.1 This is only one of many features in the overall pattern of the disorder that has been subject to continual alteration, and the biological rapidity of these epidemiological changes argues in favour of environmental influences. We have been slow, however, to learn what these various environmental factors might be. If there are such striking differences in the incidence of duodenal ulcer in the two sexes, does this imply that there is a basic difference in the disease-or, more simply, does the female state alter a single pathological process underlying duodenal ulcer? Much research has gone into this second possibility, and there are some hints to support it. For example, firstly, female sex hormones have been shown to bring symptomatic relief to men with duodenal ulcer-though at the unacceptable price of feminising side effects.2 Secondly, the clinical observation that pregnancy protects against ulcer symptoms has led to a search for hormonal agents that might simultaneously promote ulcer healing and inhibit gastric secretion. These studies have led to the isolation and characterisation of urogastrone-epidermal growth factor-and to the pursuit of agents acting directly on mucosal repair.3 One way in which women with duodenal ulcer were thought to differ from their male counterparts was in the secretion of gastric acid, women having smaller acid responses to stimulation than men. Nevertheless, when careful measurements of secretion were related to body weight both sexes were found to produce the same acid output per unit of lean body mass, so that after all there appears to be no difference in the mean acid secretory capacity.4 The duodenal ulcer diathesis seems to affect both sexes similarly, and it is femaleness that alters the clinical pattern secondarily. Nevertheless, the striking reduction in the incidence of perforated duodenal ulcer throughout the last two or three decades has been more or less parallel in the two sexes. Clinicians have looked for sex differences in response to BRITISH MEDICAL JOURNAL

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treatment too, and women have been labelled as not doing so well after elective operations for ulcer. Many gastroenterologists have counselled avoiding surgery in women with ulcers because they are said to have a greater incidence of the more troublesome and intractable unwanted sequelae-anaemia, dumping, loss of weight, bowel disturbances, pulmonary tuberculosis, and so on. We have, however, remarkably little sound scientific evidence for this belief, which arose in the days when partial gastrectomy was the routine surgical approach to duodenal ulcer and the legacy of sequelae was different from that of today. Furthermore, those specialist centres conducting good controlled trials of different surgical procedures for duodenal ulcer have mostly said nothing about sex difference in their follow-up studies. Some units have left women out of their trials, while others have simply pooled the results in men and women together for analysis. The relative fewness of women-and therefore the difficulty of securing equal numbers matched for age, weight, and length of history-has justified this approach. A recent report from a North American centre with an international reputation in the surgery of peptic ulcer has now suggested that the incidence of unwanted sequelae after operation may be the same in the two sexes after all. Admittedly, the study was retrospective, but it included three well-matched groups, each of 90 women undergoing different elective operations: truncal vagotomy with antrectomy, selective vagotomy with pyloroplasty, and proximal gastric vagotomy.5 These three groups were compared with three similar groups of men who had undergone identical operations previously at the same centre. After tests based on a wide range of indices of postoperative progress, no significant differences were found between the sexes. A Danish group has also reported no difference in postoperative symptoms between men and women in a consecutive series of 500 patients with duodenal ulcer treated by truncal vagotomy with pyloroplasty.6 Clearly the view previously held so widely that women fare worse after surgery for duodenal ulcer can no longer be justified. If indeed the two sexes are at equal risk of postoperative sequelae there should be no complaints in the current climate of opinion. The clinical conclusion, then, is that the indications for elective surgical treatment for duodenal ulcer should now be the same in the two sexes. An unanswered question is NO 6164 PAGE 641

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whether men and women respond equally well to the beneficial effects of the potent antiulcer drugs that are now available. Langman, M J S, in Clinics in Gastroenterology, 1973, 2, 219. 1960, 2, 559. Truelove, S C, British 3 Gregory, H, and Willshire, I R, Hoppe-Seylers Zeitschriftffur Physiologische Chemie, 1975, 356, 1765. 4 Baron, J H, Gut, 1969, 10, 637. 5 Herrington, J L, and Sawyers, J L, Annals of Surgerv, 1978, 187, 576. 6 Kronborg, 0, of Gastroenterology, 1971, 6, 501. 2

Medical_Journal,

Scandinavian_Journal

10 MARCH 1979

will be clear. For many drugs the advice should be that insufficient information is available. To some extent the choice between an attitude of safety first or one that no news is good news is a matter of personal philosophy. Nevertheless, when the benefits of breast-feeding are weighed against the few reports of vicarious drug toxicity, its continuation seems reasonable during treatment with drugs which have a high therapeutic ratio. The mother should be- encouraged to report any possible adverse effect on the infant, and the doctor should pass such reports to the Committee on Safety of Medicines. Tyson, R M, Shrader, E A, and Perlman, H H, Jrournal of Pediatrics, 1937, 11, 824. Patrick, M J, Tilstone, W J, and Reavey, P, Lancet, 1972, 1, 542. 3Belton, E M, and Jones, R V, Lancet, 1965, 2, 691. 4Illingworth, R S, Practitioner, 1953, 171, 533. 5 Harley, J D, and Robin, H, Pediatrics, 1966, 37, 855. 6 Finch, E, and Lorber, J, Jrournal of Obstetrics and Gynaecology of the British Empire, 1954, 61, 833. 7Eckstein, H B, and Jack, B, Lancet, 1970, 1, 672. 8 O'Brien, T E, American Journal of Hospital Pharmacy, 1974, 31, 844. 9 Tunnessen, W W, and Hertz, C G,Jrournal of Pediatrics, 1972, 81, 804. 1 Williams, V, and Shirkey, H C, in Drug Treatment. Principles and Practice of Clinical Pharmacy and Therapeutics, ed G S Avery, p 71. Edinburgh and London, Churchill Livingstone, 1976. 1 Burn, J H, British Medical Bulletin, 1947-8, 5, 190. 12 Loughnan, P M, Journal of Pediatrics, 1978, 92, 1019. 13 Baty, J D, et al, British Journal of Clinical Pharmacology, 1976, 3, 969. 14 Catz, C S, and Giacoia, G P, Pediatric Clinics of North America, 1972, 19, 151. 15 Anderson, P 0, Drug Intelligence and Clinical Pharmacy, 1977, 11, 208. 16 Association of the British Pharmaceutical Industry, Data Sheet Compendium. London, Pharmind, 1978. 17 Extra Pharmacopoea: Martindale, 27th edn, ed A Wade. London, Pharmaceutical Press, 1977. 18 Leach, F N, British Medical Journal, 1978, 1, 766. 1

Drugs and breast-feeding The doctor asked whether the drug he is prescribing will conflict with breast-feeding will probably feel a little uncomfortable. He may have learnt from irate mothers (or by personal communication from his wife) that absorbable laxatives may have a vicarious and antisocial pharmacological action on the suckling infant,' but otherwise his ignorance is likely to be comprehensive. In fact, the question often cannot be answered with any certainty, and the embarrassment properly rests with the whole profession and not with the individual doctor. It would be quite wrong to dismiss the risk as theoretical or remote. Several drugs, including some with a wide margin between therapeutic and toxic actions in the mother (a "high therapeutic ratio") nevertheless produce adverse effects on the suckling infant. Examples are diazepam,2 nalidixic acid,3 ergot derivatives,4 sulphonamides,5 phenytoin,6 phenindione,7 amantadine,8 and lithium,9 and high doses of salicylate'0 or alcohol." On the other hand, breast-feeding may be continued safely while taking some drugs with a low therapeutic ratio (where there is little margin between the therapeutic and toxic effects in the mother)-for example, digoxin'2 or warfarin.'3 Thus a commonsense approach based on the therapeutic ratio of the drug in the mother may lead to adverse effects in some instances and to unnecessary interruption of breast-feeding in others. The question cannot be tackled readily from first principles, since so many factors have to be taken into account. These include the pharmacokinetics of the drug in the mother; her renal and hepatic function; protein binding of the drug in both plasma and breast milk; the pKa and lipid solubility of the drug; variability in the constituents and the volume of milk; and the high toxicity of some drugs such as sulphonamides, tetracycline, or diazepam to the infant or neonate.'0 14 15 The doctor may turn to a standard text for help, but if he consults more than one his embarrassment will turn to sheer bewilderment. For example, the Data Sheet Compendium16 and Martindale17 advise that patients taking warfarin should not breast-feed, whereas a recent review'0 suggests that there is no contraindication. The same sources do not give complete or consistent advice on the use of phenytoin, amitriptyline, or propranolol, and none gives guidance about digoxin. Yet these five drugs are all widely used and have been studied in detail. Information is probably less satisfactory (if that is possible) for drugs used less often or introduced more recently. How, then, can the doctor answer his patient's question? If he can avoid prescribing he should clearly do so. If not, a telephone call to the nearest drug information centre18 is a sensible move. If the drug in question or a suitable alternative is considered safe, or definitely unsafe, then the correct action

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Crystals and arthritis Ten years ago the classification of crystal-deposition arthropathies appeared straightforward. Microscopy of synovial fluids with polarised light' had made it possible to identify the urate crystals of gout and to differentiate these from the calcium pyrophosphate dihydrate crystals of "pseudogout" (pyrophosphate arthropathy). Gouty patients were hyperuricaemic; while in those with pyrophosphate arthropathy the joint cartilage was seen to be calcified on radiological examination (chondrocalcinosis). In both conditions symptoms might arise either from episodes of acute crystal synovitis resulting from the phagocytosis of crystals by synovial fluid polymorphonuclear leucocytes2 or from chronic degenerative changes due to destruction of cartilage and bone. Furthermore, both gout and pseudogout seemed to occur either as primary disorders or secondary to other diseases. Over the past decade three lines of inquiry have suggested that the relation between crystals and arthritis is more complex than suggested in this scheme. Firstly, hydroxyapatite has been recognised as an additional type of crystal-producing arthritis; secondly, some joints have been found to contain mixtures of crystal types; and, thirdly, there appears to be an association between pyrophosphate deposition and "primary" osteoarthrosis. Generally, crystals of hydroxyapatite (the chief mineral of bone) are too small to identify by polarised light microscopy. Nevertheless, Dieppe and his colleagues3 and others4 have used electron microscopy and other techniques to show that these crystals occur in the synovial fluid, synovial membrane,

Sex differences in duodenal ulcer.

BRITISH MEDICAL JOURNAL LONDON, SATURDAY 10 MARCH 1979 Sex differences in duodenal ulcer In Victorian Britain peptic ulcers were mostly confined to...
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