804

phenicol, co-trimoxazole, and a range of aminoglycosides, this patient recovered on treatment with cephalothin and ampicillin. This strain of pneumococcus was fully sensitive to rifampicin, vancomycin, and bacitracin and was inhibited by 2 mg/1 of fusidic acid. Treatment with rifampicin and fusidic acid eliminated the organism from his respiratory secretions within two days, but investigation of contacts in the hospital’s pædiatric wards and intensive-care unit revealed the same multiply resistant type-19 pneumococcus in the nasopharynxes of three staff members and twenty-four patients (all children) while two patients harboured penicillin and tetracycline resistant type-6 pneumococci. At the isolation hospital to which the child had been sent with measles all eighty patients in the measles ward had this organism in the upper respiratory tract within seven days of admission. Elimination is proving difficult because some rifampicin-resistant strains have emerged. Three of the eighty patients had pneumococcal bacteræmia and one died while on treatment with rifampicin and fusidic acid.

Clearly these pneumococci, as well as being clinically resistant to antibiotics (M.I.C.⋟ 4 mg/1), are easily communicable, especially to other children. The appearance of multiply resistant strains in two centres, 300 miles apart, raises fears that such strains may emerge elsewhere in the world. Obviously, instead of assuming that a pneumococcus will be sensitive to penicillin, laboratories will now have to examine all strains of pneumo-

cocci isolated to make sure of their antibiotic sensitivity. The emergence of a multiply resistant strain of pneumococci will raise particular alarm among doctors who coped with pneumococcal infections in the days before antibiotics. How does such wide resistance arise? Transferable drug resistance seems likely, but at present there are no clues to the mechanism.

Bromocriptine for Amenorrhœa ALL types of menstrual abnormality may be associated with hyperprolactinmmia. 1-7 Serum-prolactin measurement may therefore be informative in patients with amenorrhoea, oligomenorrhoea, menorrhagia, anovulatory infertility, or a deficient luteal phase. Prospective and retrospective studies 1. Besser, G. M., Parke, L., Edwards, C. R. W., Forsyth, I. A., McNeilly, A. S. Br. med. J. 1972, iii, 669. 2. Thorner, M. O., McNeilly, A. S., Hagen, C., Besser, G. M. ibid. 1974, ii, 419. 3. Jacobs, H. S., Hull, M. G. R., Murray, M. A. F., Franks, S. Hormone Res.

1975, 6, 268. Bohnet, H. G., Dahlen, H. G., Wuttke, W., Schneider, H. P. G. J. clin. Endocr. Metab. 1976, 42, 132. 5. del Pozo, E., Wyss, H., Varga, L. in Ovulation in the Human (edited by P. G. Crosignani, and D. R. Mishell); p. 297. London, 1976. 6. Seppälä, M., Ranta, T., Hirvonen, E. Lancet, 1976, i, 229. 7. Shearman, R. P., Fraser, I. S. ibid. 1977, i, 1195.

4.

suggest that between 13% and 39% of patients with secondary amenorrhoea have hyperprolactinæmia. 4,7,8-11A history of inappropriate lactation or crusting of the nipple, or the finding of galactorrhoea or Montgomery-tubercle hyperplasia should alert the clinician to the possibility. The reported prevalence of galactorrhoea in hyperprolactinxmk women ranges from 30% to over 80%, presumably reflecting different patterns of patient referral and the care with which the breasts are examined.3,7,12 If a raised prolactin is discovered the first step is to determine its cause. Stress is one cause of prolactin release, so blood-samples have to be taken with the least possible trauma. In some very apprehensive patients it may be necessary to insert an indwelling venous cannula and then wait at least 30 minutes before drawing blood. Not surprisingly, since dopamine is thought to be the principal factor inhibiting the release of prolactin from the anterior pituitary,’ drugs which deplete dopamine such as reserpine and methyldopa, or which block dopamine receptors, such as phenothiazines, haloperidol, and metoclopramide, cause hyperprolactinxmia. In addition, oestrogens and thyrotrophin-releasing hormone (T.R.H.) will raise prolactin levels. This action of T.R.H. may explain the hyperprolactinsemia found in some patients with primary hypothyroidism.16 When, however, drug and thyroid causes have been excluded, most patients have hypothalamic or pituitary disease. In this group prolactin-

secreting pituitary tumours (prolactinomas) are the most common. As the prolactin cells are most abundant around the periphery of the anterior pituitary the adenomas usually produce asymmetrical enlargement of the pituitary fossa which can be seen as a double contour on the lateral and a sloping floor on the postero-anterior skull film. Doubts have been cast on the significance of these minor changes in the pituitary fossa since they are very common;17 but pituitary tumours are extremely common too. COSTELLO,18 for example, reported a prevalence of 22.5%. in 1000 routine necropsies.18 Bromocriptine, 2-brom-M-ergocryptine, a synthetic ergot alkaloid, is a long-acting orally effective dopamine agonist which has revolutionised the treatment of hyperprolactinsemia. In nearly all patients, lowering serum-prolactin with bromocripFranks, S., Murray, M. A. F., Jequier, A. M., Steele, S. J., Nabarro, J. D. N., Jacobs, H. S. Clin. Endocr. 1975, 4, 597. 9. Seppälä, M., Hirvonen, E., Ranta, T., Virkkunen, P., Leppälnoto, J. Br. med. J. 1975, ii, 305. 10. Jacobs, H. S., Franks, S., Murray, M. A. F., Hull, M. G. R., Steele, S. J., Nabarro, J. D. N. Clin. Endocr. 1976, 5, 439. 11. Glass, M. R., Williams, J. W., Butt, W. R., Logan Edwards, R., London, D. R. Br. J. Obstet. Gynœc. 1976, 83, 495. 12. Thorner, M. O., Besser, G. M. in Prolactin and Human Reproduction (edited by P. G. Crosignani and C. Robyn). London, 1977. 13. MacLeod, R. M. Endocrinology, 1969, 85, 916. 14. Takahara, J., Arimura, A., Schally, A. V. ibid. 1974, 95, 462. 15. Schally, A. V., Dupont, A., Arimura, A., Takahara, J., Redding, T. W., Clemens, J., Shaar, C. Acta endocr., Copenh. 1976, 82, 1. 16. Edwards, C. R. W., Forsyth, I. A., Besser, G. M. Br. med. J. 1971, iii, 462 17. Swanson, H. A., Du Boulay, G. Br. J. Radiol. 1975, 48, 366. 18. Costello, R. T. Am. J. Path. 1936, 12, 205. 8.

805

of menstruation’ and

usually well tolerated. Patients should start with a low dose, such as 1.25 mg, taken late in the day

Menstruation usually returns within four weeks of the start of treatment but occasionally the response takes several months. In patients with gonadotrophin deficiency or ovarian failure bromocrip-

with food and then gradually increased. For the treatment of hyperprolactinaemia the usual full dose is 7.5 mg per day (2-5 mg with breakfast, lunch, and supper). Side-effects at the start of treatment include postural hypotension and nausea and vomiting; and in the long term, constipation may be troublesome. Of greater concern is the fact that rats treated with bromocriptine for 100 weeks acquired malignant endometrial tumours. However, no such changes have been found in women on long-term bromocriptine,3O and prolactin has very different roles in rat and man. Bromocriptine is now being used in several diseases and not simply for hyperprolactinaemia. The drug is expensive, is unlikely to become much cheaper, and no satisfactory alternative dopamine agonist is available. Acromegaly and parkinsonism are not so common that the expense of long-term bromocriptine would be crushing; menstrual disorders, however, are

tine results in

rapid

return

ovulation. 1,19-21

tine is not effective.

Surprisingly, bromocriptine gonadal function in some amenorrhœic or oligomenorrhoeic patients who have normal serum-prolactin levels. 12,22-24 The highest response-rate in normoprolactineemic women with anovulation has been in patients with post-pill amenorrhcea or oligomenorrhoea. The mechanism by which bromocriptine restores normal gonadal function in patients with hyperprorestores

normal

lactinaemia is not well understood. Evidence both in vitro and in vivo suggests that prolactin in high concentration antagonises the action of gonadotrophins on the ovary. 12,25 There is little evidence that bromocriptine directly alters gonadotrophin secretion in man. Whether bromocriptine itself has a direct effect on the ovary is unknown. In addition, preliminary results suggest that hyperprolactinæmia is associated with increased adrenal androgen secretion and that the androgen levels are returned to normal by bromocriptine. 26,21 The physician might therefore be tempted to view bromocriptine as the drug of choice for the treatment of secondary amenorrhoea. This temptation, however, must be resisted until the patient has been properly investigated. If bromocriptine is given to a patient with a pituitary tumour and she becomes pregnant, the tumour may swell and produce a visual-field defect. When such a patient wants a baby she should have her pituitary tumour assessed and, if necessary, treated by surgery or radiotherapy.28 These treatments are aimed at preventing tumour growth during pregnancy, and after operation or irradiation the patient almost invariably requires bromocriptine therapy. In patients with prolactinomas who do not wish to become pregnant bromocriptine therapy alone may inhibit tumour growth.29 Obviously these patients should not be given oestrogen-containing oral contraceptives. Bromocriptine when properly prescribed is



19.

Lutterbeck, P. M., Pryor, J. S., Varga, L., Wenner, R. Br. med. J. 1971, iii, 228.

20 del

Pozo, E., Varga, L., Wyss, H., Tolis, G., Friesen, H., Wenner, R., Vetter, L., Uettweiller, A. J. clin. Endocr.Metab. 1974, 39, 18. 21 Thomer, M. O., Besser, G. M., Hagen, C. McNeilly, A. S.Br. med. J. 1974, ii, 419. 22 Seppälä, M., Hirvonen, E., Ranta, T. Lancet, 1976, i, 1154. 23 Tolis, G., Naftolin, F., Am. J. Obstet. Gynec. 1976, 126, 426. 24 Van der Steeg, H. J., Coelingh Bennink, H. J. T. Lancet, 1977, i, 502. 25. McNatty, K. P., Sawers, R. S., McNeilly, A. S. Nature, 1974, 250, 653. 26 Edwards, C. R. W., Jeffcoate, W. J. in Pharmacological and Clinical Aspects of Bromocriptine (Proc. Symp. R. Coll. Physns); p43. London, 1977. 27 Giusti, G., Bassi, F., Borsi, L., Cattaneo, S., Giannotti, P., Lanza, L., Pazzagli, M., Vigiani, C., Serio, M. in Prolactin and Human Reproduction edited by P. G. Crosignani and C. Robyn). London, 1977. 28 Thorner, M. O., Besser, G. M., Jones, A., Dacie, J., Jones, A. E. Br. med. 29

J. 1975, iv, 694. Wass, J. A. H., Thorner, M. O., Morris, D. V., Rees, Lesley, H., Mason, A. S., Jones, A. E., Besser, G. M. ibid. 1977, i, 875.

extremely common.... ANUS OR STOMA? IRONICALLY it was the advent of an efficient ileostomy thirty years ago which led to ileo-rectal anastomosis, for this paved the way for safe ablation of the large bowel severely damaged by ulcerative colitis. Previously, oper-

ation had been an occasional and very much a last resort, with disabling consequences if an ileostomy was needed; sometimes staged resections were associated with ileo-rectal or ileo-sigmoid anastomosis but the concept of excision and anastomosis as a deliberate policy had not been pursued during an era before the ileostomy became manageable with an adherent bag. When the benefits of bowel excision became evident, thoughts naturally turned to excision with preservation of anal function. In the 1950s the relative merits of the two procedures .were hotly contested, and the debate continues, albeit somewhat muted. The arguments for and against ileorectal anastomosis are paraded again in a review of 36 patients (4 with Crohn’s disease) so treated between 1958 and 1976 by Jones and his colleagues.’ These have altered little, if at all: advantage, the avoidance of a stoma ; disadvantage, failure to eliminate the disease and a change in bowel function. They reiterate the fact that inflammation of the rectum may become so severe as to warrant its excision and conversion to an ileostomy-as in 3 of their series. Moreover, if the disease persists because the rectum is retained, the patient is still at risk from the remote complications; so they found that ankylosing spondylitis persisted in 1 patient while arthritis of hands and knees developed after operation in another as did erythema nodosum and chronic active hepatitis in 2 others. As regards bowel function, none was incontinent but frequency of stool varied between three and six loose motions

a

day; they make

no

mention of precipitancy

or

30. Besser, G. M., Doniach, I., Canti, G., Curling, M, Setchell, M. E., Thorner, M. O., Wass, J. A. H., Grudziniskas, J. G. ibid. 1977, ii, 868. 1. Jones, P. F., Munro, A., Evan, S. W. B. Br. J. Surg. 1977, 64, 615.

Bromocriptine for amenorrhoea.

804 phenicol, co-trimoxazole, and a range of aminoglycosides, this patient recovered on treatment with cephalothin and ampicillin. This strain of pne...
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