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ŒSTROGEN TREATMENT OF RECURRENT APHTHOUS MOUTH ULCERS
1345 Research Board of the Hospital for Sick Children and the Institute of Child Health for financial support. Requests for reprints should be addressed to R. S. K.
Joint
REFERENCES
Andrade, C. (1952) Brain, 75, 408. Bartlett, G. R. (1959) J. Biochem. 234, 466. Brown, W. J. (1961) Aust. J. exp. Biol. 39, 223. Chambers, R. A., Medd, W. E., Spencer, H. (1958) Q. Jl Med. 27, 207. Cornwell, D. G., Kruger, F. A., Hamwi, G. J., Brown, J. B. (1961) Am. J. clin. Nutr. 9, 24. Engel, W. K., Dorman, J., Levy, R. I., Fredrickson, D. S. Unpublished. Fredrickson, D. S. (1966) in The Metabolic Basis of Inherited Disease (edited by J. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson); p. 486. New York. Altrocchi, P. H., Avioli, L. V., Goodman, D. S., Goodman, H. C. (1961) Ann. intern. Med. 55, 1016. Young, O. M., Shiratori, T., Briggs, N. (1964) J. clin. Invest. 43, 228. Freeman, N. K. (1964) J. lipid Res. 5, 236. Gilliatt, R. W., Goodman, H. V., Willison, R. G. (1961) J. Neurol. Neurosurg. Psychiat. 24, 305. Sears, T. A. (1958) ibid. 21, 109 Grabar, P., Williams, C. A. (1955) Biochim. Biophys. Acta. 17, 67. Hoffman, H. N., Fredrickson, D. S. (1965) Am. J. Med. 39, 582. Jones, J. W., Ways, P. (1967) J. clin. Invest. (in the press). Lewis, L. A., Zuehlke, V., Nakamoto, S., Kolff, W. J., Page, I. H. (1966) New Engl. J. Med. 275, 1097. Levy, R. I., Fredrickson, D. S. (1965) J. clin. Invest. 44, 426. (1966) Circulation, 34, suppl. III, 156. Lees, R. S., Fredrickson, D. S. (1966) J. clin. Invest. 45, 63. Pantelakis, S. N., Fosbrooke, A. S., Lloyd, J. K., Wolff, O. H. (1964) Diabetes, 13, 153. Phillips, G. B. (1959) Proc. Soc. exp. Biol. Med. 100, 19. Rukavina, J. G., Block, W. D., Jackson, C. D., Falls, H. F., Carey, J. H., Curtis, A. C. (1956) Medicine, Baltimore, 35, 239. Salt, H. B., Wolff, O. H. (1957) Arch. Dis. Childh. 32, 404. Schwartz, J. F., Rowland, L. P., Eder, H., Marks, P. A., Osserman, E. F., Hirschberg, E., Anderson, H. (1963) Arch. Neurol. 8, 438. Sobrevilla, L. A., Goodman, M. L., Kane, C. A. (1964) Am. J. Med. 37, 821. Thomas, P. K., Walker, J. G. (1965) Brain, 88, 1079. —
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ŒSTROGEN TREATMENT OF RECURRENT APHTHOUS MOUTH ULCERS P. M. F. BISHOP D.M. Oxon., F.R.C.P. ENDOCRINOLOGIST, GUY’S HOSPITAL AND CHELSEA FOR WOMEN, LONDON
HOSPITAL
P. W. R. HARRIS MEDICAL
M.B. Cantab., M.R.C.P. REGISTRAR, GUY’S HOSPITAL, LONDON S.E.1
J. A. P. TRAFFORD M.B. Lond., M.R.C.P. PHYSICIAN, ROYAL SUSSEX COUNTY HOSPITAL,
development of single or multiple erosive lesions in the oral mucosa, surrounded by an area of oedema and hyperxmia, and usually varying in size from 2 to 10 mm. In some cases the ulcers may appear at any time or may be present continuously, but in other patients the episodes of ulceration are periodic, and in women characteristically occur
premenstrually.
aetiology The
cause of recurrent aphthous ulceration of the mouth has been positively established although numerous agents have been suggested as possible aetiological factors; these include herpes simplex and other viruses, Bacillus crassus, Toxoplasma gondii, allergy and hypersensitivity to foods, and genetic influences. A pleomorphic from of an a-hxmolytic streptococcus has been incriminated by Graykowski et al. (1966). Autoimmune factors have been suggested by Lehner (1964), who found antibodies against buccal mucosa in 75 % of patients with aphthous ulcers and in 10%of patients with non-aphthous ulcerating mouth lesions. Whatever may be the precise cause, if any, of recurrent aphthous ulceration there is no doubt that factors such as dental trauma, chemical irritants, and mental stress may aggravate or precipitate the condition, and in women outbreaks may occur in relation to the menstrual never
cycle. In their series of 335 patients with recurrent aphthous ulceration Sircus et al. (1957) reported that nearly 40% of the female patients had crops of ulcers at intervals of less than eight weeks and usually of less than one month, whereas in males the intervals were very much longer. In 43 of the 45 patients considered by Strauss (1947) all the outbreaks started during the sixteen days preceding the onset of menstruation. In an analysis of twelve-month diaries of 120 young adult female students with aphthous ulceration, Ship et al. (1961) noted peak activity of the disease in the seven days preceding menstruation and during the menstrual period itself. It therefore seems that in some patients an endocrine factor may be concerned in precipitating recurrences of the ulcers, and this is further supported by the association of buccal ulcers with similar ulcers in the vagina ’and vulva; Sircus et al. (1957), for instance, reported periodic involvement of the vagina and vulva in 12 of 80 female patients with recurrent buccal ulceration. Furthermore, several workers have observed that buccal ulcers disappear or show remission during pregnancy only to recur in the postpartum period (Ziserman 1934, Sircus et al. 1957, Ship et al. 1962).
Treatment BRIGHTON
Many agents have been used in the treatment of recurrent Department of Endocrinology, Guy’s Hospital, aphthous ulceration and, as may be expected in a condition the xtiology of which is unknown, have met with little success. In a double-blind trial Sircus et al. (1957) found that folic acid, The ætiology of recurrent aphthous ulceraSummary nicotinamide, riboflavine, a vitamin-B mixture, small doses of tion of the mouth is uncertain, but there is evidence suggesting that there is an endocrine factor in cortisone by mouth, and local radiotherapy were of no significant therapeutic value. Combined aneurine-hydrochloride and recurrences, which are not prevented by any treatment folic-acid therapy induced healing in half the cases reported by hitherto described. Since œstrogen produces hyperDurocher (1966), but the ulcers quickly recurred. Fraserkeratinisation and hyperplasia of oral epithelium we gave Moodie (1960) obtained temporary healing of the ulcers in this hormone to 43 female patients with recurrent aphthous some patients with y-globulin, but this agent proved no more ulceration who were referred to our endocrine clinic. effective than a placebo in preventing recurrences. It has been There was a good response to œstrogen treatment in 30 of suggested that there may be a psychosomatic element in the 33 patients in whom the ulcers were related to the menaetiology of the condtion, but hypnosis was found to be valueless by Chalmers and Sircus (1964). strual cycle, and in 5 of 10 patients without this association. Various forms of topical therapy may induce healing of the ulcers in some patients but are generally unsatisfactory, since Introduction the reponse to treatment is unpredictable and recurrences are RECURRENT aphthous ulceration of the mouth is a not prevented. The local application of tetracycline or chlortecommon and distressing condition. According to Sircus tracycline is probably the most effective (Sircus et al. 1957, et al. (1957), the disease probably affects 1 person in every Sagar and Faulkner 1965, Graykowski et al. 1966). Hydro5 in this country at some period of their lives, the incidence cortisone hemisuccinate, prepared in a lactose base and being higher in females than in males; in more than 50% allowed to dissolve slowly in the mouth, has proved moderately of cases the ulcers first develop between the ages of ten successful in healing aphthous ulcers in the acute phase (Cooke and thirty years. The condition is characterised by the and Armitage 1960, Truelove and Morris-Owen 1958) but From the
London
BB2
1346 remission was sustained in only a quarter of the cases reported by Sircus (1959). Similar results were obtained by Zegarelli and Kutscher (1960) with topical triamcinolone acetonide. Lactobacillus tablets containing a viable culture of Lactobacillus acidophilus and L. bulgaricus have been successful in some patients but are also ineffective in preventing recurrences (Rapoport and Levine 1965). The treatment of premenstrual aphthous ulceration has been disappointing. Ethisterone, 50 mg. daily for two weeks preceding menstruation, proved ineffective in 3 patients treated by Sircus et al. (1957), and although large doses of vitamins B and C have succeeded in reducing the severity of the ulcers in some cases, the results have often been disappointing and have not been well documented (Durocher 1966).
Premenstrual Buccal Ulceration
We are chiefly concerned with women in whom the ulcers develop during the premenstrual week. Unfortunately it is still not possible to detect, by estimations of urinary cestrogens and pregnanediol, or by plasmaprogesterone estimations, the relative secretion-rates, circulation, excretion, or effect on peripheral tissues of oestrogens and progestogens through the menstrual cycle. Nevertheless it is generally agreed that premenstrually there is withdrawal of both oestrogen and progesterone. The so-called premenstrual syndrome is thought to be due to inadequate progestogenic activity in the second half of the menstrual cycle and is characterised by mood changes such as irritability and depression, sometimes
accompanied by mastalgia and fluid retention, and is sometimes relieved by the administration of progestogens from the fifteenth to the twenty-fifth day of the cycle. But it is nevertheless possible that there may be peripheral manifestations of oestrogen deficiency which become especially evident during the period of oestrogen withdrawal a few days before menstrual bleeding takes place. (Estrogen therapy is based on the assumption that premenstrual buccal ulceration is one of these manifestations. Material We report here the effects of oestrogen in the treatment of recurrent aphthous ulceration in a series of 43 women. Most of these patients had previously failed to benefit from the local application of hydrocortisone and other agents. A detailed history was taken from each patient with particular reference to the duration of the disease, to any associated genital ulceration, and to whether the ulcers had any relation to the menstrual cycle. The oral and genital mucosa: were carefully examined. The ulcers showed a clearly defined relation to the menstrual cycle in 33 patients, in that they recurred or became more numerous and painful in the premenstrual week and during menstruation. This group is of course selected in that patients with the disease who showed this periodicity were more likely to be referred to an endocrine clinic. 11 of our patients also had vaginal or vulval ulceration. Treatment and Results (Estrogen was given as tablets of ethinyloestradiol, stilboestrol, or ’Premarin ’ (conjugated oestrogens), the
CLINICAL DETAILS OF PATIENTS WITH RECURRENT APHTHOUS ULCERATION OF THE MOUTH TREATED WITH CESTROGENS
1347
minimum effective
daily doses being 0-2, 3-0, and 5-0 mg. respectively in most cases. Some patients were implanted with three 100 mg. pellets of stilboestrol every four to six months, or one or two 100 mg. pellets of oestradiol every six to eight months, and given four-day courses of progestogen every twenty-eight days in order to induce a regular monthly withdrawal bleed and prevent the development of metropathic bleeding. The accompanying table gives particulars of the patients and the results of the effect of treatment was assessed mainly subjectively, but since the ulcers were so painful that the patients hesitated to eat or drink anything that might aggravate the pain their own observations were regarded as a reliable indication of the response to treatment. In a few cases we were able to review the ulcers ourselves and therefore assess them objectively. We concluded that oestrogen produced considerable improvement and in some cases a complete remission during the therapeutic period in 30 (91%) of the 33 patients with premenstrual aphthae and in 5 of the 10 patients in whom the ulcers were not related to the menstrual cycle, although the ulcers might recur some months later and require subsequent courses of treatment. We found it necessary in cases of severe ulceration to continue oestrogen therapy for periods of up to three years, and it is these patients who are best treated by implanted pellets of oestrogen. In some patients it was possible to stop therapy after six to eighteen months, following which no further relapse occurred, but in others a further course of treatment was necessary. Although moderately large doses of oestrogen were necessary in most cases, the incidence of significant side-effects was very low. treatment.
In
most cases
Discussion is Although oestrogen known to induce proliferation and cornification of the vaginal epithelium there have been surprisingly few reports of the effect of oestrogen on the buccal mucosa, even though Schugt, in 1925, suggested that buccal ulcers might be due to ovarian dysfunction. In their experiments, in 1936, Ziskin et al. showed that treatment with oestrogen in ovariectomised monkeys induced keratinisation of the gingival mucosa and proliferation of the epithelium into the submucosa. Ziskin (1937) later observed from biopsy specimens of the gums and oral mucosa of women treated with oestrogen that this hormone caused hyperkeratinisation and hyperplasia of the oral epithelium. Harrison (1964) studied the effects of implants of stilboestrol on the nasal mucosa of the guineapig; he showed that the ciliated columnar epithelium underwent a metaplastic change to squamous epithelium, and that this was maintained as long as the oestrogen was given. Koch et al. (1952) noted that in women with familial capillary telangiectasia the epistaxes were more frequent at the end of the menstrual cycle, after ovariectomy, and at the menopause. Salvatore (1952) demonstrated increased capillary fragility in the first few days of menstruation, which suggests that a low level of circulating oestrogen may be responsible for the bleeding tendency. Harrison (1964) found that ethinyloestradiol tablets, 0-250-50 mg. daily, suppressed the epistaxes in familial capillary telangiectasia, and oestrogens are now widely used in the treatment of this condtiion. In view of the known effect of oestrogen on the vaginal epithelium, studies of the vaginal mucosa were made in several of our patients in whom recurrent aphthous ulceration was related to the menstrual cycle, and the ulcers were shown to occur when the cornification index of the vaginal
epithelium was absent or low (Lessof et al. 1961). Histological evidence of the effect of oestrogen on the oral mucosa is scanty, but Richman and Abarbanel (1943) found oestradiol and stilboestrol effective in the treatment of 25 climacteric patients with atrophic buccal mucosx and senile gingivitis; they noted hyperplasia of the prickle-cell layer, increased activity of the basal cells, and in some cases a smooth even keratinisation of the corneous layer. These observations suggest that aphthous ulceration occurring in relation to the menstrual cycle may be related to declining levels of blood-oestrogen, resulting in failure of keratinisation of the oral mucosa and a tendency for ulcers to develop. They further suggest that the administration of oestrogen might provide a protective layer of desquamating keratinised cells in the oral mucosa, and also diminish capillary fragility. It therefore seemed logical to us to try the effect of oestrogen in the treatment of female patients with recurrent aphthous ulceration. Conclusion
oestrogen therapy is effectivein healing the ulcers in patients with premenstrual apthae and some of those in whom the ulcers are not related to the menstrual cycle. most
The treatment is well tolerated and side-effects are rare, that it may be continued if necessary for long periods. We consider that oestrogens are the treatment of choice in women with premenstrual aphthous ulceration. so
The idea that buccal and vulval ulceration may be due to oestrogen was first suggested to one of us (P. M. F. B.) by the late Dr. H. W. Barber, physician in charge of the skin department at Guy’s Hospital, in the 1940s, and this form of treatment was adopted in the endocrine clinic from that time. A succession of P. M. F. B.’s registrars and clinical assistants have made contributions to this study which we gratefully acknowledge, especially those of Dr. R. de Mowbray, Dr. M. H. Lessof, and Dr. S. McHardy-Young; we are also grateful to Dr. Freda Osmond-Clarke and Dr. Moira Murray of the Chelsea Hospital for Women who studied the vaginal cytology of some of the
deficiency
patients.
Requests
for
reprints
should be addressed
to
P. W. R. H.
REFERENCES
Chalmers, D., Sircus, W. (1964) Gut, 5, 599. Cooke, B. E. D., Armitage, P. (1960) Br. med. J. i, 764. Durocher, R. T. (1966) Dent. Clin. N. Am., March, p. 51. Fraser-Moodie, W. (1960) Br. dent. J. 108, 326. Graykowski, E. A., Barile, M. F., Lee, W. B., Stanley, H. R. (1966) J. Am. med. Ass. 196, 637. Harrison, D. F. N. (1964) Q. Jl Med. 33, 25. Koch, H. J., Escher, W. C., Lewis, J. S. (1952) J. Am. med. Ass. 149, 1376. Lehner, T. (1964) Lancet, ii, 1154. Lessof, M. H., Murray, M., Osmond-Clarke, F. (1961) Br. med. J. i, 589. Rapoport, L., Levine, W. I. (1965) Oral Surg. 20, 591. Richman, M. J., Abarbanel, A. R. (1943) J. clin. Endocr. Metab. 3, 224 Sagar, J. A., Faulkner, K. D. B. (1965) Aust. dent. J. 10, 440. Salvatore, C. A. (1952) Surgery Gynec. Obstet. 95, 13. Schugt, P. (1925) Zentbl. Gynak. 49, 2180. Ship, I. I., Merritt, A. D., Stanley, H. R. (1962) Am. J. Med. 32, 32. Morris, A. L., Durocher, R. T., Burkett, L. W. (1961) Oral. Surg. 14, 30. Sircus, W. (1959) Br. med. J., ii, 804. Church, R., Kelleher, J. (1957) Q. Jl Med. 26, 235. Strauss, K. (1947) Br. dent. J. 83, 77. Truelove, S. C., Morris-Owen, R. M. (1958) Br. med. J. i, 603. Zegarelli, E. V., Kutscher, A. H. (1960) Archs Derm. Syph. 82, 1010. Ziserman, A. J. (1934) J. Am. med. Ass. 104, 826. Ziskin, D. E. (1937) J. dent. Res. 16, 367. Blackberg, S. N., Slanetz, C. A. (1936) ibid. 15, 407. —
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" ... It is not to the principle of approving or condemning books we object, for this principle we shall rigorously act up to ourselves, but to the affected sentimentality which is daily expended in common-place lamentation over the redundancy of authorism, whilst the very writers of this pitiful and puling slang are themselves increasing the evil they would fain correct, by adding their contributions to the modern Babel of books."Lancet, Jan. 22, 1825, p. 76.
Joint
REFERENCES
Andrade, C. (1952) Brain, 75, 408. Bartlett, G. R. (1959) J. Biochem. 234, 466. Brown, W. J. (1961) Aust. J. exp. Biol. 39, 223. Chambers, R. A., Medd, W. E., Spencer, H. (1958) Q. Jl Med. 27, 207. Cornwell, D. G., Kruger, F. A., Hamwi, G. J., Brown, J. B. (1961) Am. J. clin. Nutr. 9, 24. Engel, W. K., Dorman, J., Levy, R. I., Fredrickson, D. S. Unpublished. Fredrickson, D. S. (1966) in The Metabolic Basis of Inherited Disease (edited by J. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson); p. 486. New York. Altrocchi, P. H., Avioli, L. V., Goodman, D. S., Goodman, H. C. (1961) Ann. intern. Med. 55, 1016. Young, O. M., Shiratori, T., Briggs, N. (1964) J. clin. Invest. 43, 228. Freeman, N. K. (1964) J. lipid Res. 5, 236. Gilliatt, R. W., Goodman, H. V., Willison, R. G. (1961) J. Neurol. Neurosurg. Psychiat. 24, 305. Sears, T. A. (1958) ibid. 21, 109 Grabar, P., Williams, C. A. (1955) Biochim. Biophys. Acta. 17, 67. Hoffman, H. N., Fredrickson, D. S. (1965) Am. J. Med. 39, 582. Jones, J. W., Ways, P. (1967) J. clin. Invest. (in the press). Lewis, L. A., Zuehlke, V., Nakamoto, S., Kolff, W. J., Page, I. H. (1966) New Engl. J. Med. 275, 1097. Levy, R. I., Fredrickson, D. S. (1965) J. clin. Invest. 44, 426. (1966) Circulation, 34, suppl. III, 156. Lees, R. S., Fredrickson, D. S. (1966) J. clin. Invest. 45, 63. Pantelakis, S. N., Fosbrooke, A. S., Lloyd, J. K., Wolff, O. H. (1964) Diabetes, 13, 153. Phillips, G. B. (1959) Proc. Soc. exp. Biol. Med. 100, 19. Rukavina, J. G., Block, W. D., Jackson, C. D., Falls, H. F., Carey, J. H., Curtis, A. C. (1956) Medicine, Baltimore, 35, 239. Salt, H. B., Wolff, O. H. (1957) Arch. Dis. Childh. 32, 404. Schwartz, J. F., Rowland, L. P., Eder, H., Marks, P. A., Osserman, E. F., Hirschberg, E., Anderson, H. (1963) Arch. Neurol. 8, 438. Sobrevilla, L. A., Goodman, M. L., Kane, C. A. (1964) Am. J. Med. 37, 821. Thomas, P. K., Walker, J. G. (1965) Brain, 88, 1079. —
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ŒSTROGEN TREATMENT OF RECURRENT APHTHOUS MOUTH ULCERS P. M. F. BISHOP D.M. Oxon., F.R.C.P. ENDOCRINOLOGIST, GUY’S HOSPITAL AND CHELSEA FOR WOMEN, LONDON
HOSPITAL
P. W. R. HARRIS MEDICAL
M.B. Cantab., M.R.C.P. REGISTRAR, GUY’S HOSPITAL, LONDON S.E.1
J. A. P. TRAFFORD M.B. Lond., M.R.C.P. PHYSICIAN, ROYAL SUSSEX COUNTY HOSPITAL,
development of single or multiple erosive lesions in the oral mucosa, surrounded by an area of oedema and hyperxmia, and usually varying in size from 2 to 10 mm. In some cases the ulcers may appear at any time or may be present continuously, but in other patients the episodes of ulceration are periodic, and in women characteristically occur
premenstrually.
aetiology The
cause of recurrent aphthous ulceration of the mouth has been positively established although numerous agents have been suggested as possible aetiological factors; these include herpes simplex and other viruses, Bacillus crassus, Toxoplasma gondii, allergy and hypersensitivity to foods, and genetic influences. A pleomorphic from of an a-hxmolytic streptococcus has been incriminated by Graykowski et al. (1966). Autoimmune factors have been suggested by Lehner (1964), who found antibodies against buccal mucosa in 75 % of patients with aphthous ulcers and in 10%of patients with non-aphthous ulcerating mouth lesions. Whatever may be the precise cause, if any, of recurrent aphthous ulceration there is no doubt that factors such as dental trauma, chemical irritants, and mental stress may aggravate or precipitate the condition, and in women outbreaks may occur in relation to the menstrual never
cycle. In their series of 335 patients with recurrent aphthous ulceration Sircus et al. (1957) reported that nearly 40% of the female patients had crops of ulcers at intervals of less than eight weeks and usually of less than one month, whereas in males the intervals were very much longer. In 43 of the 45 patients considered by Strauss (1947) all the outbreaks started during the sixteen days preceding the onset of menstruation. In an analysis of twelve-month diaries of 120 young adult female students with aphthous ulceration, Ship et al. (1961) noted peak activity of the disease in the seven days preceding menstruation and during the menstrual period itself. It therefore seems that in some patients an endocrine factor may be concerned in precipitating recurrences of the ulcers, and this is further supported by the association of buccal ulcers with similar ulcers in the vagina ’and vulva; Sircus et al. (1957), for instance, reported periodic involvement of the vagina and vulva in 12 of 80 female patients with recurrent buccal ulceration. Furthermore, several workers have observed that buccal ulcers disappear or show remission during pregnancy only to recur in the postpartum period (Ziserman 1934, Sircus et al. 1957, Ship et al. 1962).
Treatment BRIGHTON
Many agents have been used in the treatment of recurrent Department of Endocrinology, Guy’s Hospital, aphthous ulceration and, as may be expected in a condition the xtiology of which is unknown, have met with little success. In a double-blind trial Sircus et al. (1957) found that folic acid, The ætiology of recurrent aphthous ulceraSummary nicotinamide, riboflavine, a vitamin-B mixture, small doses of tion of the mouth is uncertain, but there is evidence suggesting that there is an endocrine factor in cortisone by mouth, and local radiotherapy were of no significant therapeutic value. Combined aneurine-hydrochloride and recurrences, which are not prevented by any treatment folic-acid therapy induced healing in half the cases reported by hitherto described. Since œstrogen produces hyperDurocher (1966), but the ulcers quickly recurred. Fraserkeratinisation and hyperplasia of oral epithelium we gave Moodie (1960) obtained temporary healing of the ulcers in this hormone to 43 female patients with recurrent aphthous some patients with y-globulin, but this agent proved no more ulceration who were referred to our endocrine clinic. effective than a placebo in preventing recurrences. It has been There was a good response to œstrogen treatment in 30 of suggested that there may be a psychosomatic element in the 33 patients in whom the ulcers were related to the menaetiology of the condtion, but hypnosis was found to be valueless by Chalmers and Sircus (1964). strual cycle, and in 5 of 10 patients without this association. Various forms of topical therapy may induce healing of the ulcers in some patients but are generally unsatisfactory, since Introduction the reponse to treatment is unpredictable and recurrences are RECURRENT aphthous ulceration of the mouth is a not prevented. The local application of tetracycline or chlortecommon and distressing condition. According to Sircus tracycline is probably the most effective (Sircus et al. 1957, et al. (1957), the disease probably affects 1 person in every Sagar and Faulkner 1965, Graykowski et al. 1966). Hydro5 in this country at some period of their lives, the incidence cortisone hemisuccinate, prepared in a lactose base and being higher in females than in males; in more than 50% allowed to dissolve slowly in the mouth, has proved moderately of cases the ulcers first develop between the ages of ten successful in healing aphthous ulcers in the acute phase (Cooke and thirty years. The condition is characterised by the and Armitage 1960, Truelove and Morris-Owen 1958) but From the
London
BB2
1346 remission was sustained in only a quarter of the cases reported by Sircus (1959). Similar results were obtained by Zegarelli and Kutscher (1960) with topical triamcinolone acetonide. Lactobacillus tablets containing a viable culture of Lactobacillus acidophilus and L. bulgaricus have been successful in some patients but are also ineffective in preventing recurrences (Rapoport and Levine 1965). The treatment of premenstrual aphthous ulceration has been disappointing. Ethisterone, 50 mg. daily for two weeks preceding menstruation, proved ineffective in 3 patients treated by Sircus et al. (1957), and although large doses of vitamins B and C have succeeded in reducing the severity of the ulcers in some cases, the results have often been disappointing and have not been well documented (Durocher 1966).
Premenstrual Buccal Ulceration
We are chiefly concerned with women in whom the ulcers develop during the premenstrual week. Unfortunately it is still not possible to detect, by estimations of urinary cestrogens and pregnanediol, or by plasmaprogesterone estimations, the relative secretion-rates, circulation, excretion, or effect on peripheral tissues of oestrogens and progestogens through the menstrual cycle. Nevertheless it is generally agreed that premenstrually there is withdrawal of both oestrogen and progesterone. The so-called premenstrual syndrome is thought to be due to inadequate progestogenic activity in the second half of the menstrual cycle and is characterised by mood changes such as irritability and depression, sometimes
accompanied by mastalgia and fluid retention, and is sometimes relieved by the administration of progestogens from the fifteenth to the twenty-fifth day of the cycle. But it is nevertheless possible that there may be peripheral manifestations of oestrogen deficiency which become especially evident during the period of oestrogen withdrawal a few days before menstrual bleeding takes place. (Estrogen therapy is based on the assumption that premenstrual buccal ulceration is one of these manifestations. Material We report here the effects of oestrogen in the treatment of recurrent aphthous ulceration in a series of 43 women. Most of these patients had previously failed to benefit from the local application of hydrocortisone and other agents. A detailed history was taken from each patient with particular reference to the duration of the disease, to any associated genital ulceration, and to whether the ulcers had any relation to the menstrual cycle. The oral and genital mucosa: were carefully examined. The ulcers showed a clearly defined relation to the menstrual cycle in 33 patients, in that they recurred or became more numerous and painful in the premenstrual week and during menstruation. This group is of course selected in that patients with the disease who showed this periodicity were more likely to be referred to an endocrine clinic. 11 of our patients also had vaginal or vulval ulceration. Treatment and Results (Estrogen was given as tablets of ethinyloestradiol, stilboestrol, or ’Premarin ’ (conjugated oestrogens), the
CLINICAL DETAILS OF PATIENTS WITH RECURRENT APHTHOUS ULCERATION OF THE MOUTH TREATED WITH CESTROGENS
1347
minimum effective
daily doses being 0-2, 3-0, and 5-0 mg. respectively in most cases. Some patients were implanted with three 100 mg. pellets of stilboestrol every four to six months, or one or two 100 mg. pellets of oestradiol every six to eight months, and given four-day courses of progestogen every twenty-eight days in order to induce a regular monthly withdrawal bleed and prevent the development of metropathic bleeding. The accompanying table gives particulars of the patients and the results of the effect of treatment was assessed mainly subjectively, but since the ulcers were so painful that the patients hesitated to eat or drink anything that might aggravate the pain their own observations were regarded as a reliable indication of the response to treatment. In a few cases we were able to review the ulcers ourselves and therefore assess them objectively. We concluded that oestrogen produced considerable improvement and in some cases a complete remission during the therapeutic period in 30 (91%) of the 33 patients with premenstrual aphthae and in 5 of the 10 patients in whom the ulcers were not related to the menstrual cycle, although the ulcers might recur some months later and require subsequent courses of treatment. We found it necessary in cases of severe ulceration to continue oestrogen therapy for periods of up to three years, and it is these patients who are best treated by implanted pellets of oestrogen. In some patients it was possible to stop therapy after six to eighteen months, following which no further relapse occurred, but in others a further course of treatment was necessary. Although moderately large doses of oestrogen were necessary in most cases, the incidence of significant side-effects was very low. treatment.
In
most cases
Discussion is Although oestrogen known to induce proliferation and cornification of the vaginal epithelium there have been surprisingly few reports of the effect of oestrogen on the buccal mucosa, even though Schugt, in 1925, suggested that buccal ulcers might be due to ovarian dysfunction. In their experiments, in 1936, Ziskin et al. showed that treatment with oestrogen in ovariectomised monkeys induced keratinisation of the gingival mucosa and proliferation of the epithelium into the submucosa. Ziskin (1937) later observed from biopsy specimens of the gums and oral mucosa of women treated with oestrogen that this hormone caused hyperkeratinisation and hyperplasia of the oral epithelium. Harrison (1964) studied the effects of implants of stilboestrol on the nasal mucosa of the guineapig; he showed that the ciliated columnar epithelium underwent a metaplastic change to squamous epithelium, and that this was maintained as long as the oestrogen was given. Koch et al. (1952) noted that in women with familial capillary telangiectasia the epistaxes were more frequent at the end of the menstrual cycle, after ovariectomy, and at the menopause. Salvatore (1952) demonstrated increased capillary fragility in the first few days of menstruation, which suggests that a low level of circulating oestrogen may be responsible for the bleeding tendency. Harrison (1964) found that ethinyloestradiol tablets, 0-250-50 mg. daily, suppressed the epistaxes in familial capillary telangiectasia, and oestrogens are now widely used in the treatment of this condtiion. In view of the known effect of oestrogen on the vaginal epithelium, studies of the vaginal mucosa were made in several of our patients in whom recurrent aphthous ulceration was related to the menstrual cycle, and the ulcers were shown to occur when the cornification index of the vaginal
epithelium was absent or low (Lessof et al. 1961). Histological evidence of the effect of oestrogen on the oral mucosa is scanty, but Richman and Abarbanel (1943) found oestradiol and stilboestrol effective in the treatment of 25 climacteric patients with atrophic buccal mucosx and senile gingivitis; they noted hyperplasia of the prickle-cell layer, increased activity of the basal cells, and in some cases a smooth even keratinisation of the corneous layer. These observations suggest that aphthous ulceration occurring in relation to the menstrual cycle may be related to declining levels of blood-oestrogen, resulting in failure of keratinisation of the oral mucosa and a tendency for ulcers to develop. They further suggest that the administration of oestrogen might provide a protective layer of desquamating keratinised cells in the oral mucosa, and also diminish capillary fragility. It therefore seemed logical to us to try the effect of oestrogen in the treatment of female patients with recurrent aphthous ulceration. Conclusion
oestrogen therapy is effectivein healing the ulcers in patients with premenstrual apthae and some of those in whom the ulcers are not related to the menstrual cycle. most
The treatment is well tolerated and side-effects are rare, that it may be continued if necessary for long periods. We consider that oestrogens are the treatment of choice in women with premenstrual aphthous ulceration. so
The idea that buccal and vulval ulceration may be due to oestrogen was first suggested to one of us (P. M. F. B.) by the late Dr. H. W. Barber, physician in charge of the skin department at Guy’s Hospital, in the 1940s, and this form of treatment was adopted in the endocrine clinic from that time. A succession of P. M. F. B.’s registrars and clinical assistants have made contributions to this study which we gratefully acknowledge, especially those of Dr. R. de Mowbray, Dr. M. H. Lessof, and Dr. S. McHardy-Young; we are also grateful to Dr. Freda Osmond-Clarke and Dr. Moira Murray of the Chelsea Hospital for Women who studied the vaginal cytology of some of the
deficiency
patients.
Requests
for
reprints
should be addressed
to
P. W. R. H.
REFERENCES
Chalmers, D., Sircus, W. (1964) Gut, 5, 599. Cooke, B. E. D., Armitage, P. (1960) Br. med. J. i, 764. Durocher, R. T. (1966) Dent. Clin. N. Am., March, p. 51. Fraser-Moodie, W. (1960) Br. dent. J. 108, 326. Graykowski, E. A., Barile, M. F., Lee, W. B., Stanley, H. R. (1966) J. Am. med. Ass. 196, 637. Harrison, D. F. N. (1964) Q. Jl Med. 33, 25. Koch, H. J., Escher, W. C., Lewis, J. S. (1952) J. Am. med. Ass. 149, 1376. Lehner, T. (1964) Lancet, ii, 1154. Lessof, M. H., Murray, M., Osmond-Clarke, F. (1961) Br. med. J. i, 589. Rapoport, L., Levine, W. I. (1965) Oral Surg. 20, 591. Richman, M. J., Abarbanel, A. R. (1943) J. clin. Endocr. Metab. 3, 224 Sagar, J. A., Faulkner, K. D. B. (1965) Aust. dent. J. 10, 440. Salvatore, C. A. (1952) Surgery Gynec. Obstet. 95, 13. Schugt, P. (1925) Zentbl. Gynak. 49, 2180. Ship, I. I., Merritt, A. D., Stanley, H. R. (1962) Am. J. Med. 32, 32. Morris, A. L., Durocher, R. T., Burkett, L. W. (1961) Oral. Surg. 14, 30. Sircus, W. (1959) Br. med. J., ii, 804. Church, R., Kelleher, J. (1957) Q. Jl Med. 26, 235. Strauss, K. (1947) Br. dent. J. 83, 77. Truelove, S. C., Morris-Owen, R. M. (1958) Br. med. J. i, 603. Zegarelli, E. V., Kutscher, A. H. (1960) Archs Derm. Syph. 82, 1010. Ziserman, A. J. (1934) J. Am. med. Ass. 104, 826. Ziskin, D. E. (1937) J. dent. Res. 16, 367. Blackberg, S. N., Slanetz, C. A. (1936) ibid. 15, 407. —
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