Gut, 1979, 20, 154-157

Gynaecomastia associated with cimetidineR. W. SPENCE AND L. R. CELESTIN

From the Department of Gastroenterology, Frenchay Hospital, Bristol

SUMMARY Gynaecomastia has occurred unilaterally or bilaterally in five out of 25 male duodenalulcer patients after more than four months treatment with cimetidine 1.6 g daily. All elected tocontinue treatment to 12 months and their breast enlargement regressed rapidly and disappearedafter stopping treatment. During treatment all patients were found to have normal concentrationsof plasma testosterone and oestradiol, and serum prolactin was normal in the two patients measured.Excision biopsy of the subareolar tissue in one patient revealed histology typical of the florid stageof gynaecomastia. Blockade of androgen-responsive receptors in the target organ appears to be themost likely mechanism involved.

Since Hall (1976) reported the development ofgynaecomastia in two patients treated with cime-tidine, various other cases of gynaecomastia andgalactorrhoea have been reported (Bateson et al.,1977; Delle Fave 1977; Sharpe and Hawkins, 1977).The total number of cases reported remains smalland this report does not add materially to the total,as four of our cases were included in the overallreport by Sharpe and Hawkins (1977) and Hall(1976) mentions two. Yet in a single long-term studywe have encountered a 20% incidence of gynaeco-mastia in male duodenal ulcer patients.

Patients

Twenty five male outpatients with endoscopicallyproven duodenal ulcer or severe duodenitis havebeen treated for 12 months with cimetidine 1.6 gdaily administered as four divided doses. Five ofthese patients complained of soreness of one or bothnipples associated with breast swelling after treat-ment intervals ranging from four to nine months.One patient has ankylosing spondylitis, while theother four have no concomitant disease. All electedto remain on treatment, preferring the minorsymptom of breast soreness to their pretreatmentsymptoms, and gynaecomastia subsequently re-gressed rapidly in every case, the soreness disappear-ing within a few days of discontinuation of treat-ment. Only one of the patients experienced a tem-porary reduction in libido (the patient with anky-losing spondylitis). Unilateral excision biopsy wasperformed at the request of one of the patients two

Received for publication 1 September 1978

weeks after he developed soreness of the nipple;light microscopic examination revealed moderateduct proliferation with some heaping up of theductal epithelium in places, a little dilatation of someducts and associated moderate hyperplasia of thepeructidal connective tissue (Fig. 1), appearancetypical of the early or florid type of gynaecomastia(Bannayan and Hajdu, 1972). Electron microscopyof the tissue revealed epithelial cells of the typeusually found in breast and containing occasionaltypical milk granules (Fig. 2).

Results of hormone assays

Estimation of plasma testosterone and oestradiolwere performed in all five patients (Table). Becauseof the fluctuations that are known to occur in testo-sterone levels (Weitzman et al., 1975) two daytimesamples were obtained 30 minutes apart in cases 4and 5 (shown in parentheses in the Table). Apart fromcase 5, where an isolated plasma testosterone valuewas above the upper limit of normal, all values ob-tained for plasma testosterone and oestradiol werewithin the stated normal limits and the ratio of freeto protein-bound oestradiol was not increased inany case. In addition, in three patients plasmaoestrone LH and FSH were within the range ex-pected in normal males (V. H. T. James, personalcommunication). Plasma prolactin levels of daytimeblood samples from cases 4 and 5 were measured(sample times corresponding with testosteronesamples) and values were well within the normalrange (Table).During the course of treatment cimetidine blood

concentrations were measured in all five patients in154

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Gynaecomastia assoriated with cimetidine

Fig. 1 Case 5. Lightmicroscope photograph oJ asection of the biopsyshowing a duct lined byheaped-up columnarepithelium and proliferationof surrounding connectivetissue. x 800 (originalmagnification).

whole blood samples taken over six hours immedi-ately after the ingestion of the first 400mg dose of theday and concentrations tended to be lower than thosefound in another six similar patients in the studywho did not develop breast soreness. Results in thegynaecomastia group were as follows: residualconcentrations (from the previous day's dosing)0 - 2-4, mean 0.6 jmol/l; peak concentrations10 - 14, mean 12 ,umol/l. In the unaffected groupthe results were: residual concentrations 0- 2.8,mean 2-1 gmol/l, peak concentrations 14 - 20,mean 15 6 gmol/l - (4 gmol/l = 1 gg/ml).Discussion

The mechanism of drug-induced gynaecomastiaremains unknown, though it has been reported inassociation with drugs as unrelated as spironolac-tone (Mann, 1963), digitalis (Le Winn, 1953),monoamine oxidase inhibitors (Arroyo, 1966), andvincristine (Smith and Barrett, 1967). There arevarious mechanisms by which breast enlargementmay have arisen in this group of patients. First,refeeding, although a known cause of gynaecomastia,is an unlikely explanation in the present group, asonly two patients showed an increase in body weightduring treatment and one of these was already over-weight before treatment. Secondly, cimetidine mightinterfere in some way with the release of androgensor disturb the androgen/oestrogen balance either by

increasing the rate at which androgen is metabolisedto oestrogen, or by increasing the ratio of free toprotein-bound oestrogen. Our data do not confirmsuch changes. In an earlier study no change wasfound in the plasma concentrations of testosteronein a different group (12) of our patients before andafter six weeks' treatment with cimetidine at thesame dosage as the present study (Sharpe andHawkins, 1977). Similarly, 24 hour urinary excretionof testosterone in those patients remained withinnormal limits (unpublished data).

Thirdly, cimetidine might alter prolactin releasebut our results do not confirm this. In cases 4 and 5,samples for prolactin assay were taken at timesduring the day when circulating levels of the hor-mone would be expected to be declining after thephysiological peak in the early hours of the morning(Sassin et al., 1972). The values obtained were lowand of the order of magnitude that would be ex-pected in normal males during these hours. DelleFave et al. (1977 a, b) and Bateson et al. (1977) havefound serum prolactin concentrations increasedabove normal in both males and females after treat-ment with cimetidine, but reports are conflicting andneither Petrillo et al. (1977) nor Majumdar et al.(1978) have shown increased circulating prolactinafter various intervals of cimetidine treatment. In acontrolled study, Burland et al. (1978) have shownshort-lived increases in serum prolactin in associa-tion with very high peak blood concentrations of

155

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R. W. Spence and L. R. Celestin

s. ~~.5

Fig. 2 Electron micrograph ofportions of two epithelial cells showing surfaceprocesses (sp), abundant cytoplasmic microfibrils (mf) and ribosomes (R),mitochondria (mi), milk granules (MG), and nucleus (Nu). Approximately x 25 000.

cimetidine after 400 mg intravenous bolus injections, Cimetidine has no oestrogenic activity (Leslie andbut no increases after 800 mg oral doses. Walker, 1977) but has been shown to have weakThe remaining possible mechanism involves the anti-androgenic activity in rats and dogs as revealed

known weak anti-androgenic activity of the drug. by a reduction in the size and weight of the prostate

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Gynaecomastia associated with cimetidine 157

Table Hormonal measurements in five duodenal ulcerpatients with gynaecomastia

Case no. Testosterone Oestradiol Oestrone Prolactin(nmol/l) (ng/100 ml) (ng/ml) (mU/1OO ml)

1 14-6 9 - -2 194 8-8 - -3 10-7 49 51 -4 194 -

r24.8 5.9 6-9 14122-1 1 6-6 5.1 110°

5 28.5 2837.0] 4-9 5.5 161131[ [JlO

Quotedlaboratorynormal 10-32 < 1-12 - < 35range 9 am-9 pm

gland. It was suggested that this may be the result ofblockade of androgenic receptors in the target organ.The dosages per kilogram body weight necessary toproduce measurable reduction of prostate size inthe dog were at least 20 times greater than the dosesemployed in our patients, so it is surprising thatclinical sequelae should have resulted from thepresent dosage regimen. Certainly, testosteronelevels in the blood in our patients were not reducedafter prolonged treatment, so that the occurrence ofgynaecomastia may be the result of blockade ofreceptors mediating the normal androgenic sup-pression of the responsiveness of breast tissue tonormal (male) circulating levels of oestrogen,gonadotrophins, and prolactin. We consider this tobe the most likely causative mechanism in the lightof the available evidence.Although anti-androgenic activity was demon-

strable only in association with very high dose regi-mens in animals, blood concentrations of cimetidinein this study in the five affected patients tended to belower than in the six similar patients who did notdevelop breast symptoms, so that the individualpatient's liability to develop gynaecomastia appearsto be influenced by more factors than blood con-centrations of the drug alone. But, so far, gynae-comastia has not been reported in studies usinglower dose regimens for four to six weeks only andit seems that it is likely to be encountered only in thelong-term administration of higher doses of cimeti-dine. Gynaecomastia is on the whole a minorsymptom, does not necessitate stopping treatment,and is readily reversible on discontinuing therapy.

We are grateful to Professor V. H. T. James of St.Mary's Hospital, Paddington, for androgen andoestrogen assays and to Professor K. Griffiths andDr Graham Groom of the Tenovus Institute,Cardiff, for prolactin assays. Cimetidine bloodconcentrations were kindly measured by the Bio-

chemistry Department, Smith Kline and FrenchLaboratories (Welwyn Garden City) whose ClinicalResearch Department also kindly supplied thecimetidine. Histological examination of the biopsyspecimen was carried out by Dr R. J. Sandry andtissue for electron microscopy was prepared andphotographed by D. A. McCormick.

References

Arroyo, H. (1966). Gyn6comastie induite par un inhibiteurde la mono-amine-oxydase. Presse Mddicale, 74, 1764.

Bannayan, G. A., and Hajdu, S. I. (1972). Gynecomastia:clinico-pathologic study of 351 cases. American Journal ofClinical Pathology, 57, 431-437.

Bateson, M. C., Browning, M. C. K., and Maconnachie, A.(1977). Galactorrhoea with cimetidine. Lancet, 2, 247-248, letter.

Burland, W. L., Gleadle, R. I., Lee, R. M., Rowley-Jones,D., and Groom, G. V. (1978). Cimetidine and serumprolactin. (Letter) British Medical Journal, 1, 717.

Delle Fave, G. F., Tamburrano, G., De Magistris, L.,Natoli, C., Santoro, M. L., Carratu, R., and Torsoli, A.(1977a). Gynaecomastia with cimetidine. (Letter.)Lancet, 1, 1319.

Delle Fave, G. F., Tamburrano, G., De Magistris, L.,Natoli, C., Santoro, M., Carratu, R., and Torsoli, A.(1977b). Variations in serum prolactin following cimetidinetreatment for peptic ulcer disease. Rendiconti di Gastro-enterologia, 9, 142-143.

Hall, W. H. (1976). Breast changes in males on cimetidine.New England Journal of Medicine, 841, 295. (Letter).

Leslie, G. B., and Walker, T. F. (1977). A toxicologicalprofile of cimetidine. In Cimetidine: Proceedings of theSecond International Symposium on Histamine H2-receptor Antagonists (International Congress Series 416),pp. 24-37. Edited by W. L. Burland and M. A. Simkins.Excerpta Medica: Amsterdam.

Le Winn, E. B. (1953). Gynecomastia during digitalistherapy: report of 8 additional cases with liver-functionstudies. New England Journal of Medicine, 248, 316-320.

Majumdar, S. K., Thomson, A. D., and Shaw, G. K. (1978).Cimetidine and serum prolactin. British Medical Journal,1, 409.

Mann, N. M. (1963). Gynecomastia during therapy withspironolactone. Journal of the American Melical Asso-ciation, 184, 778-780.

Petrillo, M., Prada, A., Bevilacqua, M., Raggi, V., Norbiato,G., Bianchi Porro, G. (1977). Plasma prolactin andcimetidine (Letter). Lancet, 2, 761.

Sassin, J. F., Frantz, A. G., Weitzman, E. D., and Kapen, S.(1972). Human prolactin: 24 hour pattern with increasedrelease during sleep. Science, 177, 1205-1207.

Sharpe, P. C., and Hawkins, B. H. (1977). Efficacy and safetyof cimetidine. Long-term treatment with cimetidine. InCimetidine: Proceedings of the Second InternationalSymposium on Histamine H2-receptor Antagonists (Inter-national Congress Series 416), pp. 358-366. Edited byW. L. Burland and M. A. Simkins, Excerpta Medica:Amsterdam.

Smith, R. H., and Barrett, 0. N. Jr. (1967). Gynecomastiaassociated with vincristine therapy. California Medicine,107, 347-349.

Weitzman, E. D., Boyar, R. M., Kapen, S., and Hell-man, L. (1975). The relationship of sleep and sleep stages toneuroendocrine secretion and biological rhythms in man.Recent Progress in Hormone Research, 31, 399-446.

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