Discussion on Section H Risks of Estrogen Therapy (Part 2) Cancer Chairman: lv!r R. B. K. Rickford Mr R. B. K. Rickford (Chairman): Professor Sellwood gave estrogens to his male rats and they developed carcinoma. Did he ever think of giving them estrogens and progestogens. I also hoped that he might explain to me, as a mere gynaecologist, why we are sometimes asked to take ovaries out of patients with carcinoma of the breast, and why some patients with carcinoma of the breast are given massive doses of estrogens. Professor R. A. Sellwood (Surgeon, Manchester): I shall take the second question first. We have the concept of estrogen-dependence. Someone coined the term a long time ago, to explain the dramatic remission of the disease that occurs in about 30~ ~ of pre-menopausal women following removal of the ovaries. I cannot explain why in post-menopausal women, or at least in women who are 5 or 6 years beyond the menopause, an equally dramatic remission can be obtained by giving estrogens. Perhaps we are wrong to talk about estrogen dependence. Perhaps we should simply say that anything we do which drastically alters the sex hormone environment alters the responsiveness of the tumour. The estrogens that we give are synthetic and generally speaking they are either stilbestrol or ethinyl estradiol. One could postulate that their effect is to block the receptors on the tumour cells on which the endogenous estrogens normally work and produce their effect, but I have no evidence that this IS so. The work on rats was not mine. It is American work and I do not think that anyone has studied the effects of estrogen and progestogen together in the male rat. Mr E. S. Saunders (Gynaecologist, London): Professor Dewhurst has been kind enough to mention my work. My statistics published in 1960 concerned 500 cases which were treated with hormone implants. The duration was 15 years, and not 5 years. The expected number of cancers, according to the general population, would have been about 30; there were no cancers in my treated patients. 351
352 THE MANAGEMENT OF THE MENOPAUSE Professor Dewhurst referred to another group where two cases of cancer of the uterus were found. Those two cases are very interesting, from every point of view. One case came to see me because of severe flushes and palpitations, and also osteoporosis. I gave her the usual implant. Ten days later that woman came back complain- ing of bleeding. A thorough examination was done, and a curettage showed a polyp which was examined by the pathologist who reported malignant changes on the tip of the polyp. We cannot claim than an implant done IO days earlier provoked a cancer of the endometrium. The second case of cancer was also interesting. The patient was aged about 49 or 50, with a history of irregular periods, a slight loss every few weeks, and because of her severe menopausal symptoms-she showed no signs of malignancy-i gave her an implant. Three weeks later she came with bleeding. A curettage showed carcinoma of the endometrium. From the point of view of statistics, I have to put those cases in, although I am convinced that they have nothing to do with the implant. A second statistic of mine has not been mentioned. The material was presented at a Congress in Vienna. There were 600 cases, selected menopausal women, about the same age group. They were divided into two groups. Three hundred were given a placebo but the other three hundred were treated with implants. Ten years later a follow up of most of the cases showed that the women who had received implants had 2t times less cancer than the others. To conclude: Professor Dewhurst has said that there is no evidence that estrogen might not produce a cancer, but there is no evidence either that estrogen has produced cancers. Mr S. Campbell (Gynaecologist, London): In our 6-month crossover placebo trial which we described earlier, the patients had an outpatient (Vabra) curettage on admission to the study and again after 6 months Premarin and 6 months placebo. Twentysix of the 39 patients who had intact uteri had withdrawal bleeding on Premarin 1 25 mg, an incidence of 67 0 which is very much higher than the Io-20~~ which is quoted in the literature. A total of 6 patients (9 o) had cystic glandular hyperplasia while on Premarin 1 25 mg but did not have it on placebo. That is a very high incidence and although I quite accept that this may not be a pre-cancerous lesion, it worries me considerably. We have had one case of cancer of the endometrium in a patient who before she came to our clinic, had been one year on continuous Premarin. We put her on a cyclical dosage but discovered cancer of the endometrium a few months later when we performed Vabra curettage. The conclusion I would draw is that we cannot be complacent about the risks of cancer of the endometrium. We must use the minimum dosage to control symptoms, and for any patient with regular withdrawal bleeding I would recommend a 6- monthly Vabra curettage or preferably the. addition of a progestogen to the therapy. More and more I am using a regime of continuous estrogen, and for the first week of every calendar month prescribing norethisterone, 5 mg daily. Since adopting this regime we have had no cases of hyper stimulation of the endometrium and I feel very much happier when I see that situation. Professor C. J. Dewhurst (Gynaecologist, London): I share Mr Campbell's concern
SECTION H: RISKS OF ESTROGEN THERAPY 353 about cystic glandular hyperplasia. The fact that millions of women on the Pill which contains estrogen and progestogen, do not develop cancer, is irrelevant as to whether estrogens alone do. That is one of my points. I do not think that these facts are clearly stated in many of the papers, and my purpose here is to suggest that we should still look, and go on looking critically at the evidence that estrogens alone over long periods of time are free from risk. Ms. Tove Wisborg (Copenhagen): In the past 10 years we have seen five cases of estrogen-produced ovarian cancer and one case of breast cancer. We thought that there llught be a connection with a contmuous high level of estrogen in the body, compared with normal cyclic variations. Perhaps it might be advisable not to use continuous estrogen in post-menopausal women, but to use intermittent therapy. Professor R. A. Sellwood: I would be most interested in the data. The information is new to me. Professor C. J. Dewhurst: For other reasons, I would always approve intermittent therapy, but that is hardly relevant to the question. Mr E. V. van Hall (Lei den) : Did Professor selwood do the same studies in postmenopausal breast cancer patients? They are the more interesting group. Also it would be interesting to look at estrone, and perhaps androgens. Professor R. A. Sellwood: We have done this in post-menopausal women. We have got a group of about 30 or 40 post-menopausal women with cancer of the breast, and 30 or 40 normal women. The estradiol I7-{1 is so low in the post-menopausal women that it is at the lower limit of sensitivity of our assay, and I can make no comment about it. We have not yet measured the prolactin in those women. It should be more interesting. Of course Mr Van Hall is right. What we really want to measure is estrone, but as yet we cannot produce an antibody. Professor C. Lauritzen (Gynaecologist, Ulm): I have some comments on estrogens and mammary carcinoma. We have discussed estrogens, carcinoma of the breast, and of the endometrium, but we would be very short-sighted, or even blind, to look only at estrogens. I cannot let the discussion go without mentioning that genetic factors in the human are of great importance in mammary carcinoma, and the risk factor if a mother has a carcinoma of the breast, for the daughter, is about 5, and for disturbances of the cycle, such as anovulation, it is 2. This is a great difference*t. Professor R. A. Sellwood: It is even greater when a sister has cancer of the breast. Professor C. Lauritzen (Ulm): There is also growing evidence that mammary carcinoma may also be virus-induced.:!: I refer to the study of McMahon and co-workers*, which has not been mentioned. The risk for mammary carcinoma increases fourfold if the first pregnancy is later than 25 years. The prolactin levels are much higher at night than by day, so prolactin levels * MacMahon and Cole (1969). Callcer, 24, 1146 t Zippin and Petrallis (1971). Callcer, 28, 1381 :j: Moore et al. (1971). Nature (Lolldoll), 229. 61 I
354 THE MANAGEMENT OF THE MENOPAUSE should be studied at night*. If Professor Sellwood has some plasma left, he should use it to determine androgens too. Mr R. B. K. Rickford (Chairman): Could an American surgeon give his views on the length of time that post-menopausal women should take estrogens? To the grave? To 80, to 70, or how long? Dr C. B. Hammond (Gynaecologist, Duke University): It is nice to be asked an easy question! I plan to touch on this tomorrow in my paper and I can only give my own personal opinion. I think that there is a group of patients in whom estrogen therapy, or hormonal therapy, is beneficial. It should be carried Out for the treatment of the symptoms that they have. I am not a' member of the school which advocates estrogen for all women for all time, and I should like to leave it at that until I can lfesent the data. Dr P. Bye (Schering Chemicals, Sussex): On the question of mammary carcinoma, it may be germane to quote from, a publication that has just come out-a WHO monograph on carcinogenic risks of various types of drugs. The latest volume deals with the sex hormones. They reviewed all the data on long-term studies, those that Professor Dewhurst mentioned, and others. They made the same methodological criticisms that he made, but they came to the conclusion that despite the methodological shortcomings, they could go so far as to say that whereas it had not been proved that the risk of mammary carcinoma was reduced by the use of estrogens, at least it could be said that there was no indication of any increased risk. Dr N. G. Mussalli (Gynaecologist, Welwyn Garden City): Professor Sellwood has described clinical investigations and hormone assays in patients with breast cancer, with cystic disease of the breast and in normal controls. Extensive work has been done, especially by veterinary colleagues, on the physiology of the breast in relation to lactation. This involved tissue cultures using hormones. Could the responsiveness of the target organ be helpful in investigating this disease? Professor R. A. Sellwood: The questioner I believe suggests that if we set up cultures of mammary tumours against a battery of either hormonal or cytotoxic agents, rather in the same way that we set up cultures of a bacterium against antibiotics, we might find a sensitivity, so to speak. We might be able to pick out the tumour that will respond to estrogen, and the one that will respond to androgen. Quite a lot of tissue culture work has been done' and I have done some myself. Overall I would say that the results are very disappointing. This is because it is so very difficult to culture cancer of the breast. Almost every other cancer can be cultured by fairly straightforward methods but cancer of the breast is so often nearly all fibrous tissue and very few tumour cells. All of us who have worked in the field have had the most terrible difficulty in getting reliable standard cultures of the type that would be needed to do this. One or two peopl~ claim to have done so, and there have been suggestions that it might be possible, but I cannot go further than that. Dr Muriel G. Yates (General Practitioner, Liverpool): Could Premarin be given to a patient with severe menopausal symptoms who has had a radical mastectomy? Professor R. A. Sellwood: I know of no reason why not except for a patient with * Nokin et al. (1972). Br. Med.]., 3. 561
SECTION H: RISKS OF ESTROGEN THERAPY 355 advanced cancer of the breast who was being treated by bilateral oophorectomy. That would imply that she was a pre-menopausal woman, and most unlikely to be undergoing menopausal symptoms. If the symptoms were produced by doing the oophorectomy, I would not then give the hormone; having done the operation to remove estrogens, and I would not put them back. Miss G. S. Agerbak (Copenhagen): On the basis of the data we have heard today, does the panel consider it possibly advantageous to advocate a sequential therapy, that is estrogen plus progestogen at the end of the cycle for post-menopausal women? Professor C. J. Dewhurst: The problem would be one of patient acceptability. I should have thought that many patients would not want to go on menstruating, which by and large they would do for a period of time. However, from the point of view of cancer risk, combined estrogen/progestogen therapy would be preferable to estrogens alone. I believe that it would be preferable to use a progestogen occasionally, two or three times a year: to strip the endometrium effectively, so that probably the hyperplasia about which I am concerned would not then occur. Mr S. Campbell: Professor Dewhurst is absolutely right. Post-menopausal women do not like to have regular periods, but on the other hand, if they are given a choice between suffering menopausal symptoms or having regular withdrawal bleeding, they opt for regular withdrawal bleeding any day; they are very willing to accept this small inconvenience. Mr R. B. K. Rickford: To sum up. Estrogens are possibly dangerous, depending perhaps on dosage, and also perhaps on the length of time that they are given to post-menopausal women. There may be a lot to be said for giving a progestogen with them.