Hormonal Replacement &

Breast Cancer

Eur Menopause J 2(4):13-19, 1995 by B.G. Wren


The relationship between female sex hormones and the development of breast cancer continues to be clouded by data from epidemiological studies which impinge on clinical research and which cause misgivngs among women and some members of the medical profession regarding the use of hormone replacement therapy.

Although there are a large number of in-vitro studies suggesting that appropriate use of biological substances may substantially alter the development, growth and eventual outcome of breast cancer, there have been very few well conducted clinical trials to support these biologicalstudies. As a result of a recent publication in the New England Journal of Medicine of a paper by Colditz et al[l] in which there was a reported 45% increased risk of breast cancer among women who had been taking unopposed estrogen, or estrogen with sequential/intermiftent progestogen, for 10 years or more, a number of doctors have advised against HRT.

Consequently women are once again placed in the invidious situation of living the remainder of their postmenopausal lives without the assistance of apppropriate hormonal replacement therapy. If they do not use HRT, women are likely to suffer hot flushes, sweats, insomnia and urogenital atrophy, as well as an increased risk of heart attack, stroke, osteoporotic fracture and dementia. Yet if they do decide to use HRT, they are now being threatened with an increased risk of both uterne and breast cancer.

As a consequence of this dilemma facing women, it is now pertinent to review the biological data to ascertain exactly what are the risks of developing cancer, associated with the use of hormonal therapy.

Size of the Risk

Because of media reports of 30-50% increased risk of developing breast cancer, women gain the impression that 30-50 women in every 1 00 will develop breast cancer if they take hormonal therapy for 10-20 years. However, the risk can best be expressed as follows. If 100 women aged 50 years were followed for the next 20 years, then by the age of 70, 5 would have developed breast cancer. If those same women lived till the age of 80 years then a further 3 (or 8 in total) would have breast cancer. If given estrogen with or without short term sequential progestogen (for 7-14 day each month), then, based on epidemiological studies,[1-31 some 2 extra women would have developed breast cancer after 20 years with another 2 (or 4 in total) by the age of 80 years. This increased risk is not huge but nevertheless reflects an increase which some women find to be unacceptable.

In discussing the pros and cons of hormonal therapy, the increased risk of breast cancer must be balanced against two other issues:

a.What are the gains from using estrogen? b.Can the risks be modified so that the 30-50% increased rate of breast cancer is reduced to acceptable levels?

Benefits of Hormonal Therapy

It is now estimated that using hormonal therapy for 20 years results in a 50% reduction in the risk of dying from myocardial infarction or stroke[4-6] and there is a similar reduction in the risk of osteoporotic fractures.[7] Although different countries with different racial environmental and nutritional characteristics have different chronological end points for cardiovascular and osteoporotic disease, the reduction in risk of death from the use of hormonal therapy appears to be relatively uniform. Using Australian data as an example, we would expect a major advantage for women who continue to take hormonal therapy.

Clearly the savings in life clearly outweigh any increased risk from death regarding the use of hormonal therapy. It could be regarded as negligent for the medical profession not to cilarify these points to women before a decision is made regarding hormonal therapy.

Can the Risk of Breast Cancer be Modified?

If a regimen of therapy could be developed which not only maintains the quality of life for women, but reduces the risk of premature death from CVS diseases, without increasing the risk of developing uterine or breast cancer, then a great advantage will have been achieved. From biological, clinical and epidemiological data it is likely that such a regimen is currently available.

From some years it has been known that 10-14 days of progestogen was protective against uterine cancer when hormonal therapy was administered to post menopausal women.[8,9] However, when epidemiological data were analysed for the incidence of breast cancer it was found that the sequential (10-14 days each month) use of progestogen did not protect against the increased risk associated with estrogen.[1-3] These data and their implications caused considerable concern to patients and their medical attendants alike, so that many women have ceased using hormonal therapy. However, a closer look at the impact of progestogens on breast cell activity suggests that the sequential or intermittent regimens of therapy administered to women, may not be the optimum to prevent oncological change in breast cells.

Progestogens and Breast Cell Response

It is now realised that breast cancer cells are similar in their biological activity to the normal parent cells from which they derive with the two main differences being their inability to perform their normal specialised function, and loss of the normal reproductive regulation.

If the biological processes which control cellular reproduction and specialised function are identified it will then be possible to develop therapy regimens which not only control cancer but actually reverse the abnormal oncological actiivty. In identifying these biological processes three areas have been nominated as being critical to control of cancer.

a.Growth factors and hormones which control cell cycle mechanisms. b.Receptors which are necessary for hormones and growth factors to mediate their activity. c.Proto-oneogenes, cyclins and other regulatory substances which provide signalling systems for cell divsion and differentiation.

Already a number of the signalling processes have been identified[9-12] and there are now available a number of biological agents which will modify some of these malignant cellular actions. Progestogens are just one of the hormones which have the potential to modify the cellular response of normal breast cells as well as some breast cancers. However it is important to understand that progestogens may exert different responses depending on the dosage being delivered to the cell and the length of time the progestogen is in contact with the receptor and the cell signalling system.

Short-time exposure to Progestogen results in an increase in breast cell mitosis[13,14] while prolonged application of progestogens results in reduced cellular actiaty and mitosis. The various mechanisms involved in this biphasic response are summarised below.

Progestogens have the potential to reduce breast cell mitosis and activity by a number of mechanisms and it is likely that all of these play some part in breast cell response by:

a.inducing the production of the enzymes estradiol dehydrogenase and estrone sulfurtransferase which rapidly and successively oxidise estradiol to estrone and then conjugate estrone to the relatively inactive estrone sulfate;[9,131 b.inducing maturation of alveolar breast cells[9,14,15) which are then unlikely to undergo further cell division. Progestogens have been shown to also decrease mitosis of breast cells in-\A\to;[16,17] c.reducing the ability of the breast cell to produce estradiol receptor[17-211 thus decreasing the possibility of estrogen induced cell mitosis; d. reducing the production of the proto-oncogenes c-myc and c-fos, factors which are known to accelerate malignant breast cell mitosis.[121 Progestogens are known to transiently increase the rate of mitosis of cultured malignant breast cells in a manner thought to be initiated by temporarily increasing the production of the proteins c-myc and c-fos in the late Gl phase of cell division. In the Musgrove model of breast cancer cell response to progestogens,12 cells in the late Gl phase are driven into rapid mitosis over the following few hours, but this phase is followed by cell cycle arrest and growth inhibition as cells in the early Gl phase are inhibited following reduced production of c-myc and c- fos; e.reducing the production of Cathepsin D, a potent growth factor in breast cancer cells;[22,23] and f increasing apoptosis and death of breast cells.[24,251

It is important to realise that progestogens also reduce the production of progesterone receptor,[261 so that the unopposed administration of a progestogen is likely to eventually lead to a reduced response of the breast cells to the progestogen. The use of an intermittent or continuous estrogenic substance (tamoxifen, or an estrogen)[27,281 is therefore essential to maintain the production of progesterone receptor.

Over the last 20 years, the in-vitro activity of normal and malignant breast cells have been studied in great detail till now we can begin to understand some of the mechanisms which influence breast cell mitosis.[9,12,22,26,29-341 Histological material taken from normal breasts has been used to determine the rate of breast cell mitosis under the influence of estrogen and progesterone, during both normal menstrual cycles and erogenous hormonal activity. 7he results from biopsy material have shown conflicting data leading to differing assumptions from various. authors. Some biopsy studies have shown an increase in mitosis during the folliicular (estrogen) phase of the menstrual cycle,[16,351 while others have shown mitosis to be most prevalent during the luteal (progesterone) phase.[24,36]

What is difficult to interpret is the temporal relationship between the increased rate of mitosis and the preceding hormonal influence. Pike[37] and Spiceq38) have interpreted the increase in mitosis during the second half of a menstrual cycle as being due to the effect of progesterone and consequently have de\eloped their "Estrogen Augmented by Progestogen Hypothesis" to suggest that progestogens increase the risk of developing breast cancer. However, it is just as likely that the increased rate ofmitosis in the second half of the cycle, and on which their hypothesis depends, is consequent on the gradually increasing activity of estrogen being produced in the follicular phase of the menstrual cycle as well as being the result of the transient surge in mitotic activity which occurs at the onset of the luteal phase.[121 Musgrove[12] has performed elegant in-vitro studies which demonstrate that breast cells in the late Gl (biosynthesis of proteins) phase of cell cycle actiaty are initially driven into the S (synthesis of DNA) phase and then the G2 phase of cell cycle activity by progestogen. However, she has shown this to be a transient effect only. The continued application of progestogen suppresses cyclins so that further breast cell division is halted in the early Gl phase. Thus continuous progestogen use should lead to a diminution of cell cycle activity with a consequent reduced rate of mitosis.

It is now established that endometdum requires the unopposed influence of fbur days of estrogen to begin rapid mitosis and cell proliferation,[39] while fve days of exposure to progestogen is necessary to inhibit mitosis.[39] It is likely that breast cells are much slower to respond to estrogen than are endometrial cells and therefore the increase in mitosis in the early futeal phase might merely reflect the rising level of estrogen during the second week of the fbilicular phase, with an added surge of mitosis following the rise in progesterone.

Part II

B. Wren Study including references

Hormonal Therapy & Chemoprevention

Journal-The Breast, February 2001

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