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
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
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
the remainder of their postmenopausal lives without the assistance of
apppropriate hormonal replacement therapy. If they do not use HRT, women
likely to suffer hot flushes, sweats, insomnia and urogenital atrophy, as
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
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
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
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.
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
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
the medical profession not to cilarify these points to women before a
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
then a great advantage will have been achieved. From biological, clinical
epidemiological data it is likely that such a regimen is currently
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
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
impact of progestogens on breast cell activity suggests that the sequential
intermittent regimens of therapy administered to women, may not be the
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.
which are necessary for hormones and growth factors to mediate their
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
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
breast cell response by:
a.inducing the production of the enzymes estradiol dehydrogenase and estrone
sulfurtransferase which rapidly and successively oxidise estradiol to
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
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
late Gl phase are driven into rapid mitosis over the following few hours,
this phase is followed by cell cycle arrest and growth inhibition as cells
the early Gl phase are inhibited following reduced production of c-myc and
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
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
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
Histological material taken from normal breasts has been used to determine
rate of breast cell mitosis under the influence of estrogen and
during both normal menstrual cycles and erogenous hormonal activity. 7he
results from biopsy material have shown conflicting data leading to
assumptions from various. authors. Some biopsy studies have shown an
in mitosis during the folliicular (estrogen) phase of the menstrual
cycle,[16,351 while others have shown mitosis to be most prevalent during
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
Spiceq38) have interpreted the increase in mitosis during the second half of
menstrual cycle as being due to the effect of progesterone and consequently
have de\eloped their "Estrogen Augmented by Progestogen Hypothesis" to
that progestogens increase the risk of developing breast cancer. However,
is just as likely that the increased rate ofmitosis in the second half of
cycle, and on which their hypothesis depends, is consequent on the gradually
increasing activity of estrogen being produced in the follicular phase of
menstrual cycle as well as being the result of the transient surge in
activity which occurs at the onset of the luteal phase.[121 Musgrove
performed elegant in-vitro studies which demonstrate that breast cells in
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
activity by progestogen. However, she has shown this to be a transient
only. The continued application of progestogen suppresses cyclins so that
further breast cell division is halted in the early Gl phase. Thus
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, while fve days of exposure to
is necessary to inhibit mitosis. 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
level of estrogen during the second week of the fbilicular phase, with an
added surge of mitosis following the rise in progesterone.
B. Wren Study
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