Review

Management of menopausal symptoms in patients with

breast cancer: an evidence-based approach
Martha Hickey, Christobel M Saunders, Bronwyn G A Stuckey

Increasing numbers of women have menopausal symptoms after treatment for breast cancer. These symptoms
can result directly from cancer treatments (such as oophorectomy, ovarian suppression, chemotherapy-induced
ovarian failure, and antioestrogens), as a spontaneous event, or after discontinuation of hormone-replacement
therapy. The onset of menopausal symptoms after treatment for breast cancer can have a long-lasting effect on
quality of life, body image, sexual function, and self esteem. Hormone-replacement therapy that contains
oestrogen is the most effective treatment for menopausal symptoms in healthy women. However, evidence from
one randomised controlled trial suggests that use of hormone replacement therapy after breast cancer raises the
risk of recurrence and of new primary breast cancer. As the incidence of breast cancer increases and survival
continues to improve, the number of women with menopausal symptoms will probably rise. Safe and effective
non-hormonal treatments for severe menopausal symptoms after breast cancer are urgently needed. Few studies
have addressed the management of menopausal symptoms after breast cancer, and the quality of studies is
generally poor. Progestagens, and selective inhibitors of serotonin and norepinephrine reuptake seem to offer
reasonable symptom palliation, but the long-term effectiveness and safety of these preparations is not known. We
propose that the management of menopausal symptoms in patients with a history of cancer requires a patientcentred, but multidisciplinary, approach.

Breast cancer is the most common cause of disease and

death in middle-aged women, and in more-developed
countries it affects one in 11 women before the age of
75 years. About two-thirds of postmenopausal women
who have had breast cancer report hot ashes, which are
reported to be severe in over half of these women.1,2 In
Western Australia, about 40% of perimenopausal
and postmenopausal women are using hormonereplacement therapy when breast cancer is diagnosed
and almost all immediately stop. Cessation of hormonereplacement therapy commonly produces a recurrence
of menopausal symptoms (gure 1). Most breast cancers
are hormone-receptor positive and are treated with
endocrine agents, most of which lead to hot ashes. Up
to 20% of patients with breast cancer consider stopping
or actually cease endocrine treatment because of
menopausal symptoms,3 despite the proven value of this
therapy in reducing recurrence of breast cancer.
In premenopausal women, chemotherapy combined
with endocrine treatment causes premature menopause
in over 80% of patients during the rst year
after diagnosis.4 Of those managed with bilateral
oophorectomy, more than 90% will have hot ashes and
other menopausal symptoms, which can be more severe
and long-lasting than those that arise during natural
menopause.5 Premature menopause and the recurrence
of menopausal symptoms in patients with breast cancer
adversely affect quality of life, body image, sexual
function, and self esteem.6 Hence, menopausal
symptoms are one of the most common and
troublesome side-effects of breast-cancer treatment in
women of all ages. The occurrence of these side-effects
is particularly poignant as survival of breast cancer
continues to improve. However, few studies have
http://oncology.thelancet.com Vol 6 September 2005

addressed the natural history, severity, or nature of

menopausal symptoms in this population.
Many clinicians are uncertain about how to treat
menopausal symptoms after breast cancer. In this review,
we assess evidence for the safety and effectiveness of
existing treatments, and discuss those that have been
tested in clinical trials after breast-cancer diagnosis.

School of Womens and Infants

Health, King Edward Memorial
Hospital (M Hickey MD), School
of Surgery and Pathology
(Prof C M Saunders MD), and
Keogh Institute for Medical
Research, Department of
Endocrinology and Diabetes,
Sir Charles Gairdner Hospital,
and School of Medicine and
Pharmacology
(B G A Stuckey MD), University
of Western Australia, Australia,
Perth, Australia
Correspondence to:
Dr M Hickey, School of Womens
and Infants Health, King Edward
Memorial Hospital, 374 Bagot
Road, Perth, WA, 6008,
Australia
mhickey@obsgyn.uwa.edu.au

Menopausal symptoms
These symptoms can be classied as: vasomotor
symptoms (eg, hot ashes and night sweats); central
symptoms (eg, insomnia and changes in memory,
concentration, and mood); and urogenital symptoms
(eg, vaginal dryness, dyspareunia, urinary-tract
infections, and urinary urgency). Of these, vasomotor
symptoms, and hot ashes in particular, most

Zephyr/Science Photo Library

Introduction

Lancet Oncol 2005; 6: 68795

Figure 1: Osteoporosis is a common symptom of menopause

Coloured bone-densitometry scan (left) and radiograph (right) of the spine.

687

Review

commonly lead to requests for treatment. Hot ashes

are dened subjectively as a sudden feeling of heat in the
face, neck, or chest; they can arise with differing severity
or frequency during the day or night. Hot ashes can be
accompanied by sweating, ushing, palpitations,
anxiety, or irritability. A ash lasts for about 4 min but
they range from a few seconds to 10 min. Whether
menopausal symptoms after breast cancer, or those
experienced during treatment with antioestrogens, differ
from spontaneous menopausal symptoms is not known,
and treatments for natural menopause cannot be
assumed to be equally effective for symptoms after
treatment for breast cancer.
The pathophysiology of ashes is poorly understood,
but the symptom could be linked to instability of the
hypothalamic thermoregulatory centre induced by
oestrogen withdrawal. Low circulating concentrations of
oestrogen are not directly related to hot ashes, but
oestrogen could control thermoregulation via serotonin
receptors. Low oestrogen concentrations are also linked
to: dryness of the skin, hair, and vagina; reduced libido;
weight gain; fatigue; and urinary frequency.7 Sleep
disturbance is common in natural menopause and can
occur independently of hot ashes or night sweats.
Long-term sequelae of menopause after breast cancer
can include loss of bone density (gure 1) with an
increasing risk of osteoporotic fracture.8 Few studies
have addressed the important clinical problems of
efcacy and safety of treatments for menopausal
symptoms after breast cancer. Studies are largely limited
to a reduction in the frequency or severity of hot ashes
as the primary outcome, and there is even less
information about the rate or management of other
menopausal symptoms, quality of life, or sexual function
in patients with breast cancer.

Sex hormones and breast cancer

The Endogenous Hormones in Breast Cancer
Collaborative Group9 reanalysed nine prospective
studies showing a positive relation between premenopausal risk of breast cancer and raised serum
concentrations of oestradiol, oestrone, oestrone
sulphate, androstenedione, testosterone, and dehydroepiandrosterone. Several studies10,11 in vivo have shown
that maximum proliferation of breast epithelial tissue
occurs in the presence of progestagen and oestrogen.
For the two-thirds of women with hormone-receptorpositive breast cancer, a mainstay of treatment is to
block the effects of oestrogen, or to reduce its
production. The Multiple Outcomes of Raloxifene Trial12
showed that the greatest reduction in oestrogenreceptor-positive breast cancer with raloxifene
(a selective oestrogen-receptor modulator) occurred in
women with the highest circulating concentrations of
serum oestrodiol. Moreover, data from randomised
studies12 show that the effectiveness of antioestrogens,
aromatase inhibitors, and raloxifene in the chemo688

prevention and treatment of breast cancer are

restricted to women with oestrogen-receptor-positive
breast cancer.
In postmenopausal women, use of hormonereplacement therapy can increase the risk of breast
cancer. Level-one evidence from the Womens Health
Initiative study13 reported a signicant (26%) increase in
the relative risk of invasive breast cancer in women
randomly assigned oral conjugated horse oestrogen plus
medroxyprogesterone acetate versus placebo, calculated
as 38 versus 30 per 10 000 women per year, consistent
with ndings from other randomised trials. However,
exposure to hormone-replacement therapy is not only
associated with hormone-sensitive breast cancer,14 and
oestrogen alone was not associated with an increased
risk of breast cancer in the Womens Health Initiative,15
showing that the mechanisms underlying this
association remain poorly understood.
In clinical practice, many women are reluctant to take
hormone-replacement therapy after breast cancer, and
some believe that use of hormone-replacement therapy
has caused their disease. They therefore look to other
remedies for relief of menopausal symptoms. The safety
and efcacy of such treatments in this setting must be
established. In this paper we review such treatments and
report recommendations and our response to this
growing clinical problem.

Treatment for menopausal symptoms after

breast cancer
Progestagens
Although progesterone has long been recognised as a
mitogen of healthy breast epithelial tissue, high doses of
progestagens have been used to treat advanced breast
cancer. Alone, progesterone stimulates proliferation and
terminal differentiation of epithelial cells.16 The effects of
exogenous progestagens with or without oestrogens are
likely to be complex, and could depend on the type and
dose of progestagen and on the degree of breast
differentiation.17
Progestagens are the best studied agents for the
treatment of menopausal symptoms after a diagnosis of
breast cancer and seem moderately effective. In an open
study, megestrol acetate reduced vasomotor symptoms
by between 80% and 98% in doses of 2080 a per day.18
A prospective randomised trial19 of patients with breast
cancer found an 85% reduction in hot ashes with a
dose of 20 mg megestrol acetate twice daily compared
with a 21% reduction with placebo. Importantly,
most women in this trial were taking tamoxifen.
Medroxyprogesterone acetate also lessens hot ashes.20
In an uncontrolled pilot study,21 15 patients with breast
cancer who had hot ashes were treated 500 mg depot
medroxyprogesterone acetate given as three intramuscular injections once every 2 weeks; there was a 90%
reduction in hot ashes at 12 weeks of treatment, which
continued for 1 month after treatment was stopped.
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Review

The safety of progestagens for menopausal symptoms

after breast cancer has not been established.
Progestagens could be mitogenic in the breast,17 and in
the Womens Health Initiative the addition of
progestagen to oestrogen was associated with an
increased risk of breast cancer in healthy women.
Moreover, trials of oestrogen alone and combined
hormone-replacement therapy after breast cancer, have
shown that the combination with progestagen carries an
increased risk of cancer recurrence.22 Dose could be
important, and high-dose progestagen might be more
likely than a lower dose to arrest the cell cycle.
Interactions between progestagens and antioestrogens
have not been studied after breast cancer.

the safety of tibolone in patients with breast cancer (Livial

Intervention following Breast cancer: Efcacy, Recurrence
And Tolerability Endpoints trial) are under way.

Recommendations for practice

Tibolone has been shown to be effective for menopausal
symptoms outside the setting of breast cancer and it
could be effective after breast cancer. Although
preclinical data are reassuring about breast safety, the
results of randomised trials are not yet available and
the drug cannot yet be denitely said to be safe in this
setting. Patients should be made aware of such safety
issues when discussing treatment options.

Non-hormonal treatments
Recommendations for practice
Progestagens are probably the most widely tested of all
hormonal treatments for menopausal symptoms after
breast cancer and seem to be effective in reducing hot
ashes. They have not been investigated for other
menopausal symptoms but are unlikely to be of
substantial clinical benet.
The safety of progestagens after treatment for breast
cancer remains uncertain and large randomised trials
are needed. Meanwhile, progestagens cannot be
assumed to be safer than oestrogen and progestagen in
combination after breast cancer, and patients should be
counselled accordingly.

Tibolone
Tibolone is a synthetic compound with weak oestrogenic,
progestagenic, and androgenic actions. The effectiveness
of tibolone in treating hot ashes is established for
healthy women but not in women who have had breast
cancer. In healthy women, 25 mg tibolone a day reduced
hot ashes by 63% compared with 30% for placebo23 and
was also effective in the treatment of vaginal dryness.
Tibolone is associated with improvements in sexual
function, which could be greater than those noted for
standard hormone-replacement therapy.24 It improves
bone density but has an unfavourable effect on circulating
lipoproteins by lowering concentrations of HDL
cholesterol.25 The sulphatase pathway transforms
oestrogen sulphates into bioactive unconjugated
oestradiol. Tibolone is a strong sulphatase inhibitor and
can block the conversion of oestrone to oestradiol by the
inhibition of the 17-hydroxysteroid dehydrogenase
type I.26 Tibolone also stimulates apoptosis in breastcancer cell lines.27,28 The occurrence of breast tenderness is
low,29 and mammographic density does not increase with
tibolone treatment, by contrast with oral combined
hormone-replacement therapy.29 Whether long-term
tibolone use changes the incidence of breast cancer is not
known. A large observational study30 suggested an
association between tibolone use and breast cancer, which
was less than that for combined oestrogen and
progestagen. Prospective randomised controlled trials on
http://oncology.thelancet.com Vol 6 September 2005

Effective treatment of menopausal symptoms,

particularly hot ashes, by use of non-hormonal
methods has been a long-standing clinical goal in
patients with breast cancer and is increasingly requested
by other menopausal women. Poor understanding of the
basic physiology of hot ashes has prevented the
development of effective treatments, but a small number
of non-hormonal preparations have been shown to be
better than placebo in randomised trials. Any treatment
claimed to reduce hot ashes must be assessed in
masked trials against placebo or a validated treatment
because placebo effects are strong, with an average
improvement of 40% in vasomotor symptoms that can
persist for several weeks, from placebo alone.31 Few nonhormonal agents have been tested in clinical trials for
hot ashes in patients with breast cancer, and the quality
of studies has generally been poor. The minimum
period recommended by US Food and Drug
Administration for the assessment of treatments for hot
ashes is 12 weeks, but most studies of non-hormonal
treatments have had only 46 weeks follow-up. Most
studies included a mixture of patients with breast cancer
(some of whom were taking antioestrogens) and women
with spontaneous menopausal symptoms.

Neuroendocrine agents
Recognition of a neuroendocrine role in hot ashes has
led to interventions that interfere with adrenergic and
neurosynaptic pathways. Antidopaminergic compounds
(such as methyldopa and veralipride) and -adrenergicreceptor agonists (such as clonidine) have not been
tested in clinical trials in patients with breast cancer. In
healthy women, neuroendocrine agents are better than
placebo for treatment of hot ashes, but with frequent
and troublesome side-effects.32 The -aminobutyric acid
(GABA) analogue gabapentin (900 mg per day) is
effective for at least 12 weeks, reducing hot ashes by
54% compared with 29% for placebo.33 However,
gabapentin was not tolerated well, with half of users
reporting at least one adverse event, and has not
been tested in clinical trials in women who have had
breast cancer.
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Review

690

Selective inhibitors of serotonin and norepinephrine reuptake

Recommendations for practice

Selective serotonin-reuptake inhibitors (SSRI) were

initially studied for hot ashes on the basis of their
presumed mode of action and anecdotal observations of
improvements in premenstrual symptoms and hot
ashes. Adverse effects with these drugs are moderate,
with gastrointestinal or CNS symptoms that were
regarded as tolerable, affecting 1020% of patients in
studies of their usefulness for menopausal symptoms.34
A randomised trial34 and a pilot study35 of short followup have shown superiority of venlafaxine over placebo in
the management of hot ashes in women with a history
of breast cancer, and concluded that 75 mg slow-release
was the best dose, which reduced hot ashes by a
median of 61% compared with 27% with placebo.
However, both trials had only 6 weeks of follow-up, and
a randomised controlled trial36 of venlafaxine (375 mg
followed by 75 mg sustained release) given for 12 weeks
did not show an objective improvement in hot ashes in
the treatment group and noted a signicant increase in
anticholinergic effects in venlafaxine users. This nding
brings into question any clinically important benet in
the use of SSRIs or selective seratonin norepinephrinereuptake inhibitors (SNRI) for menopausal hot ashes.
Sexual dysfunction can occur after treatment with SSRI
or SNRI. In patients with breast cancer, libido rose in a
trial of venlafaxine and uoxetine for hot ashes.37
Paroxetine is a potent SSRI with much the same sideeffects as venlafaxine. After 6 weeks, 25 mg paroxetine a
day reduced ashes by 65% compared with a 38%
reduction with placebo.38 In a small uncontrolled study39
of patients with breast cancer who had hot ashes,
20 mg paroxetine a day improved sleep and mood. The
SSRI uoxetine reduced ashes by 50% compared with
36% for placebo.37 A small pilot study40 has suggested
that 1020 mg citalopram improves hot ashes and
general mood in healthy women, but a placebocontrolled randomised comparison41 of citalopram and
uoxetine in women with no previous history of breast
cancer (10 mg increasing to 30 mg of each) followed up
for 9 months did not show any differences between
groups in number and severity of hot ashes,
depression, quality of life, or measurements of sexual
function. The only signicant improvement was in
insomnia in the citalopram group.
The relation between SSRI, SNRI, and breast cancer
has been controversial, but a systematic review42
concluded that there is no evidence that these
preparations increase the risk of breast cancer. However,
there is concern that these drugs could interfere with
endocrine treatment for breast cancer. In patients
with the common cytochrome P450 CYP2D6 genotype,
coadministration of paroxetine decreases plasma
concentrations of the active metabolite of tamoxifen.43,44
The clinical implications of this effect are unknown, but
SSRI and SNRI might lower the effectiveness of
tamoxifen.

75 mg venlafaxine sustained release seems to be

effective initially in the treatment of hot ashes after
breast cancer, but seems not to continue for a clinically
worthwhile duration. Other SSRIs such as uoxetine
(1030 mg a day), paroxetine (25 mg), and citalopram
(1020 mg) might be effective, but there are no data to
show that this effect persists beyond 6 weeks.
Preliminary evidence suggests that citalopram improves
sleep. Patients should be advised that use of SSRI and
SNRI are probably associated with anticholinergic sideeffects and that it could potentially interfere with the
metabolism of antioestrogens.

Complementary treatments
Phyto-oestrogens
Phyto-oestrogens are polyphenol compounds of plant
origin with structural similarity to 17-oestradiol and
weak oestrogenic activity. There is preliminary evidence
that ingestion of phyto-oestrogens could have a role in
prevention of breast cancer,45 but no randomised
controlled trials have addressed the efcacy or safety of
phyto-oestrogens after a diagnosis of breast cancer, and
their efcacy in healthy women has not been
established. A few randomised controlled trials have
shown signicant improvements in hot ashes by use
of phyto-oestrogen products, including soy and
isoavones. However, a large randomised controlled
trial46 of several doses of red clover isoavones in
menopausal women in the USA did not show any
reduction in symptoms compared with placebo, and a
systematic review47 found no signicant benet of
phyto-oestrogens compared with placebo.

Black cohosh
Native Americans originally used black cohosh as a
remedy for menstrual cramps and menopausal
symptoms.48 The preparation does not seem to
stimulate the breast. Most trials for menopausal
symptoms have been done with the commercial
product remifemin. A randomised controlled trial49 of
black cohosh versus placebo for hot ashes in patients
with breast cancer who were being treated with
tamoxifen did not show any superiority of black cohosh
over placebo. However, an open label study50 in
tamoxifen users taking 40 mg black cohosh a day
in divided doses reported a signicant reduction in hot
ashes compared with no intervention. A small pilot
study51 of remifemin for hot ashes in a mixed group of
patients (some with breast cancer, some without
cancer, and only a few with cancer were taking
tamoxifen) and healthy women found a reduction in
mean daily frequency of hot ashes of 50% (95% CI
3465). A review52 of the use of black cohosh for
menopausal symptoms in healthy women concluded
that despite promise, there were no convincing data to
show a benet greater than placebo.
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Review

Black cohosh is generally tolerated well, but sideeffects include gastrointestinal disturbances and rash.
Safety has been questioned after seven reports of hepatic
reactions to black cohosh and two cases of liver failure
necessitating transplantation.53

Vitamin E
Tim Maylon and Paul Biddle/Science Photo Library

In a placebo-controlled, randomised, crossover trial54 in

survivors of breast cancer, 800 IU vitamin E succinate a
day reduced hot ashes by a mean of one per day, which
was signicant, but not of clinical importance. Patients
did not prefer vitamin E to placebo.

Recommendations for practice

There is insufcient evidence about efcacy and safety to
support the use of phyto-oestrogens or black cohosh in
the treatment of menopausal symptoms after breast
cancer. For women who wish to use a natural treatment,
the marginal benets of 800 IU vitamin E a day should
be considered.

Figure 2: Acupuncture might help manage menopausal hot ashes

Recommendations for practice

Lifestyle and non-pharmacological treatments

There are very limited clinical data for nonpharmacological treatments, such as behavioural
interventions, exercise, and acupuncture (gure 2), in
the management of menopausal hot ashes, and no
published randomised controlled trials have been done
on these interventions after treatment for breast cancer.
However, studies in healthy women have been
encouraging. Acupuncture is better than placebo, but
less effective than oestrogen, for treatment of hot
ashes.55 If sterile needles are used, acupuncture is
unlikely to cause harm, although survivors of breast
cancer who have had axillary surgery should avoid
acupuncture to the affected arm.
A randomised controlled trial56 of paced respiration
training versus biofeedback control showed a signicant
benet for paced respiration. Another randomised
controlled trial57 of trained relaxation techniques for
20 min a day versus symptom charting (the control) also
showed a signicant benecial effect. The mechanisms
by which these treatments reduce hot ashes are not
known, but adequate training is central to efcacy, and
advice to patients with hot ashes to relax without
structured guidance is unlikely to be helpful. Regular
exercise might reduce hot ashes and improve quality of
life, although studies addressing this possibility have
reached conicting conclusions.
A randomised controlled trial58 has shown signicant
improvements in menopausal symptoms and sexual
function in survivors of breast cancer after a
comprehensive menopausal assessment delivered by
a nurse practitioner, which focused on symptom
assessment,
education,
counselling,
and,
as
appropriate, specic pharmacological and behavioural
interventions for relief of symptoms and improved
sexual function.
http://oncology.thelancet.com Vol 6 September 2005

Advice to women with menopausal symptoms to try to

achieve a normal body-mass index, to stop smoking, and
to maintain a regular exercise regimen is reasonable,
since these behavioural changes will benet long-term
health. For those who can identify triggers to their hot
ashes (eg, alcohol, hot drinks, or spicy food), avoidance
of the trigger is advisable. Anecdotally, most women do
not report clear triggers for their hot ashes. Training in
relaxation techniques could also be benecial.

Hormone-replacement therapy
Given concerns about increased risk of breast-cancer
recurrence with hormone-replacement therapy, are
there any circumstances in which the therapy can be
recommended after breast cancer? Hormone-replacement therapy that contains oestrogen is the most
effective treatment for menopausal symptoms in healthy
women.31 It improves menopausal symptoms, including
vaginal dryness, and reduces the risk of fracture in both
low-risk and high-risk populations. Unless hysterectomy
has been done, oestrogen should be given in
combination with progestagen to decrease the risk of
endometrial hyperplasia or cancer. Hormonereplacement therapy is likely to be effective in treatment
of menopausal symptoms after breast cancer, although
there are few published data on this possibility, and the
effectiveness of hormone-replacement therapy in
women taking antioestrogens is unknown.
Observational studies59 have been reassuring that
hormone-replacement therapy did not seem to raise the
risk of breast-cancer recurrence, with an inverse relation
between disease-free survival and risk of recurrence. This
nding lead to several randomised controlled trials of
hormone-replacement therapy after breast cancer.
In 2004, the combined estimate of the relative hazard of
hormone-replacement therapy use for two studies,
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Review

HABITS (HRT after breast cancer, is it safe?)60 and the

Stockholm study,22 was reported to be 18 (103310),
leading to termination of the HABITS trial59 and
discontinuation because of anticipated recruitment
difculties in the Stockholm study.22 However, there was a
signicant discrepancy between the results of the two
studies: one found a hazard ratio of 33 (1574)60 and
the other of 082 (03519).22 Although these studies had
several limitations (including non-blinded design,
variability in hormonal regimens used, and low breastcancer recurrence in the study population) the
discrepancy in outcome between them could be linked to
progestagen exposure. In the Stockholm study,22 73% of
women were taking either oestrogen alone or long-cycle
progestagen (about 14 days every 3 months). This feature
suggests that low breast-cancer recurrence in this trial was
linked with less exogenous-progestagen exposure. The
possibility that oestrogen alone could be a safe and
effective treatment for menopausal symptoms in
survivors of breast cancer merits further attention.

Recommendations for practice

The efcacy of hormone-replacement therapy in the
treatment of menopausal symptoms after breast cancer
has not formally been reported but is probably high.
Although HABITS trial60 was underpowered in terms of
numbers and duration of follow-up, combined hormonereplacement therapy cannot now be considered as rstline management for menopausal symptoms after a
diagnosis of breast cancer. There is still no certainty
about whether the type or regimen of hormonereplacement therapy, or the oestrogen-receptor or
progesterone-receptor status of the tumour have any
implications for the safety of hormone-replacement
therapy after breast cancer. Hormone-replacement
therapy could be justied for quality of life when other
interventions have failed and when the woman is clearly
informed of the relative risk; it could also be considered
for women with metastatic disease in whom the
attainment of quality of life over-rides all.

Urogenital symptoms
Other common symptoms that substantially affect
quality of life include vaginal dryness, urinary
symptoms, sexual dysfunction, and loss of libido.
Topical oestrogen alleviates vaginal dryness and atrophy,
and is generally regarded as safe for women who have
not undergone hysterectomy, or when systemic
hormone-replacement therapy is contraindicated, since
systemic absorption is negligible. The systemic
absorption of topical oestrogen depends on the dose and
thickness of the vaginal mucosa. For women with
vaginal dryness who wish to avoid hormones, vaginal
lubricants (eg, polycarbophil) can be helpful, but are not
as effective as topical oestrogens.61 Small retrospective
studies62 of topical oestrogens after breast cancer suggest
that this treatment is safe.
692

Treatment of bone loss

Abrupt withdrawal of circulating oestrogen, such as that
that arises after chemotherapy-induced ovarian failure,
oophorectomy, treatment with agonists of gonadotrophinreleasing hormone, or use of aromatase inhibitors, is
accompanied by rapid bone loss.63 Aromatase inhibitors
induce complete withdrawal of the protective effect of
oestrogen on bone.64 Chemotherapy alone has not
been associated with bone loss if it is not followed by
ovarian failure.65
Mean bone density is greater in women who develop
breast cancer than in healthy women, presumably
secondary to the effects of higher long-term circulating
oestrogen. Nevertheless, bone loss and increasing risk
of fracture is of concern in long-term survivors of
breast cancer.8
Tamoxifen preserves bone density and reduces
fractures in postmenopausal women by its paradoxical
oestrogen-like effect on bone. By contrast, in premenopausal women with endogenous circulating
oestrogen, tamoxifen is associated with bone loss,
presumably because of competitive binding of tamoxifen
to the oestrogen receptor.66 Raloxifene has much the
same dichotomous actions on bone and breast but is not
established as an adjuvant treatment for breast cancer.
Both tamoxifen and raloxifene could worsen hot ashes,
and newer selective oestrogen-receptor modulators are
being assessed in clinical trials.
Evidence suggests that aromatase inhibitors signicantly improve recurrence-free survival in women with
oestrogen-receptor-positive breast cancer compared
with tamoxifen.67 However, bone loss is substantial with
aromatase inhibitors and greatest for women within
4 years of menopause and younger than 65 years.68
Moreover, aromatase inhibitors are associated with
increased risk of fracture (59% in women treated with
anastrozole and 37% in those treated with tamoxifen,
p00001, at a median follow-up of 333 months).69
Treatment with analogues of gonadotropin-releasing
hormone is associated with greater bone loss than is
seen with chemotherapy-induced ovarian failure,
although some recovery occurs after its cessation.70
To keep avoidable bone loss to a minimum, patients
should be advised about calcium intake, avoidance of
vitamin-D deciency, weight-bearing exercise, and
avoidance of bone toxins such as smoking and excessive
alcohol consumption. Bisphosphonate treatment might
prevent bone loss after breast cancer, although no effect
on fracture rate has been established.71 The ZometaFemara Adjuvant Synergy Trial (Z-FAST) trial72 is
assessing the effect of zoledronic acid for the prevention
of bone loss in postmenopausal patients with breast
cancer treated with an aromatase inhibitor.
Bisphosphonates are not helpful in the prevention of
fractures in healthy postmenopausal women without
osteoporosis (femoral-neck T score more than 25 and
no prevalent fracture). In the Fracture Intervention
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Review

Trial,73 more peripheral fractures arose with alendronate

treatment than with placebo in women with femoralneck osteopenia.

Recommendations for practice

Bone loss, especially in young women, is an important
health issue after breast cancer. How this nding
translates into fracture rates in the community is not
known, and guidelines for practice are needed. Bone
densitometry (gure 1) is recommended for women
who: become menopausal before the age of 40 years; are
older than 65 years; have a family history of
osteoporosis; or who take aromatase inhibitors. The
present guidelines on bisphosphonates for fracture
prevention in healthy postmenopausal women are
based on the absolute risk of fracture and are calculated
from bone density and age.74 We advise a lower
threshold for intervention with bone-preserving
treatment in women taking adjuvant aromatase
inhibitors, which are known to be associated with rapid
bone loss.

Sexual function
Sexual and psychological problems are commonly of
complex origin and are likely to be modied by the
diagnosis of breast cancer, change in body image, and
other treatments. Differentiation between low desire
and poor arousal is difcult and articial. After
menopause, poor arousal, lack of vaginal lubrication,
dyspareunia, and difculty with orgasm are common
and have a negative effect on sexual desire. Direct
questioning will be necessary to elicit these symptoms in
many patients. Vaginal lubrication can easily be
improved with simple agents such as polycarbophil.
Vaginal oestradiol might improve vaginal blood ow and
sensation, and tibolone can improve sexual function in
postmenopausal women.23 Type-5 phosphodiesterase
inhibitors, such as sildenal, have not fullled their early
promise and although vaginal blood ow is increased,
this effect has not translated into a perception of
improved sexual response in placebo-controlled studies
in women.75 For some patients or couples, psychological
intervention or sex therapy might improve satisfaction
with sexual function.
Although the manifestations of the menopause are
protean, not all symptoms in women with breast cancer
are secondary to oestrogen withdrawal. Underlying
psychological morbidity needs to be recognised and
treated with appropriate referral to counselling or
psychiatric services.

Conclusion
Despite the frequency and importance of menopausal
symptoms in patients with breast cancer, there are
surprisingly few data on safe and effective treatments.
Oral progestagens have been studied in the greatest
detail and seem to be effective, but their safety is
http://oncology.thelancet.com Vol 6 September 2005

unknown and cannot be assumed to be greater than

combined oestrogen and progestogen. Evidence
suggesting that progestagen exposure modulates the
risk of breast-cancer recurrence warrants further
systematic investigation. Oestrogen alone might have a
different safety prole from oestrogen plus progestagen
after breast cancer. SSRI and SNRI agents showed initial
promise, but larger studies with longer follow-up have
not conrmed that these agents are effective for a
clinically worthwhile duration. The outcome of the
LIBERATE study, which is assessing the efcacy and
safety of tibolone after treatment for breast cancer, is
eagerly awaited. Topical oestradiol is effective for vaginal
symptoms with negligible systemic absorption.76 The
safety of topical oestrogen after breast cancer has not
been established. Behavioural interventions show
promise, but have not yet been tested in this population.
Hormone-replacement therapy should only be given
with full informed consent.
Safe and effective treatments for menopausal hot
ashes after breast cancer are urgently needed.
Furthermore, there seems to be a gap in clinical service
provision for women with these symptoms. We
propose that the current management of menopausal
symptoms in patients with breast cancer has been
uncoordinated at best and haphazard at worst. General
practitioners and gynaecologists are commonly
reluctant to give advice to women who have previously
had cancer and refer patients to oncologists, who have
little expertise in managing the menopause. There is a
pressing need for a coordinated and tailored service
run by specialists, which can offer full information
about the options for symptom control in this large
group of women. In Western Australia we have
responded to this need by developing a
multidisciplinary menopause clinic for patients with
breast cancer who have menopausal symptoms. This
patient-focused clinical service combines the clinical
expertise of menopause gynaecologists, a breast
surgeon, medical oncologists, an endocrinologist
specialising in bone disease and menopause, a general
practitioner, a nurse with expertise in breast cancer and
menopause, a breast-cancer psychologist, a dietitian,
and a research associate. The multidisciplinary forum
Search strategy and selection criteria
Data for this review were identied by searches of MEDLINE,
Current Contents, PubMed, and references from relevant
articles with the search terms menopause, breast cancer,
hot ushes/ashes, vaginal dryness, hormone
replacement therapy, bone density, osteoporosis, and
endocrine treatment of breast cancer. Abstracts and
reports from meetings were included only when they related
directly to previously published work. Only papers published
in English between 1970 and 2005 have been included.

693

Review

List of useful websites

Menopause Societies
http://www.menopause.org.au/
http://www.the-bms.org/
http://www.menopause.org/
General and lifestyle information
around menopause
http://www.jeanhailes.org.au/
http://www.menopausematters.
co.uk/
Key studies
http://www.whi.org/
http://www.roc.se/HABITS.htm

allows coordination of care and means patients are not

given conicting advice about management of their
symptoms. A summary of every patient and her clinical
priorities is presented at the monthly multidisciplinary
meeting, at which investigations and treatments can be
tailored to optimise symptom control and long-term
health. The clinic also provides a unique forum for
clinical research. We suggest that other health
providers working with the growing population of
survivors of breast cancer consider offering multidisciplinary care to serve the distinct and varied needs
of this group.
Conict of interest
M Hickey has been reimbursed for attending symposia by Wyeth,
Organon, and Novo Nordisk; has also received honoraria for speaking at
symposia sponsored by pharmaceutical companies for national and
international meetings from Novo Nordisk, Wyeth, Schering, and
Organon; and is undertaking research sponsored by Organon. Astra
Zeneca provided an unrestricted educational grant to establish the
Menopause Symptoms after Cancer (MSAC) clinic. C Saunders has no
conict of interest to declare. B Stuckey has been reimbursed for
attendance at conferences by Aventis, Eli Lilly, Pzer, and Wyeth, and is
currently undertaking research sponsored by Merck Sharp and Dohme,
Novartis, Organon, and Pzer.
Acknowledgments
AstraZeneca provided an educational grant to help establish the
Managing Menopausal Symptoms after Breast Cancer clinic at King
Edward Memorial Hospital. They have had no role in the running of the
clinic or in the preparation of this review.
References
1 Couzi RJ, Helzlsouer KJ, Fetting JH. Prevalence of menopausal
symptoms among women with a history of breast cancer and
attitudes towards estrogen replacement therapy. J Clin Oncol 1995;
13: 1273744.
2 Carpenter S AA, Cordova M. Hot ashes in postmenopausal
women treated for breast carcinoma: prevalence, severity,
correlates, management and relation to quality of life. Cancer 1998;
82: 168291.
3 Fellowes DFL, Saunders CM, Houghton J. Tolerability of hormone
therapies for breast cancer: how informative are documented
symptom proles in medical notes for well-tolerated treatments?
Breast Cancer Res Treat 2001; 66: 7381.
4 Goodwin PJ, Ennis M, Pritchard KI, et al. Risk of menopause
during the rst year after breast cancer diagnosis. J Clin Oncol
1999; 17: 236570.
5 Bachmann GA. Vasomotor ushes in menopausal women.
Am J Obstet Gynecol 1999; 180: S31216.
6 Schover L. Sexuality and body image in younger women with
breast cancer. J Natl Cancer Inst Monogr 1994; 16: 17782.
7
Bachmann G. Urogenital ageing: an old problem newly recognized.
Maturitas 1995; 22 (suppl): S15.
8
Chen Z, Maricic M, Bassford TL, et al. Increased fracture risk
among breast cancer survivors results from the womens health
initiative. J Bone Miner Res 2003; 18 (suppl 2): S22.
9
Collaborative Group on Hormonal Factors in Breast Cancer. Breast
cancer and hormonal contraceptives: collaborative reanalysis of
individual data on 53 297 women with breast cancer and 100 239
women without breast cancer from 54 epidemiological studies.
Lancet 1996; 347: 171327.
10 Kaaks R, Berrino F, Key T, et al. Serum sex steroids in
premenopausal women and breast cancer risk within the European
Prospective Investigation into Cancer and Nutrition (EPIC). J Natl
Cancer Inst 2005; 97: 75565.
11 Key TJ, Pike MC. The role of oestrogens and progestagens in the
epidemiology and prevention of breast cancer. Eur J Cancer Clin
Oncol 1988; 24: 2943.
12 Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene
on risk of breast cancer in postmenopausal women: results from
the MORE randomized trial. JAMA 1999; 281: 218997.

694

13

14
15

16

17
18

19
20

21
22

23

24

25
26
27

28

29

30
31

32
33

34

35

36

37
38

Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benets of
estrogen plus progestin in healthy postmenopausal women:
principal results from the Womens Health Initiative randomized
controlled trial. JAMA 2002; 288: 32133.
Marsden J. The menopause, hormone replacement therapy and
breast cancer. J Steroid Biochem Mol Biol 2002; 83: 12332.
Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated
equine estrogen in postmenopausal women with hysterectomy: the
Womens Health Initiative randomized controlled trial. JAMA 2004;
291: 170112.
Russo IH, Russo J. Progestagens and mammary gland
development: differentiation versus carcinogenesis. Acta Endocrinol
(Copenh) 1991; 125 (suppl 1): 712.
Druckmann R. Progestins and their effects on the breast. Maturitas
2003; 46 (suppl 1): S5969.
Erlik Y, Meldrum DR, Lagasse LD, Judd HL. Effect of megestrol
acetate on ushing and bone metabolism in post-menopausal
women. Maturitas 1981; 3: 16772.
Loprinzi CL, Michalak JC, Quella SK, et al. Megestrol acetate for the
prevention of hot ashes. N Eng J Med 1994; 331: 34752.
Morrison JC, Martin DC, Blair RA, et al. The use of
medroxyprogesterone acetate for relief of climacteric symptoms.
Am J Obstet Gynecol 1980; 138: 99104.
Barton D, Loprinzi C, Quella S, et al. Depomedroxyprogesterone
acetate for hot ashes. J Pain Symptom Manage 2002; 24: 60307.
von Schoultz E, Rutqvist LE. Menopausal hormone therapy after
breast cancer: the Stockholm randomized trial. J Natl Cancer Inst
2005; 97: 53335.
Landgren MB, Bennink HJ, Helmond FA, Engelen S. Doseresponse analysis of effects of tibolone on climacteric symptoms.
BJOG 2002; 109: 110914.
Egarter C, Topcuoglu A, Vogl S, Sator M. Hormone replacement
therapy with tibolone: effects on sexual functioning in
postmenopausal women. Acta Obstet Gynecol Scand 2002;
81: 64953.
Albertazzi P, Di Micco R, Zanardi E. Tibolone: a review. Maturitas
1998; 30: 295305.
Kloosterboer H. Intracrinology: the secret of the tissue-specicity of
tibolone. J Br Menopause Soc 2000; 6 (suppl): 2327.
Gompel A, Kandouz M, Siromachkova M. The effects of tibolone on
proliferation, differentiation and apoptosis in human breast cells.
Gynecol Endocrinol 1997; 11 (suppl 11): 79.
Hammar M, Christau S, Nathorst-Boos J, et al. A double-blind,
randomised trial comparing the effects of tibolone and continuous
combined hormone replacement therapy in postmenopausal
women with menopausal symptoms. Br J Obst Gynaecol 1998;
105: 90411.
Valdivia I, Ortega D. Mammographic density in postmenopausal
women treated with tibolone, estriol or conventional hormone
replacement therapy. Clin Drug Invest 2000; 20: 10107.
Beral V. Breast cancer and hormone-replacement therapy in the
Million Women Study. Lancet 2003; 362: 41927.
MacLennan A, Lester S, Moore V. Oral estrogen replacement
therapy versus placebo for hot ushes: a systematic review.
Climacteric 2001; 4: 5874.
Hickey M, Davis S, Sturdee D. Treatment of menopausal
symptoms; what shall we do now? Lancet 2005; 366: 40921.
Guttuso T Jr, Kurlan R, McDermott MP, Kieburtz K. Gabapentins
effects on hot ashes in postmenopausal women: a randomized
controlled trial. Obstet Gynecol 2003; 101: 33745.
Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in
management of hot ashes in survivors of breast cancer: a
randomised controlled trial. Lancet 2000; 356: 205963.
Loprinzi CL, Pisansky TM, Fonseca R, et al. Pilot evaluation of
venlafaxine hydrochloride for the therapy of hot ashes in cancer
survivors. J Clin Oncol 1998; 16: 237781.
Evans ML, Pritts E, Vittinghoff E, et al. Management of
postmenopausal hot ushes with venlafaxine hydrochloride: a
randomized, controlled trial. Obstet Gynecol 2005; 105: 16166.
Loprinzi CL, Sloan JA, Perez EA, et al. Phase III evaluation of
uoxetine for treatment of hot ashes. J Clin Oncol 2002; 20: 157883.
Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled
release in the treatment of menopausal hot ashes: a randomized
controlled trial. JAMA 2003; 289: 282734.
http://oncology.thelancet.com Vol 6 September 2005

Review

39

40

41

42

43

44

45
46

47

48

49

50

51

52
53

54

55

56

57

58

59

60

Weitzner MA, Moncello J, Jacobsen PB, Minton S. A pilot trial of

paroxetine for the treatment of hot ashes and associated
symptoms in women with breast cancer. J Pain Symptom Manage
2002; 23: 33745.
Barton DL, Loprinzi CL, Novotny P, et al. Pilot evaluation of
citalopram for the relief of hot ashes. J Support Oncol 2003;
1: 4751.
Suvanto-Luukkonen E, Koivunen R, Sundstrom H, et al.
Citalopram and uoxetine in the treatment of postmenopausal
symptoms: a prospective, randomized, 9-month, placebocontrolled, double-blind study. Menopause 2005; 12: 1826.
Lawlor DA, Juni P, Ebrahim S, Egger M. Systematic review of the
epidemiological and trial evidence of an association between
antidepressant medication and breast cancer. J Clin Epidemiol 2003;
56: 15563.
Stearns V, Johnson, MD, Rae JM, et al. Active tamoxifen metabolite
plasma concentrations after coadministration of tamoxifen and the
selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst
2003; 95: 175864.
Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant
use, and tamoxifen metabolism during adjuvant breast cancer
treatment. J Natl Cancer Inst 2005; 97: 3039.
Limer JL, Speirs V. Phyto-oestrogens and breast cancer
chemoprevention. Breast Cancer Res 2004; 6: 11927.
Tice JA, Ettinger B, Ensrud K, et al. Phytoestrogen supplements for
the treatment of hot ashes: the Isoavone Clover Extract (ICE)
Study, a randomized controlled trial. JAMA 2003; 290: 20714.
Krebs E, Ensrud K, Macdonald R, Wilt T. Phytoestrogens for
treatment of menopausal ; a systematic review. Obstet Gynecol 2004;
104: 82436.
Einbond LS, Shimizu M, Xiao D, et al. Growth inhibitory activity of
extracts and puried components of black cohosh on human breast
cancer cells. Breast Cancer Res Treat 2004; 83: 22131.
Jacobson JS, Troxel AB, Evans J, et al. Randomized trial of black
cohosh for the treatment of hot ashes among women with a
history of breast cancer. J Clin Oncol 2001; 19: 273945.
Hernandez Munoz G, Pluchino S. Cimicifuga racemosa for the
treatment of hot ushes in women surviving breast cancer.
Maturitas 2003; 44: 14.
Pockaj BA, Loprinzi CL, Sloan JA, et al. Pilot evaluation of black
cohosh for the treatment of hot ashes in women. Cancer Invest
2004; 22: 51521.
Huntley A, Ernst E. A systematic review of the safety of black
cohosh. Menopause 2003; 10: 5864.
Lontos S, Jones RM, Angus PW, Gow PJ. Acute liver failure
associated with the use of herbal preparations containing black
cohosh. Med J Aust 2003; 179: 39091.
Barton DL, Loprinzi CL, Quella SK, et al. Prospective evaluation of
vitamin E for hot ashes in breast cancer patients. J Clin Oncol
1998; 16: 495500.
Wyon Y, Wijma K MA, Nedstrand E, Hammar M. A comparison of
acupuncture and oral estradiol treatment of vasomotor symptoms
in postmenopausal women. Climacteric 2004; 7: 15364.
Freedman RR, Woodward S. Behavioural treatment of menopausal
hot ushes: evaluation by ambulatory monitoring. Am J Obstet
Gynecol 1992; 167: 43639.
Irvin JH, Domar AD, Clark C, et al. The effects of relaxation
response training on menopausal symptoms. J Psychosom Obstet
Gynaecol 1996; 17: 20207.
Ganz PA, Greendale GA, Petersen L, et al. Managing menopausal
symptoms in breast cancer survivors: results of a randomized
controlled trial. J Natl Cancer Inst 2000; 92: 105464.
Col NF, Hirota LK, Orr RK, et al. Hormone replacement therapy
after breast cancer: a systematic review and quantitative
assessment of risk. J Clin Oncol 2001; 19: 235763.
Holmberg L, Anderson H, HABITS steering and data monitoring
committee. HABITS (hormonal replacement therapy after breast
canceris it safe?), a randomised comparison: trial stopped. Lancet
2004; 363: 45355.

http://oncology.thelancet.com Vol 6 September 2005

61 Nachtigall LE. Comparative study: replens versus local estrogen

in menopausal women. Fertil Steril 1994; 61: 17880.
62 Dew JE, Wren BG, Eden JA. A cohort study of topical vaginal
estrogen therapy in women previously treated for breast cancer.
Climacteric 2003; 6: 4552.
63 Sverrisdottir A, Fornander T, Jacobsson H, et al. Bone mineral
density among premenopausal women with early breast cancer in
a randomized trial of adjuvant endocrine therapy. J Clin Oncol
2004; 22: 369499.
64 Heshmati HM, Khosla S, Robins SP, et al. Role of low levels of
endogenous estrogen in regulation of bone resorption in late
postmenopausal women. J Bone Miner Res 2002; 17: 17278.
65 Shapiro CL, Manola J, Leboff M. Ovarian failure after adjuvant
chemotherapy is associated with rapid bone loss in women with
early stage breast cancer. J Clin Oncol 2001; 19: 330611.
66 Powles TJ, Hickish T, Kanis JA, et al. Effect of tamoxifen on bone
mineral density measured by dual-energy x-ray absorptiometry in
healthy premenopausal and postmenopausal women. J Clin
Oncol 1996; 14: 7884.
67 Goss PE, Ingle JN, Martino S, et al. A randomized trial of
letrozole in postmenopausal women after ve years of tamoxifen
therapy for early-stage breast cancer. N Engl J Med 2003;
349: 1793802.
68 Banerjee S Smith IE, FolkerdL, Iqbal J, Barker P, Dowsett M.
Comparative effects of anastrazole, tamoxifen alone and in
combination on plasma lipids and bone-derived resorbtion
during neoadjuvant therapy in the IMPACT trial. Ann Oncol
(published online July 19, 2005; DOI:10.1093/annonc/mdi322).
69 Baum MBA, Cuzick J, Forbes J, et al. Anastrozole alone or in
combination with tamoxifen versus tamoxifen alone for adjuvant
treatment of postmenopausal women with early-stage breast
cancer: results of the ATAC (Arimidex, Tamoxifen Alone or in
Combination) trial efcacy and safety update analyses. Cancer
2003; 98: 180210.
70 Fogelman I, Blake GM, Blamey R, et al. Bone mineral density in
premenopausal women treated for node-positive early breast
cancer with 2 years of goserelin or 6 months of
cyclophosphamide, methotrexate and 5-uorouracil (CMF).
Osteoporos Int 2003; 14: 100106.
71 Saarto T, Vehmanen L, Elomaa I, et al. The effect of clodronate
and antioestrogens on bone loss associated with oestrogen
withdrawal in postmenopausal women with breast cancer.
Br J Cancer 2001; 84: 104751.
72 Brufsky A, Harker G, Beck T, et al. Zoledronic acid for
prevention of cancer treatment-induced bone loss in
postmenopausal women with early breast cancer receiving
adjuvant letrozole: preliminary results of the Z-FAST trial. 27th
Annual San Antonio Breast Cancer Symposium 2004, San
Antonio, CA, USA: abstr 1114.
73 Cummings SR, Black DM, Thompson DE, et al. Effect of
alendronate on risk of fracture in women with low bone density
but without vertebral fractures: results from the Fracture
Intervention Trial. JAMA 1998; 280: 207782.
74 Prince RL. How to diagnose the presence of osteoporosis and
assess the risk of fracture. Best Pract Res Clin Rheumatol 2001;
15: 34558.
75 Basson R, McInnes R, Smith MD, et al. Efcacy and safety of
sildenal citrate in women with sexual dysfunction associated
with female sexual arousal disorder. J Womens Health Gend Based
Med 2002; 11: 36777.
76 Barentsen R, van de Weijer PH, Schram JH. Continuous low
dose estradiol released from a vaginal ring versus estriol vaginal
cream for urogenital atrophy. Eur J Obstet Gynecol Reprod Biol
1997; 71: 7380.

695