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Management of Menopausal Symptoms in the Cancer Patient

Management of Menopausal Symptoms in the Cancer Patient

ABSTRACT: In the decades since hormone replacement therapy (HRT) was introduced, there has never been more controversy surrounding it than at present. Physicians and patients are faced with many questions regarding risk and few definitive answers. This article will discuss the current health benefits associated with hormone replacement, including its beneficial effects on the cardiovascular system, osteoporosis, vasomotor symptoms, colon cancer risk, and Alzheimer’s disease. Epidemiologic evidence suggesting an association between HRT, estrogen in particular, and breast cancer will also be discussed. Currently, there is no definitive evidence of a link between HRT and breast cancer risk, particularly with short-term use. Yet, only about 15% of women who would benefit from such therapy actually use it. This is due, in part, to concerns regarding breast cancer risk. For the breast cancer survivor, the current dictum is that estrogen replacement is contraindicated. For these patients and those who choose not to start HRT, the list of adequate, currently available alternatives for the many menopausal symptoms is still insufficient. Because of the known beneficial effects of HRT, its extension to patients with a history of hormone-dependent cancer may be indicated. However, randomized, controlled trials must be performed to assess the potential risks in these patients. [ONCOLOGY 13(10):1363-1372, 1999]

Introduction

With the current controversy surrounding
hormone replacement therapy (HRT), there is an increased demand by
the general population for alternative therapies, particularly for
the cancer survivor. The volume of information on HRT to which
physicians and patients are exposed is growing exponentially.
Nevertheless, there still remain as many questions as answers
regarding the risks and benefits of this therapy.

Until the 1970s, women expected to have to suffer through menopausal
symptoms as part of their reproductive life. It has since been
clearly established that hormones, estrogen in particular, play a
significant role in the physical and psychological well-being of women.

The symptoms of estrogen deficiency are often debilitating. The most
commonly described are vasomotor symptoms (hot flashes), urinary
frequency, mood swings, memory loss, difficulty in concentrating,
insomnia, decreased libido, dyspareunia, and vaginal dryness and
pruritus. The “silent killers” include heart disease,
osteoporosis, and Alzheimer’s disease.

Hormone replacement was initially intended for the short-term
treatment of vasomotor symptoms, but data showing a cardioprotective
effect and a benefit on bone mineral density support a longer
duration of use. The main questions that have arisen include the following:

  1. Is HRT safe to use?

  2. For how long a period can it be safely used?
  3. When should therapy begin?
  4. Who should receive HRT?

Because of the possible role that estrogen plays in the pathogenesis
of breast and other cancers, its use for postmenopausal therapy has
been challenged. As this article will show, HRT is still a safe
option for many women, and our goal as clinicians should be to help
identify those women who will benefit most from it. This article also
will review alternative therapies that have emerged in response to
the controversy surrounding hormone replacement. The needs and
treatment options for the breast cancer survivor in particular will
be addressed.

HRT and Cardiovascular Disease

Cardiovascular disease is the leading cause of noncancer death in
postmenopausal women (Figure 1).[1]
In Caucasian women 50 to 94 years old, the cumulative risk of death
from coronary artery disease is 31%, as compared with a 2.8% risk of
death from breast cancer or osteoporosis. These data underscore the
need to address cardiovascular and fracture risk in postmenopausal
women. Ideally, those at risk should be identified during their
reproductive years.

A number of studies have evaluated the role of HRT in the prevention
of cardiovascular disease. The cardioprotective mechanism of this
therapy is not well elucidated but is postulated to relate to its
effects on lipid accumulation in arterial walls, promotion of blood
flow, and modulation of vascular responsiveness.

The Nurses’ Health Study,[2] conducted by Grodstein et al from
1976 to 1992, examined the association between hormone replacement
and the risk of cardiovascular disease, breast cancer, colorectal
cancer, and overall mortality.[2-5] The study followed 59,337 women
(age, 30 to 55 years at study entry) for 16 years.

This study showed a significant decrease in cardiovascular disease
risk among current users of HRT (Figure 2),
with a relative risk (RR) of 0.60 (95% confidence interval [CI],
0.43 to 0.78); the greatest benefit was seen among users of estrogen
alone (RR, 0.39; 95% CI, 0.19 to 0.78).[2] The apparent benefit
disappeared within 5 years after discontinuation of therapy (Table
1
).

In a subsequent publication, Grodstein et al[3] evaluated the
relationship between HRT and mortality. Current hormone use was
associated with the lowest risk of death (RR, 0.63; 95% CI, 0.56 to
0.70), and this benefit appeared to diminish after 10 or more years
of use. This was attributable primarily to a 43% increase in death
due to breast cancer (RR, 1.43; 95% CI, 0.82 to 2.48). Those women
with cardiac risk factors had the largest reduction in mortality (RR,
0.51; 95% CI, 0.45 to 0.57).

The Postmenopausal Estrogen/Progestin Interventions (PEPI) trial[6]
was designed to compare the effects of placebo, unopposed estrogen,
and three combination hormonal regimens on selected cardiac risk
factors. All of the active regimens had a positive effect on lipid
profiles. Unopposed estrogen was the most effective regimen but
carried an unacceptably high risk of endometrial hyperplasia (34%, vs
1% with combination therapy), limiting its use to women without a
uterus. Micronized progesterone had the greatest effect on lipids.
The overall findings estimated a 40% to 50% reduction in cardiac deaths.

Most recently, the results of a study evaluating the role of
estrogens in the secondary prevention of cardiac disease were
published.[7] The investigators concluded that, in individuals with
already established coronary artery disease, HRT posed an increased
risk of thromboembolic disease (RR, 2.89; 95% CI, 1.50 to 5.58) and
gallbladder disease (RR, 1.38; 95% CI, 1.00 to 1.92). The
hormone-treated group experienced an 11% decrease in low-density
lipoprotein cholesterol and a 10% increase in high-density
lipoprotein cholesterol. Despite this effect, the hormone-treated
patients exhibited a 50% increase in the rate of myocardial
infarction during the first year of the trial. This group had a 40%
decreased rate of myocardial infarction during the last 2 years of
the trial, suggesting that the positive effect of estrogen on
cardiovascular disease is delayed even when lipid profiles are improved.

This study had many limitations. The investigators did not follow
patients enrolled in the latter part of the study period long enough
to show an effect. (Mean follow-up was 4.1 years.) Moreover, no
patients were taking unopposed estrogen, and medroxyprogesterone
acetate was the only progestational agent studied. These data
underscore the need for other treatments and lifestyle alterations,
with or without HRT.

HRT and Cardiovascular Disease

Hormone replacement therapy also has been shown to be effective in
the prevention and treatment of osteoporosis—a condition that is
still largely underdiagnosed. The data point to the need to address
fracture risk and its attendant morbidity in the postmenopausal
patient and, ideally, to identify those who are at risk even during
their reproductive years.

The PEPI trial also assessed the effect of hormone replacement on
bone mineral density, and concluded that women assigned to placebo
had a significantly lower spine and hip bone mineral density than
those in the active treatment groups.[8] Medroxyprogesterone acetate
was more effective than micronized progesterone in increasing bone
mineral density. (Bone mineral density was up to 5% higher in the
spine with medroxyprogesterone vs 3.8% with other regimens.)

The Rancho Bernardo Study[9] addressed the optimal timing of hormone
replacement for maximizing bone mineral density. This study concluded
that estrogen therapy instituted at any time is beneficial, but that
the greatest benefit occurs when therapy is started at the onset of
menopause and continued indefinitely. Women who used estrogen, even
for more than 10 years, and discontinued therapy did not maintain
their protection. Among current hormone users, there was no
significant difference in bone mineral density between women who
started taking estrogen at menopause and those who started it after
60 years of age.

HRT and Alzheimer’s Disease

Alzheimer’s disease is among the most common reasons for nursing
home admissions. The disorder affects twice as many women as men, in
part because of the longer life expectancy of women.

Kawas et al[10] performed the Baltimore Longitudinal Study of Aging,
a prospective, multidisciplinary study of normal aging. The sample
consisted of 472 postmenopausal or perimenopausal women followed for
up to 16 years. Current or ever-users of estrogen were considered
“users.” The findings showed that 45% of the women in the
cohort had used estrogen replacement therapy. There were 34 incident
cases of Alzheimer’s disease, 9 of which occurred in estrogen
users. The calculated RR for Alzheimer’s disease in estrogen
users as compared to nonusers was 0.46 (95% CI, 0.209 to 0.997),
supporting a protective effect of estrogen.

HRT and Colon Cancer

At least 18 published epidemiologic studies have examined the
relationship between HRT and colon cancer.[11] Of these studies, 12
suggested an inverse association between colon cancer risk and
hormone use, with an RR usually in the 0.4 to 0.8 range. In a study
by Calle et al,[12] the greatest reduction in risk was seen in
current estrogen users (RR, 0.55; 95% CI, 0.40 to 0.76) and with
longer duration of use (P = .0001). The mechanism by which estrogen
protects against colon cancer is thought to be mediated through a
decrease in bile acid concentration and effects at the molecular level.

HRT and Vasomotor Symptoms

Hot flashes are experienced by 85% of postmenopausal women in western
countries and may begin in the perimenopausal period when
gonadotropin levels are fluctuating. The mechanism by which vasomotor
flashes occur has not been well elucidated, but they are associated
with changes in core temperature and coincide with luteinizing
hormone surges.

Vasomotor symptoms are usually self-limited, dying out by 2 to 3
years after menopause. In the interim, however, these symptoms can be
debilitating. Hormones can relieve vasomotor symptoms in up to 90% of women.

HRT and Breast Cancer

Although hormone replacement appears to have many benefits, there is
growing concern that long-term use may be associated with breast
cancer development. Current attention by the media has served only to
increase this fear.

The following findings support an association between estrogens and
breast cancer:[13,14]

  1. Oophorectomy has been shown to protect against the occurrence of
    breast cancer and to favorably alter its prognosis.

  2. The presence of estrogen receptors affects prognosis.
  3. Antiestrogens are used in the treatment of breast cancer
  4. In vitro and in vivo studies have shown that
    estrogens have a mitogenic effect on breast epithelial cells.

Estrogens have been postulated to act as growth factors, through
initiation of mutations, and as promoters and cocarcinogens.[15]

The Nurses’ Health Study concluded that the RR of breast cancer
was 1.32 (95% CI, 1.14 to 1.54) in the estrogen-only group and 1.41
(95% CI, 1.15 to 1.74) in the combination therapy group.[4] With more
than 5 years of use, the RR increased to 1.46 (95% CI, 1.20-1.74; Table
2
). Past users or those with less than 5 years of use showed
risks similar to never-users, with the exception of women over the
age of 55 years (Figure 3).

Stanford et al[16] evaluated breast cancer risk in a population-based
case-control study that involved 537 breast cancer patients and 492
controls. Hormone replacement therapy had been used by 57.6% of the
breast cancer patients and 61% of controls—a negative finding.

The Collaborative Group on Hormonal Factors in Breast Cancer[17]
provided perhaps the most informative data but was limited by the
problems inherent in a meta-analysis. The collaborative group
reviewed approximately 90% of the worldwide epidemiologic evidence on
the relationship between breast cancer risk and HRT. As shown in

Figure 4, this meta-analysis showed
that breast cancer risk appears to increase after 15 or more years of
use (RR, 1.58). Current users were at greatest risk, and the risk was
reversed 5 or more years after discontinuation of therapy. The
increase of 2.3% per year of use is comparable to the 2.8% per year
increase in risk for each year that menopause is delayed (assumed
average onset of menopause is 51 years).

The epidemiologists from the Nurses’ Health Study[18] also
performed a meta-analysis of 25 case-control and six cohort studies.
They concluded that ever-use of estrogen carried no increased risk,
and current use was associated with an increased risk, which was
reversed 2 years after discontinuation of therapy.

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