The article by Castiel highlights the benefits and potential risks of
estrogen replacement in cancer patients. For patients with
malignancies that are not estrogen sensitive, adding
hormone replacement therapy (HRT) to the therapeutic regimen can only
improve quality of life. This is a very important consideration for
many patients undergoing the trials and tribulations of cancer
therapy. For patients with breast and endometrial cancer, the issues
are somewhat more complex. However, a growing number of physicians
are becoming convinced that the patient should decide whether or not
to take hormone replacement based on a careful explanation of the
Patients should be aware that estrogen affects many tissues in the
body, in addition to the classic target tissues of the uterus and
breast.[1,2] Estrogen exerts well-established effects on bone that
can prevent osteoporosis; cardioprotective benefits through effects
on plasma lipid levels and vessel walls; and effects in the brain,
protecting against the onset and symptoms of Alzheimers disease.[3-6]
It is now known that estrogen functions differently in various
tissues. Furthermore, it is hoped that a greater understanding of the
mechanisms underlying these various actions of estrogen will
ultimately lead to the development of an estrogen that provides all
of the benefits without the potential, undesirable effects.
Cardiovascular Disease Protection
According to American Heart Association statistics, more women than
men die of cardiovascular disease in the United States every year,
and cardiovascular disease continues to be the leading cause of death
among women over age 35. A womans risk of coronary artery
disease increases dramatically after menopause, regardless of the age
of onset or cause of menopause.
Numerous factors contribute to a womans risk of cardiovascular
disease. These include smoking, inactivity, obesity, a poor
cholesterol profile, and estrogen deficiency. Retrospective studies
have shown that postmenopausal estrogen therapy reduces the risk of
cardiovascular disease by approximately 50%.[7,8] The mechanism of
this cardioprotective effect is not completely understood, but it is
believed to be multifactorial.
Estrogen has a known effect on serum lipoproteins: It increases
high-density lipoprotein cholesterol by up to 15% and decreases
low-density lipoprotein cholesterol and total cholesterol by nearly
20%. Changes in the lipid profile may account for approximately 30%
to 50% of the reduction in cardiovascular events seen with estrogen.
The addition of a progestin slightly abrogates the effect of estrogen
on the lipid profile, but, according to the Postmenopausal
Estrogen-Progesterone Intervention (PEPI) study, this abrogation is minimal.
Most observational studies have found estrogen to be effective in
both the primary and secondary prevention of cardiovascular disease.
In the Nurses Health Study, which involved over 59,000 women,
current users of estrogen replacement enjoyed up to a 50% reduction
in the relative risk of cardiovascular disease.[1,2,9] It is
important to note that most studies performed in America have
utilized conjugated equine estrogen (Premarin), whereas European
studies have used estradiol valerate.
Retrospective angiographic studies have shown that estrogen exerts a
statistically significant, independent protective effect against
coronary atherosclerosis. Improved survival has been observed in
women who use estrogen or hormone replacement after coronary
angioplasty or coronary artery bypass surgery. Four cohort studies
have found a great mortality and morbidity benefit related to
estrogen use among women with coronary atherosclerosis. These same
studies have shown that survival is significantly better among women
with serious cardiovascular disease who use HRT.
The Heart and Estrogen-Progestin Replacement Study
A randomized, double-blind, placebo-controlled trial was conducted to
assess the ability of hormone replacement to reduce the risk of death
and recurrent cardiovascular incidents (events) in women with
established cardiovascular disease. The Heart and Estrogen-Progestin
Replacement Study (HERS) enrolled more than 2,700 postmenopausal
women with documented serious coronary heart disease who ranged in
age from 44 to 79 years (mean, 67.7 years). Many of these women had
significant comorbidities and were taking a variety of cardiac
medications. The patients were randomly assigned to either placebo or
a daily dose of combined continuous conjugated equine estrogens plus
At 1 year, there was a 52% increase in the relative risk of coronary
heart disease events in the HRT group, but the actual incidence of
such events was low, occurring in 4.3 of 100 women in the HRT group
vs 2.8 of 100 women in the placebo group. In both groups, the
incidence of coronary heart disease events was less than 5%, which is
the rate used in the study to estimate the number of subjects needed
to achieve statistical power.
The trial also revealed a statistically different time trend between
the two groups with respect to coronary heart disease events: More
events occurred in the HRT group than in the placebo group during
year 1, but fewer events occurred by years 4 and 5. Specifically, the
incidence of recurrent coronary heart disease events with HRT was
comparable to that seen with placebo by the 8th month of use and was
lower after the 36th month of use.
The authors of the trial concluded that these results should not
affect the current recommendations for estrogen or hormone
replacement in women without coronary heart disease. However, in
women with newly diagnosed coronary heart disease, HRT should not be
initiated solely for the purpose of preventing additional coronary
heart disease events.
The HERS researchers did not evaluate the cardiovascular effect of
treatment with unopposed estrogen, which is commonly prescribed in
women who have undergone a hysterectomy. They also did not
investigate the usefulness of other estrogen-progestin formulations.
It is important for clinicians to recognize that HERS assessed only
one therapeutic regimen; clearly, there is a need for studies of
other regimens. In addition, the HERS participants were older and
less healthy than the average perimenopausal woman who is considering
taking estrogen or hormone replacement. Although women in the trial
who took the estrogen-progestin regimen appeared to have an increased
risk for primary coronary heart disease events during the first year
of therapy, that risk declined over subsequent years.
Advancing age brings a general decline in cognitive function. This
slowing of central processing speed may contribute to the increased
number of hip and wrist fractures among the elderly, as these older
individuals are less adept at adverting falls than their younger
counterparts. The rate of cognitive decline is determined by numerous
factors. Documented risk factors, identified by clinical research on
Alzheimers disease, include age, family history, and genetic mutations.
One current theory suggests that Alzheimers disease develops as
a result of failed processing of a protein that responds to injured
neurons. Instead of facilitating neuronal repair, this altered
protein results in the development of a fragment, beta-amyloid, that
contributes to neuronal toxicity.
Alzheimers disease has become an important womens health
issue. It occurs about two to three times more commonly in women than
in men. It has been postulated that this gender disparity is due, in
part, to the loss of estrogen in the postmenopausal woman; the
average 70-year-old male has three times the circulating estradiol
levels than the average 70-year-old female. Womens greater life
expectancy also places them at greater risk for Alzheimers disease.
Estrogen has several different effects on brain function. It
stimulates the expression of neurotropic factors within the central
nervous system. In vitro, estrogen protects neurons from beta-amyloid
toxicity by promoting the breakdown of the amyloid precursor protein
to fragments less likely to aggregate in the brain as deposits.
Estrogen also increases regional cerebral blood flow and stimulates
the production of neurotransmitters, such as acetylcholine and
serotonin. Lastly, estrogen stimulates axonal regeneration and the
production of synapses.
Colorectal cancer is the second leading cause of cancer death in US
women. In 1998, this cancer was responsible for nearly 25,000 deaths
Epidemiologic studies indicate that women who use HRT may have up to
a 34% reduction in the rate of colorectal cancer compared to women
who have never used hormone replacement. Overall, colon cancer is
reduced by 20% and rectal cancer by 15% in women who have ever taken estrogen.
The exact effect of estrogen on the colon is unknown. However, it is
thought that estrogen may affect the production of bile acids that
aid in digestion and that seem to be important for the prevention of
Hormone Replacement in Breast Cancer Survivors
Given these and other benefits of hormone replacement, it is
imperative that we inform patients who were formerly prohibited from
using HRT that, indeed, there are risks and benefits that must be
considered.[10,11] Breast cancer survivors constitute the most
important of these groups. Unfortunately, no prospective, randomized
studies have been completed to show whether hormone replacement
either favorably or adversely affects the survival of breast cancer patients.
In view of the rapidly accumulating data on the benefits of HRT in
average women, can we continue to uniformly object to its use in
breast cancer survivors? Shouldnt these patients be informed
about the risks and benefits of hormone replacement, based on current
knowledge, and then be allowed to make their own decision?
Over the past 2 decades, there has been enormous growth in our
knowledge of the mechanisms of action of estrogen, as well as the
benefits of postmenopausal estrogen and hormone replacement. Several
observational studies have proven that postmenopausal estrogen use
can significantly reduce the risk of cardiovascular disease,
osteoporosis, and bone fractures. Estrogen appears to decrease the
risk of Alzheimers disease and definitely provides relief of
menopausal symptoms. Since the cost to the American health care
system for the management of cardiovascular disease, osteo-
porosis, and Alzheimers disease runs into the tens of billions
of dollars, can we afford to ignore this option for any
postmenopausal woman? Dr. Castiel poses this question in her
thoughtful review. My comments merely reinforce her conclusions.
1. Grady D, Rubin SM, Petitti DB, et al: Hormone therapy to prevent
disease and prolong life in postmenopausal women. Ann Intern Med
2. Grodstein F, Stampfer MJ, Colditz GA, et al: Postmenopausal
hormone therapy and mortality. N Engl J Med 336:1769-1775, 1997.
3. Jacobs DM, Tang MX, Stern Y, et al: Cognitive function in
nondemented women who took estrogen after menopause. Neurology
4. Paganini-Hill A, Henderson VW: Estrogen replacement therapy and
risk of Alzheimers disease. Arch Intern Med 156:2213-2217, 1996.
5. Rice MM, Graves AB, McCurry SM, et al: Estrogen replacement
therapy and cognitive function in postmenopausal women without
dementia. Am J Med 103:26S-35S, 1997.
6. Tang MX, Jacobs D, Stern Y, et al: Effect of oestrogen during
menopause on risk and age at onset of Alzheimers disease.
Lancet 348:429-432, 1996.
7. Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen
plus progestin for secondary prevention of coronary heart disease in
postmenopausal women. JAMA 280(7):605, 1998.
8. Sacks FM, Walsh BW: The effects of reproductive hormones on serum
lipoproteins: Unresolved issues in biology and clinical practice. Ann
NY Acad Sci 592:272-285, 1990.
9. Wenger NK, Speroff L, Packard B: Cardiovascular health and disease
in women. N Engl J Med 329:247-256, 1993.
10. DiSaia PJ, Grosen EA, Kurosaki T, et al: Hormone replacement
therapy in breast cancer survivors: A cohort study. Am J Obstet
Gynecol 174:1494-1498, 1996.
11. Eden JA, Bush T, Nand S, et al: A case control study of combined
continuous estrogen-progestin replacement therapy among women with a
personal history of breast cancer. Menopause 2:67-72, 1995.
12. Vassilopoulou-Sellin R, Therriault R, Klein MY: Estrogen
replacement therapy in women with prior diagnosis and treatment for
breast cancer. Gynecol Oncol 65:89, 1997.