In some women, hormone replacement therapy (HRT) can affect the appearance of the mammogram by producing increased densities, benign cysts, and nodules. The author reviews each of these mammographic changes and advises radiologists to be prepared to perform any additional diagnostic imaging necessary to confirm their benign nature.
is with the University of Chicago Hospital's Breast Imaging
is with the Department of Health Studies and Harris School of
Public Policy, University of Chicago, and
is with the Department of Reproductive Endo-crinology at the
University of Chicago Hospital, Chicago, IL.
Radiologists must be aware of the many dynamic changes in the
female population and understand why so many menopausal women are
now using hormone replacement therapy (HRT) because it directly
affects the interpretation of many mammograms. According to the
U.S. Census Bureau, the total number of women in the United States
is continually increasing with growth of the general population.
Within this growing female population, the proportion of women
older than age 55 continues to increase with each census. In 1995,
23 million U.S. women were over age 55, and by 2015 this number is
projected to increase to 93 million women. Beginning in 1996,
10,000 Americans, one-half of them women, turn 50 years of age each
Life expectancy statistics for women during the last century
show interesting changes. In 1901, the life expectancy (at birth)
of a woman in North America was 50 years; by 1997 her life
expectancy reached 79 years. This increased life expectancy is the
result of several factors, most notably improved sanitation,
nutrition, housing, medical care, decreased infant mortality, and
antibiotic and vaccine discoveries of the 1930s. In 1901, only 6%
of women were postmenopausal, past the age of 50, with a life
expectancy after menopause of only 20 years. This made menopause a
biological marker for the last two decades of a woman's life. This
situation changed dramatically in just 95 years. A woman reaching
menopause in 1996 can expect to live 30 more years. This is a
net-gain in postmenopausal life expectancy of 10 years in one
These facts and projections illustrate how the female population
has changed in both age and number.
Since this population is older, they have a different biologic
make-up. During a woman's reproductive life, plasma 17B estradiol
ranges from 50 to 400 pg/mL, but with menopause estrogen levels
drop to <30 pg/mL. This level is lower than the estradiol levels
present in a man.
These low estrogen levels in menopausal women cause or
contribute to numerous symptoms, ranging from vasomotor hot flashes
to major depression, cardiovascular disease, and osteoporosis. In
an attempt to mitigate the many problems associated with living
longer with less estrogen, increasing numbers of menopausal women
are turning to HRT in hope of alleviating these symptoms and
cardiovascular and skeletal benefits.
Many different estrogen and estrogen/ progestin combinations are
prescribed by the millions annually in this country. These include
conjugated equine estrogens, which have been widely available for
more than 50 years; other oral forms; and transdermal patches. For
women with an intact uterus, combinations of estrogen and progestin
are generally prescribed, whereas there are no compelling data to
use progestins for post-hysterectomy patients.
Radiologists must be aware of these changes in the female
population since increased use of HRT can influence the mammogram's
appearance and how it is interpreted.
Some of the possible effects of HRT on the mammogram include: 1) a
diffuse overall increase in the density of the glandular
parenchyma; 2) development of a single asymmetric density; and 3)
Increased breast density
The majority (75%) of postmenopausal women initiating HRT will
have no appreciable change in the appearance of their mammogram on
the 1-year followup exam. In our experience, however, some women
(25%) will have changes that can be recognized by the radiologist.
The change we see most frequently is a diffuse and generalized
increase in the glandular density of both breasts (figure 1). This
diffuse and generalized bilateral appearance on the mammogram
represents the response of senescent breast tissue to hormone
stimulation, producing a benign epithelial hyperplastic change.
This mammographic change requires no special diagnostic evaluation
as long as the patient has no palpable complaint and there is no
evidence of a dominant mass in this changing parenchyma. In the
presence of these changes, we recommend the patient remain on
Frequently, multiple small (2 to 3 mm) round, benign-appearing
nodules are visible on the mammogram of a patient taking HRT. If
these nodules are nonpalpable and well circumscribed on spot
magnification imaging, they usually represent benign glandular
proliferative changes. We advise discontinuing HRT for 3 to 4
months and repeating the mammogram to demonstrate their shrinkage
or disappearance before resuming HRT. These minimal nodules often
increase and decrease in size over the years as some patients start
and stop HRT. If these nodules increase in size while the patient
is off HRT, biopsy should be considered. The development of an
irregularly shaped or spiculated mass while the patient is on or
off HRT is a suspicious mammographic finding and a biopsy should be
Benign asymmetric density
A second, but less common, mammographic finding seen following
the institution of HRT is the development of a single area of
asymmetric density (figure 2). This finding should be evaluated
with spot compression views in two projections together with
directed ultrasound (US) and directed palpation. If this asymmetric
density disperses normally on spot compression, and is
non-visualized on US without a palpable finding, it is a benign
estrogen effect. We recommend the next mammogram to be a diagnostic
exam in 1 year and we encourage the patient to continue HRT.
Another change occasionally seen on mammogram during HRT is cyst
formation. These cysts can be single or multiple and involve one or
both breasts. They are usually small, less than 1 to 2 cm,
nonpalpable, and well circumscribed on the mammogram. US is used to
document their benign nature.
The appearance of several small nonpalpable cysts is of no
significance, no interventional action (such as aspiration) is
taken, and HRT can continue (figure 3).
If a new cyst is palpable, or if there is uncertainty about its
cystic versus solid nature on US exam, an US-guided aspiration
should be performed and its disappearance should be documented with
a stat postaspiration mammogram so that HRT can continue
uninterrupted (figure 4).
Possible causal relationship with breast cancer
A potential problem with HRT is the possibility that it could be
associated with the development of breast cancer (figure 5). This
is a matter of great concern to many patients before and during
HRT. The radiologist should understand the basic statistical risks
of developing cancer while on HRT and be able to describe these
risks to the patient.
Scientists and statisticians, in an attempt to find a definitive
answer to this question have done meta-analyses of hundreds of
published studies in the scientific literature that reported data
suggesting either increased or decreased incidence of breast cancer
with HRT (figure 6). In the final assessment, statisticians
observed that the risk of developing cancer varied widely from
study to study. Because of this observation, and despite analysis
of numerous epidemiologic studies, there is no solid consensus
regarding postmenopausal estrogen use and risk of breast cancer.
The "bottom-line" summary of many studies displayed in figure 6
shows minimal, almost statistically insignificant, increased
relative risk (RR 1.10) of breast cancer associated with estrogen
During analysis of these multiple studies, scientists gave
particular attention and scrutiny to the type, duration, and dosage
of estrogen used in HRT. These analyses resulted in several causal
inferences that we will briefly explain, but we must first define
RR is the incidence of a condition in an exposed group divided
by the incidence in a non-exposed group. A RR of 1.0 means no
increased risk for the exposed group compared with the non-exposed.
An example of increased RR would be women with first-degree
relatives with breast cancer having an increased risk (RR 2.3) of
getting breast cancer as compared with women without such a family
Another example is seen in figure 6, in which there is a reported
increased RR of 1.1 associated with HRT and breast cancer. For
comparison, this risk is even smaller than the reported slightly
increased RR of 1.3 of developing breast cancer in women who have
merely had an early menarche, at <12 years of age.
It is generally accepted that the type of exogenous estrogen
used in HRT can be important. For example, one large study of
postmenopausal women using HRT therapy found only a very slight
increase in overall risk (RR 1.10) of developing breast cancer.
The portion of women in this study group taking estradiol
preparations had a slightly higher risk (RR 1.20) and those women
in the study using the injectable forms of estradiol had a
four-fold (RR 4.0) increased risk. It is important to note that
those women in this study using conjugated estrogen had no
increased risk (RR 1.0) of developing breast cancer.
The relationship between the duration of HRT and breast cancer
risk can also be important. Some authors find a modest increase in
relative risk with increasing duration (>5 years) of estrogen
use, although other authors found no increased risk with time.
Therefore, the literature is not conclusive on this issue.
A third causal factor observed by scientists is the daily dosage
of estrogen, which may influence risk. There is evidence that
dosage of 1.25 mg of conjugated estrogen may increase risk, while a
lower dosage of 0.625 mg does not appreciably increase risk (figure
In view of these three generally accepted findings about the
risk of breast cancer while using HRT, we recommend that the
radiologist interacting with postmenopausal women undergoing HRT:
1) encourage the postmenopausal patient to make an informed
decision about HRT therapy by sharing what you have learned of this
topic; 2) obtain baseline mammogram and breast palpation before HRT
begins; 3) encourage the use of estrogens in the lowest appropriate
dose; 4) advocate annual mammography and breast palpation; and 5)
evaluate new-onset mammographic densities, masses, or palpable
complaints detected on physical exam.
Radiologists interpreting screening and diagnostic mammograms
can now appreciate the changes in the female population, including
increasing numbers of menopausal women electing to use HRT to
mitigate the symptoms of menopause and improve cardiovascular and
This widespread hormone use can affect the appearance of the
mammogram in a portion of women by producing increased densities,
benign cysts, and nodules. Radiologists must be familiar with these
mammographic changes and be prepared to perform any additional
diagnostic imaging necessary to confirm their benign nature.
Finally, radiologists should be prepared to discuss with the
patient the small but possible increased risk of breast cancer with
HRT. This discussion should emphasize annual mammographic screening
and physical exams for the early detection of breast cancer, no
matter what its etiology.
1. U.S. Census Bureau
2. National Center for Health Statistics:
Division of Vital Statistics, Washington, DC, personal
3. Laya MB, Gallagher JC, Schreiman JS, et al:
Effect of postmenopausal hormone replacement therapy on
mammographic density and parenchymal pattern. Rad 196:433-437,
4. Sattin RW, Rubin GI, Webster LA, et al:
Family history and the risk of breast cancer. JAMA 253:1908-1913,
5. Dupont WD, Page DL:
Breast cancer risk associated with proliferative disease, age at
first birth, and a family history of breast cancer. Am J Epidemiol
6. Bergkvist L, Adami HO, Persson I, et al:
The risk of breast cancer after estrogen and estrogen-progestin
replacement. N Engl J Med 321:293-297, 1989.
7. Dupont WD, Page DL:
Menopausal estrogen replacement therapy and breast cancer. Arch Int
Med 151:67-72, 1991.