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Breast Cancer Research and Treatment (2020) 182:555–579 https://doi.org/10.1007/s10549-020-05744-w
REVIEW
Hormone replacement therapy and mammographic density: a systematic literature review
Shadi Azam1 · Katja Kemp Jacobsen2 · Arja R. Aro1 · Elsebeth Lynge3 · Zorana Jovanovic Andersen3
Received: 8 November 2019 / Accepted: 12 June 2020 / Published online: 22 June 2020 © The Author(s) 2020
AbstractPurpose Hormone replacement therapy (HRT) is used to reduce climacteric symptoms of menopause and prevent osteopo-rosis; however, it increases risk of breast cancer. Mammographic density (MD) is also a strong risk factor for breast cancer. We conducted this review to investigate the association between HRT use and MD and to assess the effect of different HRT regimens on MD.Methods Two of authors examined articles published between 2002 and 2019 from PubMed, Embase, and OVID using Covi-dence systematic review platform. Any disagreements were discussed until consensus was reached. The protocol used in this review was created in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Quality of each eligible study was assessed using the Oxford Center for Evidence-Based Medicine (OCEBM) hierarchy.Results Twenty-two studies met the inclusion criteria. Six studies showed that using estrogen plus progestin (E + P) HRT was associated with higher MD than estrogen alone. Four studies reported that continuous estrogen plus progestin (CEP) users had higher MD than sequential estrogen plus progestin (SEP) and estrogen alone users. However, two studies showed that SEP users had slightly higher MD than CEP users and estrogen alone users.Conclusions Epidemiological evidence is rather consistent suggesting that there is a positive association between HRT use and MD with the highest increase in MD among current users, and CEP users. Our results suggest that due to increase in MD and masking effect, current E + P users may require additional screening procedures, shorter screening intervals, or using advanced imaging techniques.
Keywords Mammographic density · Hormone replacement therapy · Breast cancer risk · Systematic literature review
AbbreviationsBI-RADS Breast imaging reporting and data systemCEP Continues estrogen plus progestinE + P Estrogen plus progestinHRT Hormone replacement therapy
MD Mammographic densityMWS Million women studyOCEBM Oxford center for evidence-based medicinePMD Percent mammographic densityPRISMA Preferred reporting items for systematic
reviews and meta-analysesRCT Randomized controlled trial
Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1054 9-020-05744 -w) contains supplementary material, which is available to authorized users.
* Shadi Azam [email protected]
Katja Kemp Jacobsen [email protected]; [email protected]
Arja R. Aro [email protected]
Elsebeth Lynge [email protected]
Zorana Jovanovic Andersen [email protected]
1 Unit for Health Promotion, Department of Public Health, University of Southern Denmark, Niels Bohrs Vej 9, 6700 Esbjerg, Denmark
2 Department of Technology, Faculty of Health and Technology, University College Copenhagen, Copenhagen, Denmark
3 Section of Environmental Health, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
556 Breast Cancer Research and Treatment (2020) 182:555–579
1 3
SEP Sequential estrogen plus progestinWHI Women’s health initiative
Introduction
Hormone replacement therapy (HRT) is recognized as an effective treatment for alleviating the climacteric symp-toms of menopause such as hot flushes, sleeping distur-bance, depressive mood, muscle and joint pain [1]. Large clinical trials showed that use of HRT prevents bone loss and decreases risk of osteoporosis and bone fractures in menopausal women [2, 3]. The most common HRT regi-mens are: estrogen alone, combined estrogen plus progestin (E + P) either as continuous estrogen plus progestin (CEP) or sequential estrogen plus progestin (SEP) [4]. For many years, HRT was used widely to improve the quality of life of menopausal women. However, after the results from two large population-based studies, the Women’s Health Initia-tive (WHI) study in the United States in 2003 [5] and Mil-lion Women Study (MWS) in the Unites Kingdom in 2003 [6] showing that HRT use increases risk of breast cancer and cardiovascular disease, the long-term benefits and poten-tial adverse effects of HRT on menopausal women were reconsidered. After the results from these two studies, new guidelines concerning amount, types, and duration of HRT for menopausal women were released, leading to a decline in use of HRT along with a reduction in the rates of breast cancer incidence by 6.7% among American women. After 2003, dramatic decline in HRT consumption and breast can-cer incidence were recognized as the consequence of the findings from WHI and MWS studies [7].
Mammographic density (MD) is a very strong predic-tor for breast cancer risk [8]. MD refers to the amount of radiologically dense breast consisting of epithelial or stro-mal tissue that appears light on a mammogram, whereas fat tissue appears dark on a mammogram [9]. There are dif-ferent methods for measuring MD including percent mam-mographic density (PMD), Breast Imaging Reporting and Data System (BI-RADS), and Wolfe [10]. Women with very dense breasts (> 75% density in the breast) have a four to six times greater risk of breast cancer than women with little density (< 5% density) or fatty breasts [8, 9]. Previous stud-ies suggested that MD is influenced by several exogenous hormones which are known to influence breast cancer risk thus, MD is known an important surrogate marker for the effects of exogenous hormones on the risk of breast cancer [11, 12]. This review used a systematic approach to explore the association between HRT use and MD. Furthermore, we investigated the effect of different HRT exposure states (never, former, current use) as well as different HRT regi-mens on MD.
Methods
Inclusion and exclusion criteria
Studies included in this review met the following criteria: original research in peer-reviewed journals, full-text avail-able online, a randomized controlled trial (RCT) as the study design, a cohort (prospective-cohort or retrospective cohort), a case–control, or a cross-sectional with a clear description of the samples and methodology, and articles available in English language. We focused on studies that examined the associations between HRT use and MD. Additionally, the MD assessment criteria in the studies had to be based on either Wolfe, PMD, or BI-RADS category. We excluded any descriptive manuscripts which did not have the focus on the association between HRT and MD.
Search strategy
Epidemiological studies from July 2002 to 2019 were retrieved from the following databases: PubMed Cen-tral (US National Institutes of Health [NIH]), OVID, and Embase using the following combinations of MeSH terms: “hormone replacement therapy”, “postmenopausal hormone replacement therapy”, “estrogen-progestin hormone replace-ment therapy”, “combined hormone replacement therapy”, “HRT”, and “estrogen alone hormone replacement therapy” in conjugation with “mammographic density” and “breast density”. An example of the search strategy used in one of the search databases (PubMed) is found in "Appendix".
Study screening
We imported and managed all study citations identified from the search strategy using the Covidence systematic review platform [13]. Two reviewers (S.A, K.J) independently screened the titles, abstract and reviewed the bibliography of articles found through electronic search engines for eli-gibility. Two pairs of co-authors reviewed all the abstracts. Disagreements occurred in less than 5% of all articles; any disagreements were discussed until consensus was reached.
Review protocol
The protocol used in this systematic review was created in accordance with the Preferred Reporting Items for Sys-tematic reviews and Meta-Analyses 2009 (PRISMA) state-ment and flowchart was used [14]. Supplementary Table 1 illustrates the PRISMA checklist of this systematic review. Furthermore, in this literature review, quality of each eli-gible study was assessed using the Oxford Centre for
557Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
Cha
ract
erist
ics o
f epi
dem
iolo
gica
l stu
dies
inve
stiga
ting
HRT
use
and
mam
mog
raph
ic d
ensi
ty
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
Byr
ne e
t al.
(201
7)
[18]
Uni
ted
Stat
esC
ase–
cont
rol
3- C
ases
: 174
wom
en
who
dev
elop
ed
brea
st ca
ncer
- Con
trols
: 733
hea
lthy
wom
en- A
ge ra
nge
50–7
9 ye
ars
- MD
was
ass
esse
d fro
m m
amm
ogra
ms
take
n pr
ior a
nd o
ne
year
afte
r ran
dom
i-za
tion
of c
ases
and
co
ntro
ls
CEP
–- A
ge- B
asel
ine
BM
I- C
linic
al c
ente
r- A
ge a
t firs
t birt
h- P
arity
- Wom
en a
ssig
ned
to C
EP g
roup
had
a
larg
er a
nd b
road
di
strib
utio
n of
mam
-m
ogra
phic
den
sity
ch
ange
(mea
n ch
ange
=
9.7
%),
whe
reas
w
omen
in n
ever
HRT
us
ers/
plac
ebo
grou
p ex
hibi
ted
min
imal
m
amm
ogra
phic
de
nsity
cha
nge
over
on
e ye
ar (m
ean
chan
ge
= −
0.0
5%)
- Afte
r adj
ustin
g fo
r co
varia
tes i
nclu
ding
ba
selin
e de
nsity
, the
di
ffere
nce
in m
ean
chan
ge in
mam
-m
ogra
phic
den
sity
be
twee
n th
e pl
aceb
o (−
0.6
5%, 9
5% C
I =
− 1
.86
to 0
.55)
and
th
e C
EP u
sers
(9.4
9%,
95%
CI =
8.2
5 to
10
.72)
trea
tmen
t arm
s w
as st
atist
ical
ly si
g-ni
fican
t (p
< .0
01)
Ols
son
et a
l. (2
014)
[3
3]Sw
eden
Coh
ort
2- 6
19 w
omen
with
in
cide
nt b
reas
t ca
ncer
- Age
rage
48–
81 y
ears
–B
I-R
AD
S–
- Fro
m 2
14 w
omen
w
ith d
ense
bre
ast 1
06
(49.
5%) w
ere
HRT
us
ers a
t the
tim
e of
br
east
canc
er d
iagn
ose
and
46 (2
1.5%
) wer
e ne
ver H
RT u
ser
558 Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
(con
tinue
d)
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
Car
mon
a-Sa
nche
z et
al.
(201
3)[2
9]Sp
ain
Coh
ort
2- 1
65 p
ostm
enop
ausa
l w
omen
- 1-y
ear s
tudy
follo
w-
up
- Estr
ogen
alo
ne- C
EP- S
EP
BI-
RA
DS
–- M
D in
crea
sed
in 7
.9%
of
wom
en re
ceiv
ing
estro
gen
alon
e co
m-
pare
d to
25.
2% w
omen
re
ceiv
ing
CEP
(p <
0.
022)
dur
ing
1 ye
ar.
- Afte
r 5 y
ears
of H
RT
7.9%
of w
omen
ver
sus
28.3
% o
f wom
en (p
<
0.0
09) h
ad M
D
incr
ease
, res
pect
ivel
y- T
here
was
sign
ifica
nt
stat
istic
al d
iffer
ence
in
wom
en tr
eate
d w
ith
estro
gen
alon
e ve
rsus
th
ose
treat
ed w
ith
com
bine
d H
RT- A
fter 5
yea
rs o
f HRT
, M
D in
crea
sed
21.8
%
in w
omen
rece
ivin
g SE
P ve
rsus
38.
8% in
th
ose
unde
r CEP
(p <
0.
039)
559Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
(con
tinue
d)
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
Cra
ndal
l et a
l. (2
012)
[2
0]U
nite
d St
ates
RCT
1- 6
95 p
ostm
enop
ausa
l w
omen
- Age
rang
e 50
–79
year
s- 1
-yea
r fol
low
-up
study
- Estr
ogen
- E +
PPM
D- A
ge- E
thni
city
(Cau
casi
an,
Bla
ck, A
mer
ican
In
dian
, Asi
an P
acifi
c Is
land
er, u
nkno
wn)
- BM
I (kg
/m2 , c
ontin
u-ou
s and
qua
rtile
s)- G
ail r
isk
scor
e
- At 1
-yea
r fol
low
-up
the
chan
ge fr
om b
asel
ine
in P
MD
was
1.4
% fo
r es
troge
n al
one
user
s an
d -0
.8%
for n
ever
H
RT u
sers
- The
PM
D c
hang
e fo
r E
+ P
use
rs w
as 6
.3%
an
d fo
r nev
er H
RT
user
s was
− 0
.9%
- Cha
nges
in P
MD
wer
e st
atist
ical
ly si
gnifi
-ca
ntly
gre
ater
am
ong
wom
en a
ssig
ned
to a
ctiv
e th
erap
y th
an a
mon
g w
omen
as
sign
ed to
pla
cebo
an
d w
ere
mor
e m
arke
d am
ong
wom
en
assi
gned
to E
+ P
than
es
troge
n al
one
- The
resu
lt fro
m th
is
study
can
not b
e as
sum
ed to
app
ly to
ot
her t
ypes
, dos
es,
rout
s of e
strog
en o
r pr
oges
tin th
erap
y
560 Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
(con
tinue
d)
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
Cou
to e
t al.
(201
2)
[19]
Nor
way
Cro
ss-s
ectio
n4
- 242
4 po
stmen
opau
sal
wom
en- A
ged
50–6
9 ye
ars
- Estr
ogen
- E +
PPM
D- A
ge a
t scr
eeni
ng- B
MI
- Num
ber o
f chi
ldre
n- A
ge a
t firs
t chi
ldbi
rth- F
irst-d
egre
e fa
mily
hi
story
of b
reas
t ca
ncer
- Num
ber o
f yea
rs
spen
t in
scho
ol
- PM
D w
as h
ighe
r (1
9.6%
with
95%
CI,
18.3
–20.
8%) i
n ev
er
user
s of H
RT c
om-
pare
d to
nev
er u
sers
(1
6.3
with
95%
CI,
15.7
–16.
8%)
- The
hig
hest
PMD
was
fo
und
in c
urre
nt H
RT
user
s (22
.6%
with
95%
C
I, 22
.1–2
3.2%
), fo
l-lo
wed
by
form
er u
sers
(1
7.7%
with
95%
CI,
17.2
–18.
2) a
nd n
ever
us
ers (
16.3
% w
ith 9
5%
CI,
15.7
–16.
8%)
- Cur
rent
E +
P u
sers
ha
d a
sign
ifica
ntly
hi
gher
PM
D 2
5.4%
(2
4.6–
26.1
%) t
han
curr
ent e
strog
en u
sers
18
.9%
(17.
6–20
.2%
) an
d ne
ver H
RT u
sers
16
.3%
(15.
7–16
.8%
)- I
n th
is st
udy,
MD
w
as m
easu
red
only
on
ce a
nd re
lied
on
cros
s-se
ctio
nal m
ean
diffe
renc
es b
etw
een
the
study
gro
ups,
rath
er th
an c
hang
es in
de
nsity
follo
win
g st
art
of H
RT u
se
561Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
(con
tinue
d)
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
Yagh
jyan
et a
l. (2
012)
[3
5]U
nite
d St
ates
Nes
ted
Cas
e–co
ntro
l3
- 522
pre
men
opau
sal
wom
en- 5
99 p
ostm
enop
ausa
l w
omen
- Age
≥ 4
0 ye
ars
- Cas
es: 2
65 w
omen
w
ith h
igh
MD
- Con
trols
: 860
wom
en
low
MD
–B
I-R
AD
S- P
arity
- Age
at fi
rst
- Chi
ld’s
birt
h w
ere
mod
eled
as c
ateg
ori-
cal w
ith th
ree
leve
ls
(par
ity 0
,1
–2, ≥
3 a
ge a
t firs
t ch
ild’s
birt
h <
20,
20
–29,
≥ 3
0)
- Pos
tmen
opau
sal
wom
en w
ith h
istor
y of
H
RT u
se h
ad in
crea
sed
odds
of h
ighe
r MD
(O
R 2
.1; 9
5% C
I 1.
4–3.
3) a
nd c
ompa
red
to p
ostm
enop
ausa
l w
omen
who
nev
er
used
HRT
- In
this
stud
y, d
ue to
th
e la
ck o
f rac
ial h
et-
erog
enei
ty, 9
9% w
ere
Whi
te-n
on-H
ispa
nic
and
ther
efor
e th
e fin
d-in
gs a
re li
mite
d to
one
ra
cial
gro
upJe
on e
t al.
(201
1) [3
2]K
orea
Cro
ss-s
ectio
n4
- 516
wom
en w
ith a
ge
rang
e be
twee
n 40
–80
year
s- 2
84 p
rem
enop
ausa
l w
omen
- 232
pos
tmen
opau
sal
–B
I-R
AD
S–
- Use
of H
RT w
as
posi
tivel
y re
late
d to
hig
her M
D, t
he
odds
of h
avin
g de
nse
brea
sts in
crea
sed
by
OR
= 2
.13
(95%
CI;
1.09
–4.1
6) fo
r wom
en
who
use
d H
RT c
om-
pare
d to
nev
er H
RT
user
s
562 Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
(con
tinue
d)
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
Boy
d et
al (
2011
)[17
]C
anad
aC
ase–
cont
rol
3- C
ase:
116
4 w
omen
w
ith b
reas
t can
cer
- Con
trol:
1155
wom
en- A
ge 4
0 to
70
year
s
–PM
D- A
ge, B
MI,
Age
at
men
arch
e- P
arity
(par
ous o
r no
npar
ous)
, Num
ber
of li
ve b
irths
- Age
at fi
rst b
irth
- Age
at m
enop
ause
(e
xcep
t in
anal
ysis
of
pre
men
opau
sal
wom
en)
- Bre
ast c
ance
r in
first-
degr
ee re
lativ
es
(non
e, o
ne, t
wo)
- Am
ong
case
s PM
D
was
gre
ater
in c
urre
nt
than
in n
ever
HRT
us
ers (
diffe
renc
e, 6
%;
p <
0.0
01) a
nd g
reat
er
in p
ast u
sers
than
in
neve
r use
rs (d
iffer
ence
3.
4%; p
= 0
.03)
- Am
ong
cont
rols
cu
rren
t use
of H
RT
was
ass
ocia
ted
with
a
slig
htly
gre
ater
mea
n PM
D (d
iffer
ence
, 1.
6%; p
= 0
.26)
than
in
nev
er u
sers
, and
pa
st us
ers o
f HRT
had
lo
wer
PM
D th
an n
ever
us
ers (
diffe
renc
e 3.
8%;
p =
0.0
1)
563Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
(con
tinue
d)
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
Che
n et
al.
(201
0) [3
0]Ta
iwan
Coh
ort
2- 4
67 p
ostm
enop
ausa
l w
omen
- Age
43–
69 y
ears
- Estr
ogen
- E +
PB
I-R
AD
S- B
MI
- Age
at m
enop
ause
- Age
at s
tart
of H
RT- D
urat
ion
from
ons
etof
men
opau
se to
the
star
t of H
RT
- The
dur
atio
n of
HRT
us
e w
as p
ositi
vely
as
soci
ated
with
in
crea
se in
MD
(p <
0.
001)
- Wom
en u
sing
E +
P,
the
prob
abili
ty
of in
crea
sed
MD
w
as p
rogr
essi
vely
in
crea
sed
as th
e du
ra-
tion
of a
dmin
istra
tion
exte
nded
(fro
m 7
.5%
to
22.
4%) b
ut n
ot in
w
omen
who
use
d es
troge
n al
one
- Wom
en u
sing
E +
P fo
r m
ore
than
4 y
ears
had
si
gnifi
cant
incr
ease
in
thei
r mea
n de
nsity
sc
ore,
com
pare
with
th
ose
usin
g on
ly
estro
gen
alon
e (p
=
0.01
3). H
owev
er, a
fter
adju
stmen
t for
effe
cts
of o
ther
var
iabl
es, t
he
asso
ciat
ion
betw
een
choi
ces o
f HRT
re
gim
ens (
E +
P v
s. es
troge
n al
one)
did
not
re
ach
the
sign
ifica
nce
leve
l
564 Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
(con
tinue
d)
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
Cra
ndal
l et a
l. (2
008)
[21]
Uni
ted
Stat
esRC
T 1
- 428
Pos
tmen
opau
sal
wom
en- A
ge ra
nge
45–6
4 ye
ars
- Estr
ogen
alo
ne- C
EP- S
EP
PMD
- Bas
elin
e m
amm
o-gr
aphi
c de
nsity
- Age
- BM
I- C
hang
e in
BM
I (1
2 m
onth
s min
us
base
line)
- Dai
ly a
lcoh
ol in
take
- Par
ity (n
one
vers
us
1–2
vers
us ≥
3 p
reg-
nanc
ies)
- Cig
aret
te sm
okin
g (c
urre
nt v
ersu
s not
cu
rren
t)- E
thni
city
(Cau
casi
an
vers
us n
ot C
auca
-si
an)
- Phy
sica
l act
ivity
- Age
at fi
rst p
reg-
nanc
y
- The
mea
n se
rum
es
troge
n su
lfate
(E1S
) le
vel c
hang
ed a
fter 1
2 m
onth
s com
pare
to
base
line
leve
l was
1.9
3 ng
/mL
for e
strog
en
alon
e us
ers,
and
the
diffe
renc
e w
as m
ore
pron
ounc
ed in
E +
P
user
s 2.4
9 ng
/mL
(p
=0.
02)
- Cha
nge
in E
1S le
vel
and
chan
ge in
MD
af
ter 1
2 m
onth
s w
ere
sign
ifica
ntly
po
sitiv
ely
corr
elat
ed
(p =
0.0
001)
. Thi
s is
for e
very
1 n
mol
/L
incr
ease
in E
1S
leve
l at 1
2 m
onth
s fo
llow
-up,
PM
D w
as
1.3%
hig
her.
E1S-
MD
as
soci
atio
n w
as m
ore
poun
ced
in w
omen
ta
king
SEP
com
pare
to
estro
gen
alon
e us
ers
The
incr
ease
in P
MD
w
as 0
.5%
(SD
, 5.1
%)
amon
g ne
ver H
RT
user
s, 1.
2% (S
D, 7
.5%
) am
ong
estro
gen
alon
e us
ers,
4.9%
(SD
, 8.7
%)
amon
g SE
P us
ers,
and
4.7%
(SD
, 10.
8%)
amon
g C
EP u
sers
Cha
nge
in P
MD
was
si
gnifi
cant
ly m
ore
pro-
noun
ced
amon
g E
+ P
us
ers t
han
estro
gen
alon
e us
ers
565Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
(con
tinue
d)
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
Har
vey
et a
l. (2
008)
[24]
Uni
ted
Stat
esC
ase–
cont
rol
- Cas
e: 2
8pos
tmen
o-pa
usal
wom
en u
sing
H
RT- C
ontro
ls: m
atch
ed
with
28
postm
eno-
paus
al w
omen
not
us
ing
HT
at th
e tim
e of
bre
ast c
ance
r di
agno
sis
- Age
rang
e: 4
5–84
ye
ars
PMD
- Age
- HRT
stat
us- T
here
was
a st
atist
i-ca
lly si
gnifi
cant
diff
er-
ence
in b
reas
t den
sity
no
ted
betw
een
the
HRT
use
rs a
nd n
ever
H
RT u
sers
gro
ups (
p <
0.
0001
) with
a m
edia
n di
ffere
nce
in M
D 5
4%
for H
RT u
sers
and
31
% fo
r non
-HRT
us
ers
- Per
cent
fibr
ous s
tom
a w
as 7
% h
ighe
r for
H
RT u
sers
com
pare
d w
ith n
on-H
RT u
ser;
how
ever
, the
diff
er-
ence
was
not
stat
isti-
cally
sign
ifica
nt.
- Inc
reas
ing
MD
in
wom
en u
sing
HRT
w
as a
ssoc
iate
d w
ith
incr
ease
d fib
rous
str
oma
(p =
0.0
2)
566 Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
(con
tinue
d)
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
Dui
jnha
ven
et a
l. (2
007)
[27]
Ned
erla
nd a
nd U
KC
ohor
t2
From
Net
herla
nd- 6
20 H
RT u
sers
- 620
nev
er H
RT u
sers
w
ith- A
ge ra
nge
betw
een
49–6
9 ye
ars
From
UK
- 175
HRT
use
rs- 1
61 n
ever
HRT
use
rs- A
ge 5
1 to
71
year
s
- Estr
ogen
- E +
PPM
D- T
ype
of H
RT u
se (n
o H
RT u
se, E
T us
e,
com
bine
d H
RT u
se,
or ti
bolo
ne u
se)
- Den
sity
at fi
rst m
am-
mog
ram
- Age
, BM
I- A
ge a
t men
arch
e- P
arity
/age
at fi
rst f
ull
term
pre
gnan
cy (n
ul-
lipar
ous,
≤ 2
5 ye
ars,
and
≥ 2
5 ye
ars)
- Men
opau
sal s
tatu
s (P
rem
enop
ausa
l, pe
rimen
opau
se/p
ost-
men
opau
sal)
- Fam
ily h
istor
y of
br
east
canc
er- P
revi
ous o
ral c
ontra
-ce
ptiv
e us
e- S
mok
ing
(0, <
5,
5–15
and
≥ 1
5 pa
ck-
year
s)- A
lcoh
ol c
onsu
mpt
ion
- Phy
sica
l act
ivity
(in
activ
e, m
oder
atel
y in
activ
e, m
oder
atel
y ac
tive,
act
ive)
- Stu
dy p
opul
atio
n (P
rosp
ect-E
PIC
/EP
IC-N
orfo
lk)
- PM
D a
t the
firs
t m
amm
ogra
m w
as
low
er fo
r nev
er H
RT
user
s (37
.0%
) tha
n fo
r es
troge
n al
one
user
s (3
9.3%
) and
E +
P
(46.
1%).
The
dens
e ar
ea a
t firs
t mam
mo-
gram
was
low
er fo
r ne
ver H
RT u
sers
(40.
6 cm
2 ) tha
n fo
r estr
ogen
al
one
user
s (45
.9 c
m2 )
and
E +
P u
sers
(50.
8 cm
2 )- A
t the
seco
nd m
am-
mog
ram
the
abso
lute
m
ean
dens
ity w
as
low
er fo
r nev
er H
RT
user
s (31
.7%
) tha
n fo
r es
troge
n al
one
user
s (3
2.6%
) and
E +
P
(35.
6%).
The
dens
e ar
ea a
t the
seco
nd
mam
mog
ram
s was
lo
wer
for n
ever
HRT
us
ers (
38.0
8 cm
2 ) tha
n es
troge
n al
one
user
s (4
0.78
cm
2 ) and
E +
P
user
s (41
.93
cm2)
. The
m
edia
n be
twee
n th
e fir
st an
d se
cond
mam
-m
ogra
m w
as 3
yea
rs- L
onge
r use
of H
RT (>
1
year
) app
eare
d to
ha
ve a
larg
er e
ffect
on
MD
than
shor
ter u
se
of H
RT (<
1 y
ear)
567Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
(con
tinue
d)
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
Aie
llo e
t al.
(200
6)
[28]
Uni
ted
Stat
esC
ross
-sec
tion
4- 3
9,29
6 po
stmen
o-pa
usal
- Age
≥ 4
0 ye
ars
- Estr
ogen
- E +
PB
I-R
AD
S- A
ge a
t mam
mog
ram
- BM
I- A
ge a
t firs
t birt
h (5
-yea
r int
erva
ls)
- Typ
e of
men
opau
se
(nat
ural
, bila
tera
l oo
phor
ecto
my
with
or
with
out h
yste
rec-
tom
y, h
yste
rect
omy
only
, hys
tere
ctom
y w
ith u
nkno
wn
ooph
orec
tom
y, a
nd
othe
r)
- The
Odd
s of h
avin
g de
nse
brea
st in
crea
sed
sign
ifica
ntly
in c
urre
nt
HRT
use
rs b
y O
R 1
.91
(95%
CI,
1.81
–2.0
0)
and
for f
orm
er H
RT
user
s inc
reas
ed
by 1
.14
(95%
CI,
1.08
–1.2
1) c
ompa
red
to n
ever
HRT
use
rs- C
urre
nt E
+ P
use
rs h
ad
sign
ifica
nt in
crea
se in
od
ds o
f hav
ing
dens
e br
easts
(OR
1.9
8;
95%
CI 1
.87–
2.09
) an
d es
troge
n al
one
user
s had
sign
ifica
nt
incr
ease
in th
e od
ds o
f ha
ving
den
se b
reas
ts
by (O
R 1
.71;
95%
CI
1.56
–1.8
7) c
ompa
red
to n
ever
HRT
use
rs- I
n th
is st
udy,
the
study
po
pula
tion
is la
rgel
y w
hite
, whi
ch m
ay li
mit
the
gene
raliz
abili
ty
of th
e re
sults
to o
ther
ra
ce
568 Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
(con
tinue
d)
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
Cra
ndal
l et a
l. (2
006)
[2
2]U
nite
d St
ates
RCT
1- 8
75 p
ostm
enop
ausa
l w
omen
- Age
d 45
to 6
4 ye
ars
- 1-y
ear f
ollo
w-u
p stu
dy
- Estr
ogen
- CEP
- SEP
PMD
- Age
- Par
ity- A
ge a
t firs
t pre
g-na
ncy
- BM
I- A
lcoh
ol in
take
- Sm
okin
g- E
thni
city
- Bas
elin
e PD
- Tre
atm
ent a
ssig
n-m
ent (
Plac
ebo,
co
njug
ated
equ
ine
estro
gens
, or
prog
estin
-con
tain
ing
regi
men
)
- At 1
2 m
onth
s mea
n PM
D h
ad si
gnifi
cant
ly
incr
ease
d in
SEP
and
C
EP u
sers
by
4.6%
an
d 4.
4%, r
espe
ctiv
ely
- The
cha
nge
in P
MD
w
as 4
.0%
in th
e pr
oges
tin-c
onta
inin
g ar
ms,
and
it w
as si
g-ni
fican
tly h
ighe
r tha
n th
at in
estr
ogen
alo
ne
arm
p =
0.00
1 an
d in
th
e pl
aceb
o ar
m (p
<
0.00
1)- M
ean
PMD
incr
ease
d in
estr
ogen
alo
ne
user
s afte
r 12
mon
ths
follo
w-u
p by
0.9
%
com
pare
d to
pla
cebo
ar
m; h
owev
er, t
he
resu
lt is
not
sign
ifica
nt
(p =
0.25
)B
oyd
et a
l. (2
006)
[16]
Can
ada
Cas
e–co
ntro
l3
- 174
8 po
stmen
opau
sal
wom
en- C
ases
: 365
wom
en
who
had
dev
elop
ed
inva
sive
bre
ast
canc
er a
t lea
st 12
m
onth
s afte
r the
in
itial
scre
en.
- Mat
ched
con
trols
: 87
9 co
ntro
ls- A
ge ≥
50
year
s
–PM
D- A
ge, B
MI-
Age
at
men
arch
e- P
arity
- Num
ber o
f liv
e bi
rths
- Age
at fi
rst b
irth
- Age
at m
enop
ause
- Bre
ast c
ance
r in
first-
degr
ee re
lativ
es (0
, 1,
2+
)
- Per
cent
den
sity
in th
e ba
selin
e m
amm
ogra
m
was
am
ong
case
s gr
eate
r in
curr
ent u
sers
of
hor
mon
es th
at in
ne
ver u
sers
(diff
eren
ce
= 5
.0%
, p <
0.0
01),
but t
he d
iffer
ence
w
as sm
alle
r and
no
sign
ifica
nt in
con
trols
(d
iffer
ence
= 1
.6%
, p
= 0
.3)
- Ave
rage
PM
D
incr
ease
d si
gnifi
-ca
ntly
with
incr
eas-
ing
expo
sure
to H
RT
amon
g ca
ses,
but n
ot
in c
ontro
ls
569Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
(con
tinue
d)
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
Topa
l et a
l. (2
006)
[34]
Turk
eyC
ohor
t2
113
postm
enop
ausa
l w
omen
- Age
≥ 5
0 ye
ars
- Estr
ogen
alo
ne- C
EP- S
EP
-BI-
RA
DS
-- I
n to
tal 2
6 w
omen
sh
owed
MD
incr
ease
af
ter H
RT u
se. A
t fir
st m
amm
ogra
phy,
24
wom
en (9
2.3%
) sh
owed
incr
ease
in
MD
and
in se
cond
m
amm
ogra
phy,
2
wom
en (7
.7%
) sho
wed
M
D- 2
3 w
omen
(38.
3%)
of C
EP, 2
wom
en
(12.
5%) o
f SEP
, and
1
wom
an (2
.7%
) of
estro
gen
alon
e us
er
show
ed in
crea
se in
M
D- I
ncre
ase
in M
D w
as
mor
e co
mm
on a
mon
g w
omen
with
CEP
than
ot
her g
roup
s of H
RT
(p =
0.0
009)
- Wom
en w
ere
exam
ined
ac
cord
ing
to th
e pr
oges
tin d
ose,
in th
e C
EP u
sers
60%
of
wom
en w
ith h
ighe
r pr
oges
tin d
ose
(5m
g/da
y) re
veal
ed a
MD
in
crea
se, o
nly
16.7
%
of w
omen
with
lo
wer
pro
gesti
n do
se
(2.5
mg/
day)
incr
ease
M
D. T
he d
iffer
ence
be
twee
n th
ese
two
grou
ps w
ere
stat
isti-
cally
sign
ifica
nt (p
<
0.05
)
570 Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
(con
tinue
d)
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
McT
iera
nan
et a
l (2
005)
[26]
Uni
ted
Stat
esRC
T 1
- 413
pos
tmen
opau
sal
wom
en- A
ge ra
nge
50–7
9 ye
ars
CEP
PMD
- Tre
atm
ent a
ssig
n-m
ent
- Mam
mog
raph
ic d
en-
sity
at b
asel
ine
and
chan
ge in
den
sity
at
follo
w-u
p- B
asel
ine
char
acte
ris-
tics (
age,
bod
y m
ass
inde
x, a
nd ra
ce/
ethn
icity
)
- Mea
n PM
D w
as
incr
ease
d by
6.0
%
at y
ear 1
in C
EP b
ut
decr
ease
d in
nev
er
HRT
use
rs (p
<
0.00
1). A
fter 2
yea
rs,
the
mea
n ch
ange
s in
PMD
incr
ease
d by
4.
9% in
CEP
gro
up
and
decr
ease
d by
0.8
%
in n
ever
HRT
use
rs.
- App
roxi
mat
ely
75%
of
the
wom
en a
ssig
ned
to
CEP
gro
up e
xper
i-en
ced
an in
crea
se in
PM
DM
arch
eson
i et a
l. (2
005)
[4]
Italy
RCT
1- 1
03 p
ostm
enop
ausa
l w
omen
- Age
rang
e 47
–56
year
s- 1
- yea
r fol
low
-up
study
CEP
Wol
fe–
- Afte
r 12
mon
ths o
f H
RT 1
6 ou
t to
35
(45.
1%) o
f CEP
use
rs
had
incr
ease
d in
MD
co
mpa
red
to n
ever
H
RT u
sers
and
resu
lts
wer
e hi
ghly
sign
ifica
nt
(p <
0.0
01)
571Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
(con
tinue
d)
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
Hen
g et
al.
(200
4) [2
5]Si
ngap
ore
Cro
ss-s
ectio
n- 2
9,19
3 w
omen
- Age
45–
69 y
ears
–PM
D- A
ge- A
ge a
t men
arch
e- M
enop
ause
- Eve
r use
of O
Cs o
r H
RT- S
mok
ing
- Fam
ily h
istor
y of
br
east
canc
er- H
eigh
t, w
eigh
t- P
arity
- Age
at fi
rst d
eliv
ery
- Men
opau
sal s
tatu
s- H
istor
y of
a b
reas
t bi
opsy
- Use
of H
RT w
as
asso
ciat
ed w
ith h
ighe
r PM
D b
y 4.
4% a
nd
dura
tion
of u
sing
HRT
w
as a
lso
sign
ifica
ntly
as
soci
ated
with
hig
her
PMD
by
0.07
% w
ith
p =
0.0
01 in
age
-ad
juste
d an
alys
is b
ut
not i
n m
ultiv
aria
te
anal
ysis
- HRT
use
was
pos
i-tiv
ely
asso
ciat
ed w
ith
incr
ease
den
se a
rea
in
brea
sts b
y 3.
61 (c
m2 )
and
dura
tion
of H
RT
was
ass
ocia
ted
with
in
crea
se th
e de
nse
area
by
0.0
6 (c
m2 ) w
ith p
=
0.0
1 in
age
-adj
uste
d an
alys
is b
ut n
ot in
m
ultiv
aria
te a
naly
sis
572 Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
(con
tinue
d)
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
Gre
enda
leet
al.
(200
3) [3
1]U
nite
d St
ates
RCT
1- 5
71 p
ostm
enop
ausa
l w
ith- A
ge ra
nge
45–6
4 ye
ars
- Estr
ogen
- SEP
- CEP
BI-
RA
DS
- Mam
mog
raph
ic
perc
ent
dens
ity a
t bas
elin
e- B
MI
- Dai
ly g
ram
s of a
lco-
hol c
onsu
med
- Cig
aret
te sm
okin
g- L
evel
s of p
hysi
cal
activ
ity- 1
2-m
onth
cha
nge
in
BM
I- R
ando
miz
atio
n an
d bl
ocki
ng v
aria
ble
(i.e.
, clin
ic si
te a
nd
hyste
rect
omy
stat
us)
-Afte
r 12
mon
ths
follo
w-u
p th
e ab
solu
te
mea
n ch
ange
s in
MPD
w
ere
obse
rved
in C
EP
and
SEP
user
s; 4
.76%
(9
5% C
I 3.2
9–6.
23%
) an
d 4.
58%
(95%
CI
3.19
–5.9
7%) r
espe
c-tiv
ely.
No
chan
ges i
n M
D w
as o
bser
ved
in
estro
gen
user
s com
-pa
red
to n
ever
HRT
us
ers
-A m
odes
t 3–5
%
incr
ease
in M
PD
was
obs
erve
d am
ong
wom
en w
ho w
ere
treat
ed w
ith c
ombi
na-
tion
HRT
and
thos
e in
crea
ses d
id n
ot d
iffer
by
pro
gesti
n fo
rmul
a-tio
n or
sche
dule
Gap
stur e
t al.
(200
3)[2
3]U
nite
d St
ates
Cro
ss-s
ectio
n4
- 296
His
pani
c w
omen
- Age
rang
e ≥
40
year
s- P
rem
enop
ausa
l w
omen
(n =
105
)- P
ostm
enop
ausa
l w
omen
(n =
191
)
–PM
D–
- PM
D w
as si
gnifi
cant
ly
high
er fo
r pos
tmen
o-pa
usal
wom
en w
ho
curr
ently
use
HRT
co
mpa
red
to n
ever
/pas
t us
ers;
this
diff
eren
ce
was
3.3
% (p
= 0
.03)
573Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Tabl
e 1
(con
tinue
d)
Aut
hor,
year
Cou
ntry
Stud
y de
sign
Qua
lity
of st
udy
desi
gn
Sam
ple
size
and
cha
r-ac
teris
tics
HRT
regi
men
sM
D a
sses
smen
tC
onfo
unde
rs in
clud
ed
in th
e fin
al a
naly
sis
Resu
lts/F
indi
ngs
Chr
istod
oula
kos e
t al.
(200
3) [3
6]G
reec
eC
ohor
t2
- 121
pos
tmen
opau
sal
wom
en- A
ge 3
8–66
yea
rs- 1
-yea
r fol
low
-up
study
- Estr
ogen
alo
ne- C
EPW
olfe
-- M
D d
id n
ot in
crea
se in
ne
ver H
RT u
sers
afte
r 12
mon
ths o
f fol
low
-up
. Tw
o w
omen
(8%
) in
estr
ogen
alo
ne
grou
p sh
owed
an
incr
ease
in M
D- F
our w
omen
(11.
8%)
in C
EP g
roup
show
ed
incr
ease
in M
D. T
he
resu
lts su
gges
ted
that
H
RT m
ay su
spen
d br
east
invo
lutio
n bu
t do
es n
ot in
crea
se M
D
in m
ajor
ity o
f wom
en.
In th
e m
inor
ity o
f pa
tient
s who
show
a
dens
ity in
crea
se,
the
mag
nitu
de o
f thi
s in
crea
se v
arie
s acc
ord-
ing
to th
e re
gim
en
used
574 Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Evidence-based Medicine – Levels of Evidence (OCEBM) hierarchy [15]. The OCEBM levels is a widely used system, which categories studies into different levels ranging from 1 to 5 based on their study designs; it helps the researcher to evaluate the reported results. In The OCEBM system, levels 1, 2, 3, 4 and 5 represent well-designed and high quality RCTs, prospective and retrospective cohort studies, case–control studies, cross-sectional and case-series stud-ies, and expert opinion or unpublished clinical observations, respectively [15]. Level 1 is the highest quality and level 5 is the lowest [15]
Data extraction
Data extraction included the information about author and year of publication, country, study design, quality of study design, sample size and characteristics of the participants, HRT regimens, MD assessment, confounders included in the final analysis, final results and findings are included in Table 1 from each study. The term “progestin” has been used to replace all progesterone synthetic names, such as progestogen and progesterone.
Results
Study characteristics
The initial search identified 6676 articles. Of these, 6331 were removed due to duplication. Of the remaining 345 articles, 250 were excluded as not relevant based on thor-ough review of titles and abstracts, and 95 were preselected for further evaluation. Of the 95 remaining articles, 72 did not fulfill the inclusion criteria (Fig. 1). Thus, only 22 arti-cles published between 2002 and 2019 (6 cohort, 6 RCT, 5 case–control and 5 cross-sectional studies) were selected. These 22 studies were conducted in North America (n = 12), Europe (n = 6), and Asia (n = 4) (Table 1).
In all 22 included studies, at least one of the three main methods of MD assessment (PMD, BI-RADS and Wolfe) was used. 12 studies used PMD [16–27], 8 studies used BI-RADS [28–35], and 2 studies assessment MD according to the Wolfe criteria [4, 36].
State of HRT exposure and MD
Ever and never HRT users
From all 22 studies, there were n = 12 (54.5%) which inves-tigated the association between ever and never use of HRT and MD [4, 20–22, 26, 27, 31–33, 36]. All these studies reported a significant increase in MD among ever HRT users
Fig. 1 Flow chart of the search and selection process for arti-cles included in the systematic review
Literature search
(6,676 articles identified)
Databases: PubMed (n= 6,020), OVID
(n=600), and Embase (n=56)
Number of duplications (n= 6,331)
Number of removed articles on the
basis of title and abstract (n= 250)
95 preselected papers
73 articles were excluded for the following
reasons:
- 29 citations were not full-text
- 10 citations were review papers
- 25 studies were not RCT, cohort, case
control, or cross-sectional
- 9 studies used different methods than
BI-RADS, PMD, and Wolfe for
assessment of MD
22 articles selected by eligibility criteria
and included in the systematic review
575Breast Cancer Research and Treatment (2020) 182:555–579
1 3
compare to never users; however, the results from two stud-ies did not reach the statistical significance (Table 1) [22, 25]. In a RCT of 695 postmenopausal women, at 1-year follow-up the PMD change from the baseline was 1.4% for estrogen users and -0.8% for placebo group with a signifi-cant increase in MD among women assigned to HRT than women assigned to placebo [20]. In a case–control study, Harvey et al. showed that there is a statistically significant difference in MD among HRT ever and never users groups (p-value < 0.001) with a median difference in MD 54% for ever HER users and 31% for never users. They reported that percent fibrous stroma was 7% higher for ever users com-pared to never users; however, the result was not statisti-cally significant [24]. In another case–control study, Jeon et al. found positive association between HRT and MD. The odds of having dense breasts increased by 2.13; 95% CI (1.09–4.16) for women who used HRT compared to never users [32].
Former, current and never HRT users
Five studies examined the association between HRT use and MD among former, current and never HRT users [16, 17, 19, 23, 28]. Three studies showed that MD increased in current HRT users compared to former and never users. Aiello et al. in a cross-sectional study of 39,296 women reported that odds of having high MD increased significantly in women who were the current HRT users (OR 1.91; 1.81–2.00) and former (OR 1.14; 1.08–1.21) as compared to never users [28]. Couto et al. have in a cross-sectional study of 2,424 postmenopausal women found that PMD was highest in cur-rent HRT users followed by former and never users with breast densities of 22.6%, 17.7%, and 16.3%, respectively [19]. Additionally, Gapstur et al. in a small cross-sectional study of 296 Hispanic women found that mean PMD was significantly higher in current HRT users than in former and never HRT users: 18.2%, 14%, and 14% (p-value = 0.02), respectively [23].
In a case–control study Boyed et al. showed that mean PMD among cases was greater in current HRT users than in never users (difference, 6%; p-value < 0.001) and greater in former users than never users (difference, 3.4% p-value 0.03). Among controls, current use of HRT was associated with a slightly greater mean PMD; however, the results were not statistically significant [17]. In another case control study, Boyd et al. found that among cases, mean PMD was greater in current (25.1%) and former (28.1%) HRT users than in never users (30.7%; p-value < 0.001). However, among controls the results were not statistically significant [16].
Finally, a study which examined the effect of HRT on MD among postmenopausal women who previously used HRT and women who never used HRT and that postmenopausal
women with history of HRT use had increased odds of hav-ing higher MD (OR 2.1; 1.4–3.3) compared to never HRT users [35].
HRT regimens and MD
Different HRT regimens were addressed in 14 (63.6%) stud-ies [4, 18–22, 26–31, 34, 36]. Five studies compared the effect of estrogen alone and E + P on MD [19, 20, 27, 28, 30], six studies compared the effect of estrogen alone, CEP, and SEP regimens on MD [21, 22, 29, 31, 34, 36]. Finally, three studies assessed the effect of CEP use on MD com-pared to never HRT use [4, 18, 26] (Table 1).
Estrogen alone versus E + P
The results from all five studies showed that E + P users had higher MD compared to estrogen alone users [19, 20, 27, 28, 30]. In a RCT of 695 postmenopausal women, Crandall et al. found that at 1-year follow-up changes in PMD were statistically greater among women assigned to E + P than women assigned to estrogen alone (p-value = 0.001) [20]. A cohort study of 1240 postmenopausal women showed that PMD at the first and second mammograms were higher in E + P users than in estrogen alone and never HRT users [27]. Additionally, in a large cross-sectional study of 39,296 postmenopausal women, Aiello et al. reported that current E + P users had significantly increased odds of having dense breasts (OR 1.98; 1.87–2.09) followed by estrogen alone users (OR 1.71, 1.95–1.87) compared to never HRT users [28]. Couto et al. have in a cross-sectional study showed that current E + P users had significantly higher PMD (25.4%) than current estrogen (18.9%) and never users (16.3%) [19]. Finally a small retrospective study of 467 postmenopausal study showed that women using E + P more than 4 years had significantly higher mean MD compared to women who used estrogen only (p-value = 0.01); however, after adjustment for other variables the association between MD and HRT regi-mens diminished [30].
Estrogen alone versus CEP and SEP
From six studies which compared the association between estrogen alone, CEP, and SEP regimens on MD [21, 22, 29, 31, 34, 36], four studies showed that CEP users had signifi-cantly higher MD compared to SEP and estrogen alone users [29, 31, 34, 36]. In a RCT study of 571 postmenopausal women randomly assigned to receive placebo, daily estrogen alone, SEP, or CEP, after 12 months of follow-up the abso-lute mean increase in PMD was observed in CEP and SEP users; 4.76% and 4.48%, respectively. No changes in MD were observed in estrogen alone users compared to never HRT users [31]. Additionally, in a retrospective study of
576 Breast Cancer Research and Treatment (2020) 182:555–579
1 3
113 of healthy postmenopausal women, Topal et al. showed that 38.3% of CEP users, 12.5% of SEP users and 2.7% of estrogen alone users had increased in MD. Increase in MD was more pronounced among CEP users than other regimens of HRT (p-value = 0.009) [34]. Finally, Carmona-Sanchez et al. reported that after 5 years of HRT use, MD increased significantly in 21.8% women receiving SEP versus 38.8% of women receiving CEP (p-value = 0.039) [29].
Two studies showed that SEP users had slightly higher MD compared to CEP and estrogen alone users. In a RCT study by Crandall et al. at 12 months, PMD was significantly increased in SEP users by 4.6% and in CEP users by 4.4% [22]. In another RCT by Crandall et al. increase in PMD was 1.2% among estrogen users, 4.7% among CEP users, and 4.9% among SEP users [21].
CEP users versus never HRT users
Three studies addressed the increase in MD among CEP users compared to never HRT users. In a RCT study of 103 postmenopausal women, after 12 months 45.1% of CEP users had increased in MD, whereas no changes was observed among never HRT users. The difference between CEP users and never users were statistically significant (p-value < 0.001). In another RCT study of 413 postmen-opausal women, McTiernan et al. reported an increase in mean PMD by 6% and decrease in MD in placebo group (p-value < 0.001) after 1-year follow-up. Finally a case–con-trol study by Byrne et al. showed that women assigned to CEP group had a larger and boarder distribution of MD change (mean change = 9.49%) compared to women in never HRT/placebo group. Women assigned to placebo group experienced decrease in MD over 1 year (mean change = − 0.65%) after adjusting for possible confounders [18].
Discussion
Our review is the first to systematically investigate the asso-ciation between HRT and MD, comparing different status of HRT exposure and MD, and finally reporting the effect of different HRT regimens on MD. A consistent finding in the literature is that MD was increased in ever HRT users compared to never users. Furthermore, the highest increase in MD was observed in current HRT users compared to never users [16, 17, 19, 23, 28]; in line with previous stud-ies published before 2003 [37, 38]. Marugg et al. found that, compared to never HRT users, 14.3% of women using HRT showed an increase in MD [37]. Another study concluded that current HRT users were more than twice as likely to have higher MD as never users (OR 2.48; 1.32–4.16) [38].
All selected studies which compared the effect of estrogen alone and E + P on MD showed that E + P users had a higher MD compared to estrogen alone users [19, 20, 27, 28, 30]. Similar to this result, previous studies showed a strong posi-tive association between E + P use and increase in MD [37, 39]. According to Marugg et al. 31% of women treated with E + P showed an increase in MD compared with only 8.7% in the group treated with estrogen alone [37]. Vachon et al. found that odds of having higher MD increased in women using E + P by 1.9 compared to women using estrogen alone [39].
Among the studies which provided data on the sub-type of HRT regimens (CEP, SEP and estrogen alone), four stud-ies reported that women who used CEP, where both estrogen and progestin are taken daily, had higher MD than women who used SEP, where estrogen is used daily but progestin is taken only during a certain time of the month and estrogen alone users [29, 31, 34, 36]. These results are in agreement with the results from other studies that examined the associa-tion between HRT and MD with respect to sub-types HRT regimens [40, 41]. In a Swedish study of 31,498 women, Persson et al. has found that MD was significantly increased in 28% of CEP users, 10% of SEP and 5% of estrogen alone users [41]. Another Swedish study by Lundstrom et al. reported that MD was greater among CEP users (52%) than SEP users (13%), estrogen alone users (18%) over 2 years of follow-up [40]. However, two studies showed that SEP users had slightly higher MD compared to CEP and estrogen alone users [21, 22]. It is important to mention that, different HRT regimens influence MD change differently but the mecha-nism for MD change among CEP and SEP users remain to be unclear. Lundstrom et al. claimed that the inconsistent result on the association between CEP and SEP users with MD maybe due to variation in progestin components, dos-age, and duration of administration [40].
The biological explanation in increasing MD with respect to HRT use is not yet fully understood. However, one estab-lished hypothesis to explain the increase of MD in relation to use of HRT is based on the breast cell proliferation theory. In menstruating women, it has been observed that breast epi-thelial cell proliferation is increasing due to high levels of estrogen and progestin [42]. In a cross-sectional study of 56 pre- and 86 postmenopausal women, Hofseth et al. found that, use of HRT especially E + P is associated with higher level of breast epithelial cell proliferation in post- and premenopausal women compared to never HRT users [43]. Breast epithelial cell proliferation is also known as epithelial hyperplasia which defines as abnormal growth and accumulation of cells that line the ducts or the lobules in the breasts [44]. Hofseth et al. also found that breast epithelial cell density was significantly higher in women using HRT, especially in E + P users than estrogen alone and never HRT users [43]. Another hypothesis to explain the association between increasing MD with respect to use
577Breast Cancer Research and Treatment (2020) 182:555–579
1 3
of E + P is the stromal oedema theory. Stroma is the major tissue in the breasts therefor any changes in MD primarily reflect alteration of the stroma architecture and composition [44]. Longacre et al. found that stromal oedema is greater in the luteal phase of menstrual cycle which progestin is the main hormone associated with this stage [45]. Therefore receiving E + P should lead to greater MD than estrogen alone.
To our knowledge, this is the first systematic review, which studied not only the effect of different states of HRT expo-sure on MD but also the effect of different HRT regimens on MD. Strengths of our study are all studies included in this review appropriately reported their study design (RCT, cohort, case–control, and cross-sectional), inclusion criteria, and sam-pling methods. Sample size was quite large in observational studies and adequate samples were also reported in several RCT studies. Ethical considerations were reported according to the international standards in 18 papers [4, 16–24, 26–28, 31–33, 35, 36]. Most of studies addressed potential confound-ers, biases and a discussion of limitations. To minimize bias, in this review we used PRISMA checklist and follow chart to ensure transparency and completeness of the reporting (Sup-plementary material 1). In addition, we assess the quality of each eligible study based on their study designs using the OCEBM hierarchy. Another important strength of this review is that the results can be generalized since the selected stud-ies were from different geographical regions (North America, Europe, and Asia) and these studies presented diverse ethnic groups (Asian, Hispanic, and White). Finally, this review included only peer-reviewed studies, since including unpub-lished and gray literature increase the risk of publication bias due to the absence of peer-review and low methodological quality. Moreover, the authors did not include their personal opinion or prior knowledge during the review process in order to avoid publication bias.
There are some limitations regarding the studies included in this review. By far the most common limitations men-tioned in included studies were; misclassification in the assessment of MD, small sample size, unknown HRT com-position, and lack of racial heterogeneity. Other limitations regarding this study are the search for the qualified articles was conducted only in English language, only articles that were accessible electronically were included, and this review found studies with different methodological designs, sample size and demographic factors, therefore due to methodologi-cal heterogeneity between studies included in this review it was not possible to conducted a meta-analysis.
Conclusions
In conclusion, this review showed that MD significantly increased in ever HRT users compared to never users with highest increase in MD among current HRT users.
Furthermore, this review found that E + P users had a higher MD compared to estrogen alone users. Results with regards to HRT regimens and MD showed that CEP users had the highest increase in MD followed by SEP users and estrogen alone.
The findings from this systematic review on the asso-ciation between HRT use and MD can be used in primary prevention of breast cancer incidence as well as secondary prevention of false-negative diagnosis of small tumours. From the primary prevention perspective, our results sug-gest that the use of HRT should be minimized at the low-est does needed for as short time as possible. In addition, from the secondary prevention perspective, women who are current HRT users and increase in MD is detected by mammography screening may require additional screening procedures, shorter screening intervals, and using advanced imaging techniques such as MRI/ultrasound for detecting small tumours.
Acknowledgements Open access funding provided by Karolinska Institute.
Funding This study received funding from “University of Southern Denmark – School of Public Health” The funding had no role in the study design, data collection and data interoperation, in writing of the manuscript or in the decision to submit the manuscript for publication. The authors declare that they have no conflict of interest.
This article does not contain any studies with human participants performed by any of the authors.
Compliance with ethical standards
Conflict of interest The authors declare that have no conflict of interest
Informed consent As this study was a systematic review and we did not involve contact with individual women it was not applicable for informed consent to be obtained.
Open Access This article is licensed under a Creative Commons Attri-bution 4.0 International License, which permits use, sharing, adapta-tion, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/.
Appendix
An example of the search strategy used in one of the search databases.
578 Breast Cancer Research and Treatment (2020) 182:555–579
1 3
Search strategy for PubMed
Restriction used: English Language, year July 2002 to 2019
1. Search (hormone replacement therapy) and mammo-graphic density
2. (Hormone replacement therapy) and breast density 3. (Postmenopausal hormone replacement therapy) and
mammographic density 4. (Postmenopausal hormone replacement therapy) and
breast density 5. (Estrogen-progestin hormone replacement therapy) and
mammographic density 6. (Estrogen-progestin hormone replacement therapy) and
breast density 7. (Combined hormone replacement therapy) and mam-
mographic density 8. (Combined hormone replacement therapy) and breast
density 9. (HRT) and mammographic density 10. (HRT) and breast density 11. (Estrogen alone hormone replacement therapy) and
mammographic density 12. (Estrogen alone hormone replacement therapy) and
breast density.
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