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source: https://doi.org/10.7892/boris.94180 | downloaded: 22.10.2021
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Climacteric
ISSN: 1369-7137 (Print) 1473-0804 (Online) Journal homepage: http://www.tandfonline.com/loi/icmt20
The impact of micronized progesterone on theendometrium: a systematic review
P. Stute, J. Neulen & L. Wildt
To cite this article: P. Stute, J. Neulen & L. Wildt (2016) The impact of micronizedprogesterone on the endometrium: a systematic review, Climacteric, 19:4, 316-328, DOI:10.1080/13697137.2016.1187123
To link to this article: http://dx.doi.org/10.1080/13697137.2016.1187123
© 2016 The Author(s). Published by InformaUK Limited, trading as Taylor & FrancisGroup.
Published online: 09 Jun 2016.
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REVIEW
The impact of micronized progesterone on the endometrium:a systematic review
P. Stutea, J. Neulenb and L. Wildtc
aDepartment of Obstetrics and Gynecology, University of Bern, Switzerland; bClinic for Gynecological Endocrinology and ReproductiveMedicine, RWTH University of Aachen, Germany; cDepartment of Gynecological Endocrinology and Reproductive Medicine, Medical Universityof Innsbruck, Austria
ABSTRACTPostmenopausal women with an intact uterus using estrogen therapy should receive a progestogen forendometrial protection. International guidelines on menopausal hormone therapy (MHT) do not specifyon progestogen type, dosage, route of application and duration of safe use. At the same time, the debateon bioidentical hormones including micronized progesterone increases. Based on a systematic literaturereview on micronized progesterone for endometrial protection, an international expert panel’s recom-mendations on MHT containing micronized progesterone are as follows: (1) oral micronized progesteroneprovides endometrial protection if applied sequentially for 12–14 days/month at 200 mg/day for up to 5years; (2) vaginal micronized progesterone may provide endometrial protection if applied sequentially forat least 10 days/month at 4% (45 mg/day) or every other day at 100 mg/day for up to 3–5 years (off-labeluse); (3) transdermal micronized progesterone does not provide endometrial protection.
ARTICLE HISTORYReceived 4 March 2016Revised 15 April 2016Accepted 4 May 2016
KEYWORDSMicronized progesterone;endometrium; menopause;combined estrogenprogestogen therapy;hormone therapy
Introduction
The steroid hormone progesterone plays a key role in femalereproduction1. For therapeutic reasons, micronized progester-one (MP) can be used for endometrial protection when estro-gens are applied in menopausal women with an intactuterus2. However, there is considerable debate about whetherand at which dosage MP provides effective endometrial pro-tection if applied orally, vaginally, or transdermally3. To dis-cuss various topics on MP, an international expert meeting ofgynecological endocrinologists from the German-speakingcountries Austria, Germany and Switzerland was held in April2015 aiming to provide scientifically proven statements onMP treatment in peri- and postmenopausal women, based ona systematic literature search and discussion of the results.Endometrial protection by MP will be the first topic of theplanned series.
Material and methods
A systematic literature search was performed using databases(Medline (Pubmed), Biosis (Medpilot) and Cochrane (CochraneLibrary)), clinical trial registers (www.clinicaltrialsregister.eu,www.clinicaltrial.gov, http://apps.who.int/trialsearch/), and theexperts’ own literature collection). Searches were performedusing a combination of keywords and Mesh-terms and textwords related to ‘‘(post-/peri)menopause’’ or ‘‘hormone/estro-gen replacement therapy’’, ‘‘progesterone’’, ‘‘endometrial
cancer/neoplasm/hyperplasia’’ or ‘‘endometrial biopsy’’ or‘‘endometrial proliferation/atrophy’’. Estrogen dosages wereclassified as high-dose, standard-dose, low-dose and ultra-low-dose by the expert group according to the definition ofthe International Menopause Society4. No time restriction wasapplied. The selection process involved a pre-selection viatitle and/or abstracts by two independent reviewers (A.L., B.H.)based on the PICO criteria (Table 1). Discrepancies betweenthe reviewers were discussed and resolved by consensus.Included abstracts were ordered as full articles. The selec-tion process for full articles was performed accordingly.Meta-analyses and systematic reviews were searched forsecondary literature. The final eligibility assessment andevaluation of the studies’ quality were performed by theexpert group (P.S., J.N., L.W.)
Results
Of 1028 hits, 40 studies were selected for the systematicreview and expert panel’s discussion5–45.
Oral application of MP
The effect of oral MP on the endometrium has been assessedby transvaginal ultrasound (TVUS)5,6,10,16,21, endometrialbiopsy10–26 and endometrial cancer incidence7–9 (Table 2).
CONTACT Professor Dr med. P. Stute [email protected] Department of Gynecologic Endocrinology and Reproductive Medicine, University Clinic ofObstetrics and Gynecology, Inselspital Berne, Effingerstrasse 102, 3010 Berne, Switzerland� 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/Licenses/by-nc-nd/4.0/),which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
CLIMACTERIC, 2016VOL. 19, NO. 4, 316–328http://dx.doi.org/10.1080/13697137.2016.1187123
Endometrial thicknessEndometrial thickness measured by TVUS was assessed inpostmenopausal women in one 3-year, placebo-controlled,randomized, controlled trial (RCT) (n¼ 167)21 and two 1-yearRCTs (n¼ 100) with head-to-head comparisons5,6. Participantsreceived continuous, transdermal estradiol (E2) (2521–505,6 lg/day) which was sequentially combined with either differentoral progestogens (medroxyprogesterone acetate (MPA),nomegestrol acetate (NOMAC), dydrogesterone (DYD), MP)6,MP applied orally or vaginally at different dosages (100 or200 mg/day)5 or oral MP 100 mg/day for 2 weeks every 6months (extended cycle)21. In those studies with head-to-head comparisons, there were no significant group differen-ces for endometrial thickness at baseline and after 12cycles5,6. When comparing the baseline endometrial thicknesswith that at study closure, there was either no change(extended cycle regimen at oral MP 100 mg/day21, sequentialregimen at vaginal MP 200 mg/day5), or a significantincrease5,6. Another two small, non-controlled studies usingeither oral MP 200–300 mg/day for 10 days per month16 or100 mg/day for 23 days per month10 reported no change10 oran endometrial thickness of less than 2 mm after 1 year16.
The method of endometrial thickness assessment wasdescribed by two authors only5,6 using the maximal thicknessof the endometrium in the longitudinal plane of the uterus.
Endometrial histologyEndometrial biopsies were performed in 17 studies10–26 ofwhich eight were RCTs12,13,15,17,18,21,22,24 including two pla-cebo-controlled RCTs15,21. Endometrial biopsy procedure wasdescribed by all but six authors12,13,16,20,21,25. The majorityeither used a pipelle de Cornier14,15,18,22,24,26 or Novak’s cur-ette14,15,18,22,26. Others used a needle aspiration (pistoletmethod)23, vabra suction curettage10,11,15,19 or performed aconventional dilatation and curettage17,19. A hysteroscopywas only performed in one study if no tissue was obtained20.The sample size ranged from 1716 to 59615 women being
postmenopausal in all but one study16. Treatment durationranged from 4 months12,24 to 5 years20. Conjugated equineestrogens (CEE) were the most common estrogen componentof menopausal hormone therapy (MHT) while others used17b-estradiol. Estrogen dosage was either high-dose14,17,19,standard-dose10–16,18,20,22–26, low-dose25 or ultra-low-dose21.Estrogens were applied either orally or transdermally. MP wasexamined either at different dosages ranging from 50 mg/day12, 100 mg/day10–12,14,19,21,24–26, 200 mg/day9,13,15–20,22,23,300 mg/day14,16,17,19,24 to 400 mg/day24 or compared to otherprogestins (intrauterine levonorgestrel (LNG)23, oral chlormadi-none acetate (CMA)18,22, oral MPA15,16). The regimen of com-bined MHT differed, ranging from continuously combinedMHT (28 days per cycle/whole month), intermittently com-bined MHT (25 days per cycle followed by a 5-day hormonebreak) to sequentially combined MHT (continuous estrogentherapy combined with a progestogen for 10–14 days percycle/month). Endometrial biopsies were taken at the end ofall trials and also at baseline in all but four studies14,19–21.Evaluation of tissue biopsies differed tremendously.Histomorphology was the most common method used to dif-ferentiate between proliferative, secretory and atrophic endo-metrium10–14,16–20,22–26, and, if applicable, normal, hyperplasticand cancerous endometrium10,11,15,19–21,24. Treatment successmay be defined as yielding an atrophic, inactive or secretoryendometrium whereas treatment failure corresponds to a pro-liferative endometrium response or hyperplasia22. In addition,some investigators assessed histomorphometry17, mitoticcount14,26, mitotic index20, DNA synthesis26, proliferationindex (MIB)24, or used transmission electron microscopy andbiochemistry markers19.
Treatment success by oral MP was reported by 11 stud-ies10–14,16,18,19,22,24,25. Seven studies used a continuous11,12,16
or intermittent10,14,24,25, and four studies a sequential13,18,19,22
MHT regimen. Treatment success was achieved by MP100–400 mg/day if an intermittent MHT regimen wasapplied10,12,14,16,24,25. However, absolute numbers rangedbetween 3.8% (MP 100 mg/day)14 and 100% (MP 200 mg/day)12 for atrophic, and between 0% (MP 200 mg/day)12 and64% (MP 400 mg/day)24 for secretory endometrium, while aproliferative or mildly active endometrium was found in 0%(MP 100–200 mg/day)12 to 23.1% (MP 100 mg/day)14.Accordingly, treatment success was achieved with a sequen-tial MHT regimen if MP 200–300 mg/day was applied13,18,19,22.In detail, the endometrium was found to be atrophic in20.8%22 to 56% (MP 200 mg/day)13, secretory in 62.5% (MP200 mg/day)18,22 to 83% (MP 300 mg/day)19 and proliferativein 8.3%22 to 31%13 (MP 200 mg/day). In contrast, other studiesfound an insufficient endometrial transformation if oral MPwas applied intermittently or continuously at 100–200 mg/day23,26 or sequentially at 100–300 mg/day17,19,20. The hetero-geneity of results and their interpretation by the authors maybe attributed to the differences between cohorts, studydesigns, endometrium evaluation techniques, thresholds fortreatment success, and also to the lack of sufficient correl-ation between histomorphology and endometrial safety. Forexample, the lack of complete glandular and stromal proges-tational changes has not been found to be associated withany detectable impairment in antiproliferative effects.
Table 1. Literature search strategy (PICO criteria); status March 2015.
E1 Population/Patient All (post/perimenopausal) women(natural or surgical menopause)using systemic estrogen replace-ment therapy (estradiol or conju-gated equine estrogen; estriol andestrogen were excluded)
E2 Intervention Progesterone (natural), exogenouslyadministered on oral, transdermalor vaginal route; duration of studyat least 3 months; in humans
E3 Comparison/control Synthetic progestogens, placebo, nocomparison
E4 Outcome Endometrium hyperplasia or endo-metrium carcinoma, endometrialbiopsies investigating proliferative/antiproliferative effects, endomet-rial transformation or atrophy
E5 Article type Clinical studies, observational/epi-demiological studies (meta-analy-ses and systematic reviews wereincluded in order to search for sec-ondary literature)
E6 Language All English and German abstracts
CLIMACTERIC 317
Tabl
e2.
Ove
rvie
wof
tria
lsin
vest
igat
ing
men
opau
salh
orm
one
ther
apy
(MH
T)co
ntai
ning
oral
mic
roni
zed
prog
estin
(MP)
.
Dos
age
and
appl
icat
ion
regi
men
Endo
met
rium
Refe
renc
eSt
udy
desig
nSa
mpl
esiz
eaSt
udy
dura
tion
Repr
oduc
tive
stag
ecPr
oges
toge
nEs
trog
enTh
ickn
essb
Hist
olog
y(b
iops
y)Re
sults
Writ
ing
Gro
upfo
rPE
PI15
PC-R
CT59
6/52
7(b
iops
ies)
3ye
ars
Post
Ora
lMPA
10m
g/da
yda
ys1–
12,o
ralM
PA2.
5m
g/da
y,or
alM
P20
0m
g/da
yda
ys1–
12
Ora
lCEE
0.62
5m
g/da
yN
oYe
s:ba
selin
ean
dan
nual
lyw
ithou
tre
gard
tow
oman
’sm
enst
rual
cycl
e
His
tolo
gyin
plac
ebo
grou
p(n¼
119)
:no
rmal
n¼
116,
sim
ple
hype
rpla
sia
n¼
1,co
mpl
exhy
perp
lasi
an¼
1,ad
enoc
arci
nom
an¼
1;in
CEE-
only
grou
p(n¼
119)
:nor
mal
n¼
45,s
impl
ehy
perp
lasi
an¼
33,c
ompl
exhy
perp
la-
sia
n¼
27,a
typi
an¼
14;i
nCE
Eþ
MPA
(seq
uent
ial)
grou
p(n¼
118)
:nor
mal
n¼
112,
sim
ple
hype
rpla
sia
n¼
4,co
mpl
exhy
perp
lasi
an¼
2;in
CEEþ
MPA
(con
tinuo
us)
grou
p(n¼
120)
:nor
mal
n¼
119,
sim
-pl
ehy
perp
lasi
an¼
1;in
CEEþ
MP
(seq
uent
ial)
(n¼
120)
:nor
mal
n¼
114,
sim
ple
hype
rpla
sia
n¼
5,at
ypia
n¼
1;si
gnifi
cant
diffe
renc
efo
rCE
Evs
.pla
-ce
bo,p<
0.00
1)H
arm
an9
PC-R
CT72
7/46
437
.4±
16.6
mon
ths
Post
Ora
lMP
200
mg/
day
onda
ys1–
12of
each
mon
th
Ora
lCEE
0.45
mg/
day
ortr
ansd
erm
alE2
50l
g/da
y
No
No
Endo
met
rialc
ance
ras
sess
edas
adve
rse
even
ts;n
osi
gnifi
cant
diffe
renc
ebe
twee
nM
HT
and
plac
ebo
Pres
twoo
d21PC
-RCT
167/
112
3ye
ars
Post
Ora
lMP
100
mg/
day
for
2w
eeks
ever
y6
mon
ths
Ora
lE2
0.25
mg/
day
Yes:
base
line
and
ever
y6
mon
ths
Yes:
afte
r3
year
sEn
dom
etria
lthi
ckne
ss:s
light
incr
ease
,but
nosi
gnifi
cant
diffe
renc
ebe
twee
ngr
oups
exce
ptat
year
2;no
sign
ifica
ntdi
ffere
nce
inhi
stol
ogy,
one
case
ofhy
perp
lasi
ain
each
grou
pJo
ndet
18RC
T33
6/24
4(b
iops
ies)
6-m
onth
dou-
ble-
blin
d,th
en12
-mon
thop
en-la
bel
Post
Gro
up1:
oral
CMA
10m
g/da
y;gr
oup
2:or
alM
P20
0m
g/da
yon
days
10–2
4
Tran
sder
mal
E21.
5m
g/da
yon
days
1–24
No
Yes:
base
line
18m
onth
s(d
ays
10–2
4)
His
tolo
gyat
base
line:
atro
phic
in91
.8%
,pr
olife
rativ
ein
4.1%
,sec
reto
ryin
3.3%
;fo
rE2þ
CMA
atm
onth
18:a
trop
hic
in19
.5%
,pro
lifer
ativ
ein
3.7%
,sec
re-
tory
in76
.8%
;for
E2þ
MP
atm
onth
18:a
trop
hic
in27
.1%
,pro
lifer
ativ
ein
8.3%
,sec
reto
ryin
62.5
%H
olst
17RC
T32
/6fo
rhi
sto-
mor
-ph
omet
ry
6m
onth
sPo
stG
roup
1:or
alM
P20
0m
g/da
yon
days
11–2
1;gr
oup
2:or
alM
P30
0m
g/da
yon
days
11–2
1
Tran
sder
mal
E23
mg/
day
for
21da
yspe
rm
onth
No
Yes:
base
line,
at6
mon
ths
befo
rean
dat
end
ofM
Pap
plic
atio
n
His
tolo
gyan
dhi
stom
orph
omet
ryat
base
-lin
e:al
latr
ophi
c;at
mon
th6:
nosi
g-ni
fican
tch
ange
sin
area
sof
glan
dula
rce
lls,g
land
ular
nucl
eian
dst
rom
alnu
clei
with
any
MP
dosa
geM
oyer
24RC
T10
7(2
1pr
e-m
enop
ausa
lco
ntro
ls)/
64(1
9)
425
-day
cycl
es(1
cycl
eCE
Eon
ly,t
hen
RCT)
Post
Gro
up1:
oral
MP
100
mg/
day;
grou
p2:
oral
MP
200
mg/
day;
grou
p3:
oral
MP
300
mg/
day;
grou
p4:
oral
MP
400
mg/
day
for
10da
ys/2
5-da
ycy
cle
Ora
lCEE
0.62
5m
g/da
yfo
r25
days
No
Yes:
base
line
(aft
erCE
Eon
ly)
toaf
ter
3EP
Tcy
cles
(day
26)
Prol
ifera
tion
inde
x(M
IB):
sign
ifica
ntre
duct
ion
inM
P20
0–40
0m
g/da
yan
dlu
teal
phas
eco
mpa
red
toCE
Eon
ly;n
odi
ffere
nce
for
100
mg/
day;
secr
etor
ym
atur
atio
n:0
inCE
E-on
ly,2
/22
inM
P10
0m
g/da
y,5/
25in
MP
200
mg/
day,
10/1
9in
MP
300
mg/
day,
14/2
2in
MP
400
mg/
day,
allp
rem
enop
ausa
lwom
enin
lute
alph
ase,
1si
mpl
ehy
perp
lasi
aw
ithou
tat
ypia
inM
P30
0m
g/da
yD
upon
t13Si
ngle
-blin
ded
RCT
63;g
roup
s1
and
2(h
ys-
tere
ctom
y)n1¼
16,
24w
eeks
Post
Gro
ups
3an
d4:
oral
MP
200
mg/
day
onda
ys12
–25
each
mon
th
Gro
ups
1an
d3:
tran
s-de
rmal
E21.
5m
g/da
y;gr
oups
2an
d4:
oral
CEE
No
Yes:
base
line,
wee
k24
His
tolo
gyba
selin
e–w
eek
24:a
trop
hic
in23
/32–
18/3
2,pr
olife
rativ
ein
7/32
–10/
32,m
ixed
in1/
32–3
/32
(cav
e:on
eis
mis
sing
)(c
ontin
ued)
318 P. STUTE ET AL.
Tabl
e2.
Cont
inue
d
Dos
age
and
appl
icat
ion
regi
men
Endo
met
rium
Refe
renc
eSt
udy
desig
nSa
mpl
esiz
eaSt
udy
dura
tion
Repr
oduc
tive
stag
ecPr
oges
toge
nEs
trog
enTh
ickn
essb
Hist
olog
y(b
iops
y)Re
sults
n2¼
15;
grou
ps3
and
4(in
tact
ute-
rus)
n3¼
16,
n4¼
16
0.62
5m
g/da
yfo
r25
days
each
mon
th(d
osag
ead
just
eddu
ring
first
3cy
cles
acco
rdin
gto
sym
ptom
s)
Dar
j12RC
The
ad-t
o-he
adco
mpa
rison
30/2
64
mon
ths
Post
Ora
lMP
grou
p1:
50m
g/da
y;gr
oup
2:10
0m
g/da
y;gr
oup
3:20
0m
g/da
yfo
r25
days
each
mon
th
Ora
lE2
2m
g/da
yfo
r25
days
each
mon
th
No
Yes:
base
line,
mon
th4
His
tolo
gyat
base
line
and
mon
th4
for
grou
p1:
atro
phic
in80
%an
d60
%,
prol
ifera
tive
in10
%an
d20
%,s
ecre
-to
ryin
10%
and
10%
(dro
pout
10%
);fo
rgr
oup
2:at
roph
icin
90%
and
60%
,pr
olife
rativ
ein
10%
and
0%,s
ecre
tory
in0%
and
10%
(3dr
opou
ts;f
orgr
oup
3:at
roph
icin
70%
and
100%
,pro
lif-
erat
ive
in20
%an
d0%
,sec
reto
ryin
10%
and
0%D
iCar
lo5
Ope
n-la
belR
CT10
0/80
12cy
cles
Post
Gro
upA:
oral
MP
100
mg/
day;
grou
pB:
oral
MP
200
mg/
day;
grou
pC:
vagi
nalM
P10
0m
g/da
y;gr
oup
D:v
agin
alM
P20
0m
g/da
y;se
quen
tial
regi
men
(14–
25th
cycl
eda
y/28
-day
cycl
e)
Tran
sder
mal
E2pa
tch
50lg
/day
Yes:
base
line,
end
oftr
ial(
afte
rpr
oges
toge
nw
ithdr
awal
blee
ding
)
No
No
sign
ifica
ntgr
oup
diffe
renc
esat
base
-lin
ean
daf
ter
12cy
cles
;sig
nific
ant
incr
ease
ofen
dom
etria
lthi
ckne
ssw
hen
com
parin
gen
dom
etria
lthi
ckne
ssat
base
line
and
afte
r12
cycl
esfo
rgr
oups
A–C,
but
belo
w6
mm
inal
lca
ses
DiC
arlo
6O
pen-
labe
lRC
T10
0/79
12cy
cles
Post
Gro
upA:
oral
MPA
10m
g/da
y;gr
oup
B:or
alN
OM
AC5
mg/
day;
grou
pC:
oral
DYD
10m
g/da
y;gr
oup
D:
oral
MP
200
mg/
day;
sequ
entia
lreg
imen
(14–
25th
cycl
eda
y/28
-day
cycl
e)
Tran
sder
mal
E2pa
tch
50lg
/day
Yes:
base
line,
end
oftr
ial(
afte
rpr
oges
toge
nw
ithdr
awal
blee
ding
)
No
No
sign
ifica
ntgr
oup
diffe
renc
esat
base
-lin
ean
daf
ter
12cy
cles
;sig
nific
ant
incr
ease
ofen
dom
etria
lthi
ckne
ssw
hen
com
parin
gen
dom
etria
lthi
ckne
ssat
base
line
and
afte
r12
cycl
esfo
ral
lgr
oups
,but
belo
w6
mm
inal
lcas
es
Pelis
sier
22RC
T33
6/26
518
mon
ths
(6m
onth
sdo
uble
-bl
ind,
12m
onth
sop
en-la
bel)
Post
Gro
up1:
oral
CMA
10m
g/da
y;gr
oup
2:or
alM
P20
0m
g/da
yfr
omda
y11 to
24
Tran
sder
mal
E21.
5m
g/da
yfr
omda
y1
to24
/cyc
le
No
Yes:
base
line,
mon
ths
6an
d18
Base
line
CMA:
insu
ffici
ent
in13
.7%
,atr
o-ph
icin
75.6
%,i
nact
ive
in4.
4%,s
ecre
-to
ryin
3.8%
,pro
lifer
ativ
ein
1.9%
;ba
selin
eM
P:in
suffi
cien
tin
16.6
%,
atro
phic
in70
.7%
,ina
ctiv
ein
5.1%
,se
cret
ory
in1.
9%,p
rolif
erat
ive
in5.
1%;
CMA
atm
onth
18:a
trop
hic
in15
.8%
,in
activ
ein
3.7%
,sec
reto
ryin
76.8
%,
prol
ifera
tive
in3.
7%,t
reat
men
tsu
cces
s63
.7%
,tre
atm
ent
failu
re2.
4%;M
Pat
mon
th18
:atr
ophi
cin
20.8
%,i
nact
ive
in3.
6%,s
ecre
tory
in62
.5%
,pro
lifer
a-tiv
ein
8.3%
,tre
atm
ent
succ
ess
35.8
%,
trea
tmen
tfa
ilure
3.3%
Lane
19N
on-r
ando
m-
ized
pro-
spec
tive
5012
mon
ths
Post
Gro
up1:
oral
MP
300
mg/
day;
grou
p2:
oral
MP
200
mg/
day;
grou
p3:
Ora
lCEE
1.25
mg/
day
No
Yes:
atm
onth
3on
day
6H
isto
logy
ingr
oup
1(n¼
12):
83%
with
vary
ing
degr
ees
ofse
cret
ory
chan
ge,
17%
with
non-
secr
etor
ypa
tter
n;in
(con
tinue
d)
CLIMACTERIC 319
Tabl
e2.
Cont
inue
d
Dos
age
and
appl
icat
ion
regi
men
Endo
met
rium
Refe
renc
eSt
udy
desig
nSa
mpl
esiz
eaSt
udy
dura
tion
Repr
oduc
tive
stag
ecPr
oges
toge
nEs
trog
enTh
ickn
essb
Hist
olog
y(b
iops
y)Re
sults
tria
lor
alM
P10
0m
g/da
yfr
omda
y1
to10
ofth
eca
lend
arm
onth
grou
p2
(n¼
13):
69%
with
early
secr
etor
ych
ange
sm
ixed
with
prol
if-er
ativ
eor
non-
secr
etor
yty
pegl
ands
,23
%w
ithno
n-se
cret
ory
patt
ern;
ingr
oup
3(n¼
11):
36%
with
vary
ing
degr
ees
ofse
cret
ory
chan
ge,2
7%w
ithno
n-se
cret
ory
patt
ern,
27%
with
mild
tom
oder
ate
atyp
ical
hype
rpla
sia.
Addi
tiona
lmet
hods
:tra
nsm
issi
onel
ec-
tron
mic
rosc
opy,
bioc
hem
istr
yH
argr
ove16
Non
-ran
dom
-iz
edpr
o-sp
ectiv
etr
ial
17/1
512
mon
ths
Peri,
n¼
4;po
st,
n¼
13G
roup
1:or
alM
P2–
3�
100
mg/
day;
grou
p2:
oral
MPA
10m
g/da
yfr
omda
y1
to10
ofth
eca
lend
arm
onth
Gro
up1:
oral
E22–
3�
0.35
mg/
day;
grou
p2:
oral
CEE
0.62
5m
g/da
y
Yes:
base
line,
1,3,
6,12
mon
ths
Yes:
base
line,
1,3,
6,12
mon
ths
Endo
met
rialt
hick
ness
(onl
yda
taat
stud
yco
mpl
etio
npr
ovid
ed):
CEEþ
MP
<2
mm
,CEEþ
MPA
nopa
thol
ogy;
His
tolo
gy(o
nly
data
at6
mon
ths
pro-
vide
d):C
EEþ
MP
atro
phy,
CEEþ
MPA
prol
ifera
tive
orse
cret
ory
Foid
art26
Non
-ran
dom
-iz
edpr
o-sp
ectiv
etr
ial
50po
st-
and
30pr
eme-
nopa
usal
wom
en/5
0po
st-
and
30pr
eme-
nopa
usal
wom
en
3–6
mon
ths
Post
and
pre
Gro
up2:
oral
MP
100
mg/
day
acro
ss25
days
/m
onth
Gro
up1:
estr
ogen
only
(ora
lCEE
0.62
5m
g/da
yor
tran
sder
mal
E21.
5m
g/da
yfo
r3
mon
ths)
,fol
low
edby
3m
onth
sof
com
bine
dEP
Tre
gi-
men
(ora
lMP
100
mg/
day
acro
ss25
days
/mon
th);
grou
p2:
tran
sder
-m
alE2
1.5
mg/
day
acro
ss25
days
/m
onth
No
Yes:
base
line,
3rd
EPT
cycl
e(c
ycle
days
21–2
5)
No
dist
inct
secr
etor
ypa
tter
nno
rhy
per-
plas
ia;p
refe
rabl
ym
ildpr
olife
rativ
epa
tter
n;m
itotic
activ
ityan
dD
NA
syn-
thes
isin
crea
sed
inET
but
redu
ced
inEP
Tgr
oup
Suva
nto-
Luuk
kone
n23N
on-r
ando
m-
ized
pros
pect
ive
tria
l
30/2
724
mon
ths
Post
Gro
up1:
LNG
-IUD
(20lg
/da
y);g
roup
2:or
alM
P20
0m
g/da
yfo
r25
days
per
cale
ndar
mon
th;
grou
p3:
vagi
nalM
P10
0–20
0m
g/da
yon
25da
yspe
rca
lend
arm
onth
Tran
sder
mal
E21.
5m
g/da
yN
oYe
s:ba
selin
e,12
,24
mon
ths
His
tom
orph
olog
yat
base
line:
atro
phic
in10
/14,
mild
prol
ifera
tion
in3/
14,
inac
tive
in1/
14;f
orLN
Gat
mon
th24
:at
roph
icin
15/1
6,pa
rtly
prol
ifera
tive
in1/
16;f
oror
alM
Pat
mon
th24
:pro
-lif
erat
ive
in9/
10,i
nact
ive
in1/
10;f
orva
gina
lMP
atm
onth
24:i
nact
ive
in3/
3G
illet
14N
on-r
ando
m-
ized
pro-
spec
tive
tria
l
101/
91;h
igh-
dose
n¼
3,lo
w-d
ose
n¼
98
6m
onth
sPo
stG
roup
1(h
igh
dose
):or
alM
P30
0m
g/da
yfr
omda
y16
to25
;gro
up2
(low
-dos
e):o
ralM
P10
0m
g/da
yfr
omda
y1
to21
or25
Gro
up1
(hig
h-do
se):
tran
sder
mal
E23
mg/
day
from
day
1to
25of
each
cal-
enda
rm
onth
;gr
oup
2(lo
w-d
ose)
:tr
ansd
erm
alE2
1.5
mg/
day
from
day
1to
21pe
rcy
cle
orda
y25
ofth
eca
lend
arm
onth
(dos
age
coul
dbe
Yes,
ifbi
opsy
was
insu
ffici
ent
Yes:
afte
r6
mon
ths
afte
rat
leas
t12
days
ofM
Pdu
ring
that
cycl
e
Mito
ses
coun
tin
glan
dula
rep
ithel
ialc
ells
;gr
oup
1(n¼
2):n
om
itosi
sor
1m
itosi
s/10
00ce
lls,g
roup
2(n¼
78):
insu
ffici
ent
in3.
8%,a
trop
hic
in3.
8%,
quie
scen
tin
61.5
%,m
ildly
activ
ein
23.1
%,p
artia
llyse
cret
ory
in7.
7%
(con
tinue
d)
320 P. STUTE ET AL.
Tabl
e2.
Cont
inue
d
Dos
age
and
appl
icat
ion
regi
men
Endo
met
rium
Refe
renc
eSt
udy
desig
nSa
mpl
esiz
eaSt
udy
dura
tion
Repr
oduc
tive
stag
ecPr
oges
toge
nEs
trog
enTh
ickn
essb
Hist
olog
y(b
iops
y)Re
sults
adap
ted
durin
gth
efir
st3
mon
ths
acco
rdin
gto
sym
ptom
s)Bo
laji10
Ope
npr
ospe
ct-
ive
tria
l40
/32
12m
onth
sPo
stO
ralM
P10
0m
g/da
yfo
r23
days
ofev
ery
cale
ndar
mon
th
Ora
lCEE
0.62
5m
g/da
yYe
s:ba
selin
e,en
dof
tria
lYe
s:ba
selin
e,6
mon
ths,
12m
onth
sbe
twee
nda
ys20
and
23
Endo
met
rialt
hick
ness
with
out
chan
ge;
His
tolo
gyat
base
line:
atro
phic
in74
%,
prol
ifera
tive
in15
%,s
ecre
tory
in7%
,si
mpl
ehy
perp
lasi
ain
2%;a
fter
12m
onth
s:at
roph
icin
73%
,pro
lifer
ativ
ein
17%
,sec
reto
ryin
7%,s
impl
ehy
per-
plas
iain
3%Bo
laji11
Ope
npr
ospe
ct-
ive
tria
l40
/29
12m
onth
sPo
stO
ralM
P10
0m
g/da
yfo
r23
days
ofev
ery
cale
ndar
mon
th
Ora
lCEE
0.62
5m
g/da
yN
oYe
s:ba
selin
e,6
mon
ths,
12m
onth
sbe
twee
nda
ys20
and
23
His
tom
orph
olog
yat
base
line:
inad
equa
tein
7%,a
trop
hic
in47
%,s
ecre
tory
in7%
,pro
lifer
ativ
ein
15%
,cys
tichy
per-
plas
iain
2%;a
tm
onth
12:a
trop
hic
in17
%,s
ecre
tory
in7%
,pro
lifer
ativ
ein
17%
,cys
tichy
perp
lasi
ain
3%Al
len7
Pros
pect
ive
coho
rtst
udy
115
474
Mea
nfo
llow
-up
9.0
year
sPo
stCu
rren
tM
HT
user
29%
,co
mbi
ned
estr
ogen
–-pr
oges
toge
nth
erap
y74
%(s
eque
ntia
lreg
i-m
en45
%,c
ontin
uous
regi
men
16%
)co
ntai
n-in
gsy
nthe
ticpr
oges
tins
(91%
)or
MP
(9%
)
Estr
ogen
sno
tfu
rthe
rsp
ecifi
edN
oN
oEn
dom
etria
lcan
cer.
HR
(95%
CI):
curr
ent
MH
Tus
e1.
41(1
.08–
1.83
),se
quen
tial
MH
Tre
gim
en1.
52(1
.00–
2.29
),co
n-tin
uous
MH
Tre
gim
en0.
24(0
.08–
0.77
),M
Pas
prog
esto
gen
cons
titue
nt2.
42(1
.53–
3.83
)
Four
nier
8Pr
ospe
ctiv
eco
hort
stud
y
6563
0M
ean
follo
w-
up10
.8ye
ars
Post
Perc
enta
geof
curr
ent
MH
Tus
ers
isno
tpr
o-vi
ded;
40.2
%of
com
-bi
ned
estr
ogen
–pro
ges-
toge
nth
erap
yco
ntai
ned
oral
MP
for
am
ean
dura
tion
of4.
2ye
ars
E292
.8%
,CEE
2.2%
,w
eak
estr
ogen
s(e
strio
l,pr
ome-
strie
ne)
11.1
%
No
No
Endo
met
rialc
ance
r.H
R(9
5%CI
):an
yM
HT
use
1.33
(1.0
1–1.
76),
MP
aspr
o-ge
stog
enco
nstit
uent
:eve
rus
e1.
80(1
.38–
2.34
),cu
rren
tus
e1.
96(1
.41–
2.73
),us
efo
r�
5ye
ars
1.39
(0.9
9–1.
97)
and
for>
5ye
ars
2.66
(1.8
7–3.
77)
Mar
engo
25Pr
ospe
ctiv
eco
ntro
lled
tria
l
112/
110
12m
onth
sPo
stO
ralM
P10
0m
g/da
yfo
r25
days
per
cale
ndar
mon
th
Tran
sder
mal
E21.
5or
0.75
mg/
day
for
25da
yspe
rca
lend
arm
onth
Yes,
but
only
ifin
adeq
uate
tis-
sue
(n¼
5)
Yes:
base
line,
2,6,
12m
onth
sAt
12m
onth
s:at
roph
y81
%,s
ub-a
trop
hy14
.5%
,ina
dequ
ate
tissu
e4.
5%(m
ean
endo
met
rialt
hick
ness
inth
ose
3m
m)
Moy
er20
Obs
erva
tiona
lex
pand
edcl
inic
alca
sere
port
236/
153
(n¼
53w
ithad
equa
tetis
sue)
5ye
ars
Post
Ora
lMP
200
mg/
day
14da
ys/2
8da
ys(in
crea
seto
300
mg/
day
and/
orsh
orte
nto
10–1
2da
ysif
requ
ired)
Tran
sder
mal
E21.
5m
g/da
yon
21da
ys/2
8da
ys(in
crea
seto
3m
gan
d/or
25da
ysac
cord
ing
tosy
mpt
oms)
No
Yes:
afte
r5
year
sat
day
2–14
ofM
Ptr
eatm
ent
(hys
tero
-sc
opyþ
biop
syif
notis
sue
was
obta
ined
)
His
tolo
gy:n
ohy
perp
lasi
aor
carc
inom
a,in
none
ofth
ebi
opsi
esdi
dth
equ
antit
yof
secr
etor
ym
atur
atio
neq
uala
fully
deve
lope
dgl
andu
lar
and
stro
mal
pat-
tern
equi
vale
ntto
late
lute
alph
ase.
Mod
erat
ese
cret
ory
mat
urat
ion
in78
%of
high
E2/h
igh
MP
grou
p(3
/300
for
10da
ys)
but
only
in8%
oflo
wE2
/low
MP
grou
p(1
.5/2
00fo
r14
days
)a ,r
ecru
ited/
anal
yzed
;b,m
easu
red
bytr
ansv
agin
alul
tras
ound
;c ,pos
t,po
stm
enop
ause
,pre
,pre
men
opau
se;p
eri,
perim
enop
ause
PEPI
,Po
stm
enop
ausa
lEs
trog
en/P
roge
stin
Inte
rven
tions
Tria
l;PC
-RCT
,pl
aceb
o-co
ntro
lled,
rand
omiz
edco
ntro
lled
tria
l;RC
T,ra
ndom
ized
cont
rolle
dtr
ial;
CEE,
conj
ugat
edeq
uine
estr
ogen
;E2
,17
b-e
stra
diol
;M
PA,
med
roxy
pro-
gest
eron
eac
etat
e;CM
A,ch
lorm
adin
one
acet
ate;
NO
MAC
,nom
eges
trol
acet
ate;
DYD
,dyd
roge
ster
one;
LNG
-IUD
,lev
onor
gest
rel-r
elea
sing
intr
aute
rine
devi
ce;E
PT,e
stro
gen–
prog
esto
gen
ther
apy;
ET,e
stro
gen
ther
apy;
HR,
haz-
ard
ratio
;95%
CI,9
5%co
nfid
ence
inte
rval
CLIMACTERIC 321
Thus, the inhibition of endometrial proliferation may be disso-ciated from secretory maturational changes20 and therefore acomplete secretory maturation may not be required for theprevention of hyperplasia14. Jondet and colleagues evenstated that the histological classification using proliferativeand secretory items does not represent the physiologicalaspects seen in normal cycles but rather indicates whetherthe pathologist is able to detect any progestogenic action18.
That said, it might be more revealing to assess the preva-lence of endometrial hyperplasia in endometrium biopsies.Two small (n¼ 40–50)10,11,19, one short (4 months)24 and onestudy using an extended cycle regimen (MP every 6months)21 reported one case with (simple) hyperplasiaeach21,24, or an 1% increase of the prevalence of simplehyperplasia10,11, respectively, using a sequentially19 or quasicontinuously combined MHT7,8 with MP 100 mg/day. In con-trast, the study with the longest intervention (5 years) did notfind any case of endometrial hyperplasia or carcinoma inwomen having applied an 17b-estradiol (E2) patch sequen-tially combined with MP 200 mg/day20. However, there wereonly 53 endometrial biopsies with adequate tissue in 153women completing the study. Thus, the largest study to date(n¼ 596) is the placebo-controlled RCT PostmenopausalEstrogen/Progestin Interventions Trial (PEPI) with a 3-yearintervention phase using a sequentially combined MHT withMP 200 mg/day among others15. In this study, all combinedMHT regimens were effective in preventing hyperplasia com-parable to placebo.
Endometrial cancer incidenceEndometrial cancer incidence in respect to MHT containingoral MP was assessed by two prospective cohort studies, theEuropean Prospective Investigation into Cancer and Nutritionstudy (EPIC)7 and the E3N8, with E3N being the French cohortof EPIC. The sample size ranged from 65 6308 to 115 4747
postmenopausal women; the mean follow-up was 9.07 and10.88 years, respectively. A self-administered questionnairecontaining information on MHT use was sent to participantsonce at baseline7 or every 2–3 years8. Within the E3N cohort,a woman who successively took different types of MHT simul-taneously contributed to each category. The study designsdid not include gynecological examinations. Information onthe type of estrogen–progestogen therapy (EPT) regimen(sequential or continuous) was available for 61% of EPT usersin EPIC7 and missing in E3N8. Data on adherence to medica-tion, prescription and diagnostic bias were not assessed.While E3N only included EPT users with oral MP, EPIC did notdifferentiate between oral, vaginal and transdermal MP appli-cation. MP dosage was not reported in both, EPIC and E3N.Mean duration of EPT use was 2.5 years in EPIC (irrespectiveof progestogen constituent)7, and 4.2 years in users of MP-containing EPT in E3N8. During follow-up, 6017 and 3018 inci-dent endometrial cancers were reported (e.g. self-report,population cancer registries, health insurance records). Tumorhistology was reported in EPIC7 (not in E3N) and tumor stagein E3N8 (not in EPIC). In current users of MP-containing EPT,there were 26 endometrial cancer cases in EPIC (2231 non-cases) and 54 cases in E3N (number of non-cases not given).
Current use of MP-containing EPT was associated with asignificantly increased risk of endometrial cancer in both,EPIC (hazard ratio (HR) 2.42; 95% confidence interval (CI)1.53–3.83)7 and E3N (HR 1.96; 95% CI 1.41–2.73)8. Theimpact of treatment duration was only analyzed in E3N,showing an increased risk after more than 5 years of usebut not below8. Endometrial cancer risk was not assessedin respect to tumor histology, specifically to hormonedependency or independency of the tumor. There is onlyone 4-year RCT, the Kronos Early Estrogen Prevention Study(KEEPS), comparing oral sequential MHT containing MP(200 mg/day) to placebo9. The incidence of endometrialcancer was assessed as an adverse event. There was nosignificant difference in endometrial cancer cases betweenMHT users (n¼ 3) and placebo (n¼ 0).
Vaginal application of MP
The effect of vaginal MP on the endometrium has beenassessed by TVUS5,27–36, endometrial biopsy23,27–39 and endo-metrial cancer incidence40 (Table 3).
Endometrial thicknessEndometrial thickness measured by TVUS was assessed in 11studies5,27–36 of which four were RCTs5,27,28,34. In RCTs, vaginalMP was either compared at different dosages5,28,34 or to intra-uterine LNG27. The sample size ranged from 2032,36 to 13629
postmenopausal women, and treatment duration from 21days32 to 3 years33. Estrogens were either applied as a vaginalring27,28, orally in standard dose29, or transdermally in stand-ard dose5,27,29,31,33–36 and low-dose30. Vaginal MP was appliedas either a capsule or gel at different dosages ranging from45 mg/day29,31, 100 mg/day5,27,30,33,35,36 to 200 mg/day5,32,35 oras a vaginal ring28,34. Application regimens were eithersequential (7–12 days/month)5,27,29, intermittent29–31,33,35,36 orcontinuous28,32,34. The method of endometrial thicknessassessment was described by six authors only5,27,30,32,33,35.Endometrial thickness was measured at the maximal thicknessof the endometrium in the longitudinal plane of the uterus,specified as double layer in some studies27,30,35. In most stud-ies, endometrial thickness remained unchanged with asequential (45 mg/day29, 100 mg/day27, 200 mg/day5) or inter-mittent (100 mg/day30,33,36,35, 200 mg/day35) regimen. In con-trast, three studies reported a significant increase ofendometrial thickness with a sequential (100 mg/day5), inter-mittent (45 mg/day31) or continuous (vaginal MP ring34).
Endometrial histologyEndometrial histology was assessed by biopsy in 14 stud-ies23,27–39 of which five were RCTs27,28,34,38,39. In RCTs, vaginalMP was either compared at different dosages28,34,39 to oralMPA or transdermal norethisterone sacetate (NETA)38 or tointrauterine LNG27. Baseline biopsies were performed in allbut four studies32,33,36,37. In few studies, endometrial biopsieswere only performed if indicated (e.g. suspect TVUS, uterinebleeding)28–30. Endometrial biopsy procedure was describedby all authors. The majority either used a pipelle de
322 P. STUTE ET AL.
Cornier28,30,32,34 or performed a hysteroscopy-guided tar-geted biopsy29,33,36,38. Others used a Novak’s curette31,37,needle aspiration (pistolet method)23,35, Gynoscan method27
or vabra endometrial biopsy39. The sample size rangedfrom 937 to 13629 postmenopausal women, and treatmentduration from 21 days32 to 3 years33. Systemic estrogens athigh37, standard23,27,29,31,33–36,38,39 or low30 dose wereapplied either orally29,39, transdermally23,27,29–31,33–38 or vagi-nally27,28. Vaginal MP was applied as a capsule or as gel atdifferent dosages ranging from 45 mg/day29,31,39, 90 mg/day39, 100 mg/day23,27,30,33,35–38 to 200 mg/day23,32,35, asintramuscular injection32 or a vaginal ring28,34. Applicationregimens were either sequential (7–12 days/month)27,29,37,38,intermittent23,29–31,33,35,36,39 or continuous28,34. Treatmentsuccess22 was reported by the majority of studies, yieldinga predominantly atrophic (intermittent MP 45 mg/day31,sequential or intermittent MP 100 mg/day30,33,36,27,38, MPvaginal ring28,34) or secretory (intermittent MP 45–90 mg/day39, sequential37,38 or intermittent MP 100–200 mg/day23,36 endometrial response. Treatment failure22 wasreported by three studies showing some proliferative endo-metrial responses (MP vaginal ring34, sequential or intermit-tent MP 100–200 mg/day35,38). Only one study reported ahyperplastic endometrium in 10% of women after 1 yearwithout remarkable difference between groups (sequentialvaginal MP cream 100 mg/day, oral MPA 10 mg/day, ortransdermal NETA 0.25 mg/day)38.
Endometrial cancer incidenceThere was only one 5-year RCT, Early versus Late InterventionTrial with Estradiol (ELITE), comparing sequential MHT con-taining vaginal MP (45 mg/day) to placebo40. The incidence ofendometrial cancer was assessed as an adverse event. Therewas no significant difference in endometrial cancer casesbetween MHT users and placebo (preliminary data presentedat World Congress of International Menopause Society,Cancun, 2014).
Transdermal application of MP
Five studies have been identified investigating the impact oftransdermal MP on the endometrium41–45 (Table 4). All butone study43 were RCTs, some of which had placebo41 or aprogestin42 as comparator. Sample size ranged from 2744,45 to5443 postmenopausal women, and study duration from 441 to4843 weeks. Estrogens were applied either orally41,42 or trans-dermally43–45 with the dosage falling either within the high-dose44,45 or moderate-dose41–43 category46. Transdermal MPcream was applied either sequentially41,44,45 or continu-ously42,43, and the dosage ranged from 16 mg/day to 64 mg/day44,45. Transvaginal ultrasound for endometrial thicknessassessment was only performed in one study43 showing a sig-nificant increase when combining estrogens with transdermalMP cream. Endometrial biopsy was performed by all studiescomparing pre- and post-treatment histology. While two stud-ies indicated an adequate progesterone opposing effect41,42,the remainder did not43–45. There were two cases of complexhyperplasia43 but no endometrial cancer was found.
Discussion
Current international guidelines on MHT recommend tocombine a progestogen when using estrogen therapy inperi- and postmenopausal women with an intact uterus forendometrial protection2,47–49. Progestogen addition shouldbe continuous or sequential for at least 12 days per month,as recently again pointed out by the US Endocrine Society.However, long-term endometrial safety of sequential pro-gestogen addition may be reduced since the combinationof estrogens with MP (or dydrogesterone) is associatedwith an increased risk of endometrial cancer if used formore than 5 years48. Yet, compliance, dosage and route ofapplication of MP were not exactly known. Internationally,systemic MP is available at different dosages and routes ofapplication. Also, indication and approval by regulatoryauthorities may differ from country to country. In Europe,systemic MP is available as a capsule (100 mg, 200 mg) forvaginal or oral application or as vaginal gel (8% corre-sponding to 90 mg).
During the last years, the debate about (compounded) bio-identical hormones has increased tremendously50–52.Therefore, the aim of this international expert group was toprovide recommendations on the use of estrogens combinedwith MP in postmenopausal women in respect to endometrialsafety.
The European Medicines Agency (EMA) recommends endo-metrial biopsies at baseline and study closure as the gold-standard method for evaluation for endometrial hyperplasiaduring MHT53. Per definition, a biopsy is evaluable if there is’endometrial tissue sufficient for diagnosis’. Endometrial biop-sies should be classified into the general classes of atrophic,proliferative, secretory, hyperplasia without atypia, hyperplasiawith atypia, cancer and others. Biopsies with insufficient tis-sue for diagnosis may be categorized as ’atrophic endomet-rium’ if the sonographic endometrial thickness is <5 mm. Fora new MHT, combination studies of at least 12 months’ dur-ation are required. The upper limit of the 95% confidenceinterval of the incidence of hyperplasia or carcinoma shouldnot exceed 2% after 1 year, requiring a sample size of 300patients.
For oral MP, there are only three RCTs following EMA’sguideline15,18,22 All studies used sequential (12–14 days/month) MP at 200 mg/day for either 1.518,22 or 315 years.When comparing sequential CMA (10 mg/day) to sequentialMP (200 mg/day), CMA provided a more complete progesto-genic transformation18,22. However, according to the PEPI trial,sequential MP (200 mg/day) provided adequate endometrialprotection for up to 3 years, comparable to sequential or con-tinuous MPA15. When further taking into account the resultsfrom KEEPS (sequential MP at 200 mg/day for 4 years)9 andE3N8, the panel concluded that in postmenopausal womencombining estrogens with sequential (12–14 days/month) oralMP at 200 mg/day (EMA approval) for up to 5 years providessufficient endometrial protection. If oral MP is to be appliedcontinuously, the initial dosage should also be 200 mg/day.This dose may be lowered off-label to 100 mg/day if an (ultra-)low-dose estrogen therapy has been chosen and amenorrheapersists.
CLIMACTERIC 323
Tabl
e3.
Ove
rvie
wof
tria
lsin
vest
igat
ing
men
opau
salh
orm
one
ther
apy
(MH
T)co
ntai
ning
vagi
nalm
icro
nize
dpr
oges
tin(M
P).
Dos
age
and
appl
icat
ion
regi
men
Endo
met
rium
Refe
renc
eSt
udy
desig
nSa
mpl
esiz
eaSt
udy
dura
tion
Prog
esto
gen
Estr
ogen
Thic
knes
sbH
istol
ogy
(bio
psy)
Resu
lts
Ben-
Chet
rit28
RCT
29/1
84–
6m
onth
sH
igh
MP
(3.6
g/rin
g);L
owM
P(1
.8g/
ring)
Vagi
nalE
2rin
g(0
.36
g/rin
g)Ye
s:ba
selin
e,1,
2,4,
6m
onth
sYe
s:if
endo
met
rial
thic
knes
s>
6.5
mm
(n¼
6)
Endo
met
rialt
hick
ness
incr
ease
din
20.7
%(7
.7–9
.5m
m);
hist
olog
y:at
roph
icin
4/6
sam
ples
,sec
reto
ryin
1/6
sam
ples
,po
lyp
in1/
6sa
mpl
es,n
ohy
perp
lasi
aRo
ss39
RCT
31/2
43
mon
ths
Gro
up1:
45m
gva
gina
l;gr
oup
2:90
mg
vagi
nalM
Pev
ery
48h
CEE
oral
0.62
5m
g/da
yN
oYe
s:ba
selin
e,1
cycl
e,3
cycl
es(e
ach
2nd
cycl
eph
ase)
His
tolo
gyaf
ter
3cy
cles
ingr
oup
1:at
ro-
phic
in2/
11,e
arly
secr
etor
yin
6/11
,la
tese
cret
ory
in2/
11;i
ngr
oup
2:at
ro-
phic
in1/
13,e
arly
secr
etor
yin
9/13
,la
tese
cret
ory
in2/
13;n
ohy
perp
lasi
aor
prol
ifera
tive
endo
met
rium
Noe
34RC
T44
/42
12w
eeks
MP
vagi
nalr
ing:
grou
p1:
0.5
(5m
g/da
y)or
grou
p2:
1g
(10
mg/
day)
Tran
sder
mal
E250
lg/d
ayYe
s:ba
selin
e,12
wee
ksYe
s:ba
selin
e,12
wee
ksEn
dom
etria
lthi
ckne
ssin
grou
p1:
3.0>
4.5
mm
,gro
up2:
3.2>
4.8
mm
(sig
nific
ant
incr
ease
inbo
thgr
oups
,no
com
paris
onbe
twee
ngr
oups
)H
isto
logy
ingr
oup
1:at
roph
icin
14/2
1,in
suffi
-ci
ent
in1/
21,p
rolif
erat
ive
in6/
21;i
ngr
oup
2:at
roph
icin
15/2
1,in
suffi
cien
tin
2/21
,pro
lifer
ativ
ein
3/21
(non
-si
gnifi
cant
)Fe
rrer
o38RC
T60
/60
1ye
arG
roup
1:M
PAor
al10
mg/
day
for
12da
ys/m
onth
;gro
up2:
NET
Atr
ansd
erm
al0.
25m
g/da
yfo
r14
days
;gr
oup
3:M
Pva
gina
l10
0m
g/da
y12
days
/mon
th
E2tr
ansd
erm
al50
lg/d
ayN
oYe
s:ba
selin
e,6,
12m
onth
s(a
lway
sin
clud
ing
hyst
eros
copy
)
His
tolo
gyin
MPA
grou
p:at
roph
icin
13/
20,p
rolif
erat
ive
in4/
20,h
yper
plas
ticin
1/20
,sec
reto
ryin
2/20
;in
NET
Agr
oup:
atro
phic
in11
/20,
prol
ifera
tive
in5/
20,h
yper
plas
ticin
3/20
,sec
reto
ryin
1/20
,sim
ple
hype
rpla
sia
in1/
20;i
nM
Pgr
oup:
atro
phic
in9/
20,p
rolif
era-
tive
in2/
20,h
yper
plas
ticin
2/20
,se
cret
ory
in7/
20An
toni
ou27
RCT
56/5
612
mon
ths
Gro
up1:
vagi
nalM
P10
0m
g/da
yfo
r7
days
/mon
th;
grou
p2:
LNG
-IUD
(20l
g/da
y)
Gro
up1:
vagi
nal
E2rin
gfo
r3
mon
ths
(2m
g);
grou
p2:
tran
s-de
rmal
E250
lg/d
ay
Base
line,
1ye
arBa
selin
e,1
year
Endo
met
rialt
hick
ness
:gro
up1
2.9
mm
>2.
6m
m,g
roup
23.
0m
m>
2.8
mm
His
tolo
gy:g
roup
1:at
roph
icin
27/2
8sa
mpl
es,i
nsuf
ficie
ntin
1/28
sam
ples
;gr
oup
2:at
roph
icin
20/2
8sa
mpl
es,
insu
ffici
ent
in1/
28sa
mpl
es,n
opr
olife
ratio
nCi
cine
lli37
Pros
pect
ive
coho
rttr
ial
94
wee
ksVa
gina
lMP
100
mg/
day
for
10da
ys/m
onth
Tran
sder
mal
E210
0l
g/da
yN
oAf
ter
4w
eeks
Secr
etor
yen
dom
etriu
m(a
llsa
mpl
es)
DiC
arlo
5O
pen-
labe
lRCT
100/
8012
men
stru
alcy
cles
Gro
upA:
oral
MP
100
mg/
day;
grou
pB:
oral
MP
200
mg/
day;
grou
pC:
vagi
nalM
P10
0m
g/da
y;gr
oup
D:v
agi-
nalM
P20
0m
g/da
y;se
quen
tialr
egim
en(1
4–25
thcy
cle
days
/28-
day
cycl
e)
Tran
sder
mal
E250
lg/d
ayYe
s:ba
selin
e,en
dof
stud
y(a
fter
prog
esto
gen
with
draw
albl
eedi
ng)
No
Endo
met
rialt
hick
ness
:no
sign
ifica
ntgr
oup
diffe
renc
esat
base
line
and
afte
r12
men
stru
alcy
cles
;sig
nific
ant
incr
ease
ofen
dom
etria
lthi
ckne
ssw
hen
com
parin
gba
selin
ew
ithaf
ter
12cy
cles
for
grou
psA–
C(b
ut<
6m
min
allc
ases
)
deZi
egle
r29N
on-r
ando
miz
edpr
ospe
ctiv
etr
ial
136
6m
onth
sG
roup
1:M
Pva
gina
l45
mg/
day
for
10da
ys/m
onth
;gr
oup
2:M
Pva
gina
l45
mg
2/w
eek
Estr
ogen
s(o
ralE
2va
lera
te2
mg/
day,
oral
CEE
0.62
5m
g/da
y;tr
ansd
erm
alE2
50lg
/day
)
Yes:
base
line,
6,18
mon
ths
Yes,
but
only
ifab
norm
alut
er-
ine
blee
ding
and/
oren
do-
met
rialt
hick
-ne
ss>
10m
m
Endo
met
rialt
hick
ness
:gro
up1
5.1>
4.9
mm
;gro
up2:
not
give
n.H
isto
logy
(nno
tgi
ven)
:no
hype
rpla
sia
orca
ncer
(con
tinue
d)
324 P. STUTE ET AL.
Tabl
e3.
Cont
inue
d
Dos
age
and
appl
icat
ion
regi
men
Endo
met
rium
Refe
renc
eSt
udy
desig
nSa
mpl
esiz
eaSt
udy
dura
tion
Prog
esto
gen
Estr
ogen
Thic
knes
sbH
istol
ogy
(bio
psy)
Resu
lts
Fern
ande
z-M
urga
30N
on-r
ando
miz
edpr
ospe
ctiv
etr
ial
64/2
71
year
MP
100
mg
2/w
eek
E2tr
ansd
erm
al2lg
/day
Yes:
base
line,
6,12
mon
ths
Yes,
ifab
norm
albl
eedi
ngoc
curr
ed
Endo
met
rialt
hick
ness
:2.9
mm>
3.5
mm
(non
-sig
nific
ant)
.His
tolo
gy:a
trop
hyin
all(
n¼
7)Ci
cine
lli31
Pros
pect
ive
obse
r-va
tiona
ltria
l35
/26
1ye
arVa
gina
lP4
45m
g2/
wee
kE2
tran
sder
mal
50lg
/day
Yes:
base
line,
12m
onth
sYe
s:ba
selin
e,12
mon
ths
Endo
met
rialt
hick
ness
:3.6
mm>
4.6
mm
(sig
nific
ant)
.His
tolo
gy:a
tba
selin
eal
lat
roph
y,at
12m
onth
sat
roph
yin
92.3
%M
iles32
Non
-ran
dom
ized
pros
pect
ive
tria
l20
post
men
o-pa
usal
,4pr
emen
o-pa
usal
wom
en
21da
ysG
roup
1:va
gina
lP4
200
mg
ever
y6
h,st
artin
gon
cycl
eda
y15
;gro
up2:
intr
amus
-cu
lar
P450
mg
2/da
y
Incr
easi
ngE2
dos-
ages
for
oocy
tedo
natio
n
Yes:
cycl
eda
y21
Yes:
cycl
eda
y21
Endo
met
rialt
hick
ness
:11.
4m
m(g
roup
1)an
d11
.1m
m(g
roup
2).H
isto
logy
:no
diffe
renc
ebe
twee
ngr
oups
Cici
nelli
33Pr
ospe
ctiv
etr
ial
30/2
33
year
sVa
gina
lP4
100
mg
ever
yot
her
day
Tran
sder
mal
E21.
5m
g/da
yYe
s:ba
selin
e,ev
ery
6m
onth
sYe
s:Af
ter
3ye
ars
Endo
met
rialt
hick
ness
:3.4
mm>
2.7
mm
(3ye
ars)
.His
tolo
gy:a
trop
hyin
all
case
sSu
vant
o-Lu
ukko
nen35
Non
-ran
dom
ized
pros
pect
ive
tria
l60
/51
1ye
arG
roup
1:LN
G-IU
D;g
roup
2:or
alM
P10
0m
g/da
y;gr
oup
3:M
P10
0–20
0m
g/da
yva
gina
lfor
25da
ys/m
onth
E2tr
ansd
erm
al1.
5m
g/da
yYe
s:ba
selin
e,3,
6,12
mon
ths
Yes:
base
line,
12m
onth
sEn
dom
etria
lthi
ckne
ss:g
roup
1:2.
0>
3.0
mm
;gro
up2:
2.4>
2.7
mm
;gr
oup
3:2.
5>
2.4
mm
(non
-sig
nific
ant
chan
gew
ithin
grou
ps).
His
tolo
gy:
grou
p1:
atro
phy
in12
/18,
inac
tive
in5/
18;g
roup
2:in
activ
ein
4/19
,par
tlypr
olife
rativ
ein
5/19
,mos
tlypr
olife
ra-
tive
in8/
19,s
ecre
tory
in1/
19;g
roup
3:in
activ
ein
5/14
,par
tlypr
olife
rativ
ein
1/14
,mos
tlypr
olife
rativ
ein
7/14
,se
cret
ory
in1/
14Su
vant
o-Lu
ukko
nen23
Non
-ran
dom
ized
pros
pect
ive
tria
l30
/27
24m
onth
sG
roup
1:LN
G-IU
D(2
0lg
/day
);gr
oup
2:or
alM
P20
0m
g/da
yfo
r25
days
per
cale
n-da
rm
onth
;gro
up3:
vagi
-na
l100
–200
mg/
day
on25
days
per
cale
ndar
mon
th
Tran
sder
mal
E21.
5m
g/da
yN
oYe
s:ba
selin
e,12
–24
mon
ths
His
tom
orph
olog
yat
base
line:
atro
phic
in10
/14,
mild
prol
ifera
tion
in3/
14,
inac
tive
in1/
14;f
orLN
Gat
mon
th24
:at
roph
icin
15/1
6,pa
rtly
prol
ifera
tive
in1/
16;f
oror
alM
Pat
mon
th24
:pro
-lif
erat
ive
in9/
10,i
nact
ive
in1/
10;f
orva
gina
lMP
atm
onth
24:i
nact
ive
in3/
3Vi
lodr
e36O
pen,
unco
ntro
lled
pros
pect
ive
tria
l20
/20
1ye
arM
Pva
gina
l100
mg/
day
for
21/2
8da
ysE2
1.5
mg/
day
for
21/2
8da
ysYe
s:ba
selin
e,1
year
Yes:
base
line,
1ye
arEn
dom
etria
lthi
ckne
ssun
chan
ged.
His
tolo
gyaf
ter
12m
onth
s:at
roph
yin
11/2
0,pr
olife
rativ
eor
secr
etor
ypa
tter
nin
9/20
a ,rec
ruite
d/an
alyz
ed;b
,mea
sure
dby
tran
svag
inal
ultr
asou
ndRC
T,ra
ndom
ized
cont
rolle
dtr
ial;
CEE,
conj
ugat
edeq
uine
estr
ogen
;E2,
17b-
estr
adio
l;M
PA,m
edro
xypr
oges
tero
neac
etat
e;N
ETA,
nore
this
tero
neac
etat
e;P4
,pro
gest
eron
e;LN
G-IU
D,l
evon
orge
stre
l-rel
easi
ngin
trau
terin
ede
vice
CLIMACTERIC 325
Tabl
e4.
Ove
rvie
wof
tria
lsin
vest
igat
ing
men
opau
salh
orm
one
ther
apy
(MH
T)co
ntai
ning
tran
sder
mal
mic
roni
zed
prog
estin
(MP)
.
Dos
age
and
appl
icat
ion
regi
men
Endo
met
rium
Refe
renc
eSt
udy
desig
nSa
mpl
esiz
eaSt
udy
dura
tion
Repr
oduc
tive
stag
ecPr
oges
toge
nEs
trog
enTh
ickn
essb
Hist
olog
y(b
iops
y)Re
sults
Leon
etti41
PC-R
CT37
/32
28da
ysPo
stTr
ansd
erm
alM
Pcr
eam
;2�
/day
at0%
,1.5
%or
4.0%
(bas
edon
patie
nt’s
wei
ght)
Ora
lCEE
0.62
5m
g/da
yN
oYe
s:pr
ean
dpo
stM
Pap
plic
atio
n.H
isto
logy
:0,
inac
tive;
1,sc
antly
prol
ifera
tive;
2,m
oder
-at
ely
prol
ifera
tive;
3,pr
olife
rativ
e;4,
high
lypr
olife
rativ
e.En
dpoi
nt:
EPS
byra
nkin
gal
lsl
ides
rela
tive
toea
chot
her
Sign
ifica
ntEP
Sre
duct
ion
by1.
5%an
d4.
0%M
Pcr
eam
com
pare
dto
pre-
trea
tmen
tw
ithes
trog
ens
Wre
n44,4
5RC
T27
/21
12w
eeks
Post
Tran
sder
mal
MP
crea
mat
16m
g/da
y(n¼
9)or
32m
g/da
y(n¼
8)or
64m
g/da
y(n¼
10)
for
14da
ys/c
ycle
(seq
uent
ial)
Tran
sder
mal
E2pa
tch
100lg
/da
y
No
Yes:
pre
and
post
MP
appl
icat
ion
AtBL
,n¼
6pr
olife
rativ
e;at
wee
k48
,n¼
19pr
o-lif
erat
ive
(res
ults
for
grou
psno
tgi
ven)
Leon
etti42
Unb
linde
dcr
oss-
over
RCT
33/2
66
mon
ths
per
trea
tmen
tar
mPo
stTr
ansd
erm
alM
Pcr
eam
40m
g/da
y(c
ontin
uous
)or
oral
MPA
2.5
mg/
day
(con
tinuo
us)
Ora
lCEE
0.62
5m
g/da
yN
oYe
s:pr
ean
dpo
stM
P/M
PAap
plic
atio
nH
isto
logy
inM
Pcr
eam
grou
p:at
roph
icin
81%
,pr
olife
rativ
ein
19%
;hi
stol
ogy
inor
alM
PAgr
oup:
atro
phic
in73
%,
prol
ifera
tive
in27
%;n
ohy
perp
lasi
aVa
shis
ht43
Ope
n-la
bels
ingl
ear
mst
udy
54/4
148
wee
ksPo
stTr
ansd
erm
alM
Pcr
eam
40m
g/da
y(c
ontin
uous
)Tr
ansd
erm
alE2
crea
m1
mg/
day
Yes:
pre
and
post
MH
TYe
s:pr
ean
dpo
stM
HT
Endo
met
rialt
hick
ness
:sig
-ni
fican
tin
crea
sefr
omm
ean
3.3
mm
tom
ean
5.3
mm
;His
tolo
gyat
BL:1
00%
atro
phic
orin
suffi
cien
t;hi
stol
ogy
atw
eek
48:a
trop
hic
in29
%,s
ecre
tory
in8%
,pr
olife
rativ
ein
26%
,co
mpl
exhy
perp
lasi
a(±
atyp
ia)
in5%
a ,rec
ruite
d/an
alyz
ed;b
,mea
sure
dby
tran
svag
inal
ultr
asou
nd;c ,p
ost,
post
men
opau
se.
PC-R
CT,
Plac
ebo-
cont
rolle
d,ra
ndom
ized
cont
rolle
dtr
ial;
RCT,
rand
omiz
edco
ntro
lled
tria
l;CE
E,co
njug
ated
equi
nees
trog
en;
E2;
17b-
estr
adio
l;M
PA,
med
roxy
prog
este
rone
acet
ate;
EPS,
endo
met
rial
prol
ifera
tion
scor
e;BL
,ba
selin
e
326 P. STUTE ET AL.
For vaginal MP, no study completely followed EMA’sguideline and gained approval as an adjunct to meno-pausal estrogen therapy. However, six studies investigatedvaginal MP for at least 1 year and performed endometrialbiopsies at baseline and at study closure23,27,31,35,36,38.Vaginal MP (45–200 mg/day) was applied either sequentially(7–12 days/month)27,38 or intermittently (25 days/month)23,35,36. The majority of investigators concluded thatsequential vaginal MP (100–200 mg/day) was insufficient toproduce an adequate endometrial response23,35,36,38. Whentaking into account long-term studies (3–5 years)33,40, theuse of sequential or intermittent vaginal MP does not seemto increase the risk of endometrial hyperplasia or cancer.However, due to the heterogeneity of studies and lack ofsufficient data, the panel concluded that in postmenopausalwomen combining estrogens with sequential (4% corre-sponding to 45 mg/day on 10 days per month) or intermit-tent (100 mg every other day) vaginal MP for up to 3–5years may be safe (off-label use). However, 4% MP vaginalgel is not available on the European market. Finally, theuse of transdermal MP for endometrial protection cannotbe recommended in postmenopausal women using estro-gen therapy.
It remains difficult to interpret these data as there is abroad variety in study designs in terms of dosage per cycle,route of administration, clinical findings, sample size perprotocol and even histological readings. Therefore, oral MP at200 mg daily for at least 12 days per month is the preferredroute, dose and duration for postmenopausal women with anintact uterus when using estrogen therapy for up to 5 yearsdue to the currently available data. This conclusion seems tobe applicable also for the vaginal treatment route. However,this procedure remains off-label use.
Conclusion
Postmenopausal women with an intact uterus using estrogentherapy should receive a progestogen for endometrial protec-tion. International guidelines on MHT do not specify on pro-gestogen type, dosage, route of application and duration ofsafe use. Based on a systematic literature review on MP forendometrial protection, an international expert panel’s recom-mendations on MHT containing MP are as follows: (1) oral MPprovides endometrial protection if applied sequentially for12–14 days/month at 200 mg/day for up to 5 years; (2) vagi-nal MP may provide endometrial protection if appliedsequentially for 10 days/month at 4% (45 mg/day) or everyother day at 100 mg/day for up to 3–5 years (off-labeluse); (3) transdermal MP does not provide endometrialprotection.
Acknowledgements
The authors are grateful for the support of Dr. Kade/Besins PharmaGmbH for helping with ordering the identified publications.
Conflict of interest The authors have been part of an German-speak-ing expert board funded by Dr. Kade/Besins Pharma GmbH. The authorsalone are responsible for the content and writing of the paper.
Source of funding This publication was developed by an expertboard from Austria, Germany and Switzerland. The board meeting wasfunded by Dr. Kade/Besins Pharma GmbH without influence on thecontent.
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