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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 petra.stute@insel.ch 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

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for

21/2

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for

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year

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base

line,

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CLIMACTERIC 325

Tabl

e4.

Ove

rvie

wof

tria

lsin

vest

igat

ing

men

opau

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orm

one

ther

apy

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T)co

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ning

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sder

mal

mic

roni

zed

prog

estin

(MP)

.

Dos

age

and

appl

icat

ion

regi

men

Endo

met

rium

Refe

renc

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mpl

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tion

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oduc

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olog

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sults

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edon

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wei

ght)

Ora

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0.62

5m

g/da

yN

oYe

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atio

n.H

isto

logy

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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:

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byra

nkin

gal

lsl

ides

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her

Sign

ifica

ntEP

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duct

ion

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d4.

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Post

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sder

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MP

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mat

16m

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32m

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10)

for

14da

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ycle

(seq

uent

ial)

Tran

sder

mal

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tch

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y

No

Yes:

pre

and

post

MP

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icat

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AtBL

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6pr

olife

rativ

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wee

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,n¼

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(res

ults

for

grou

psno

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ven)

Leon

etti42

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linde

dcr

oss-

over

RCT

33/2

66

mon

ths

per

trea

tmen

tar

mPo

stTr

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erm

alM

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eam

40m

g/da

y(c

ontin

uous

)or

oral

MPA

2.5

mg/

day

(con

tinuo

us)

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lCEE

0.62

5m

g/da

yN

oYe

s:pr

ean

dpo

stM

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PAap

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nH

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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

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;His

tolo

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00%

atro

phic

orin

suffi

cien

t;hi

stol

ogy

atw

eek

48:a

trop

hic

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%,s

ecre

tory

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,pr

olife

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,co

mpl

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perp

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a(±

atyp

ia)

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a ,rec

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post

men

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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.

References

1. Csapo AI, Pulkkinen M. Indispensability of the human corpusluteum in the maintenance of early pregnancy. Luteectomy evi-dence. Obstet Gynecol Surv 1978;33:69–81

2. de Villiers TJ, Pines A, Panay N, et al. Updated 2013 InternationalMenopause Society recommendations on menopausal hormonetherapy and preventive strategies for midlife health. Climacteric2013;16:316–37

3. Ruan X, Mueck AO. Systemic progesterone therapy – oral, vaginal,injections and even transdermal? Maturitas 2014;79:248–55

4. Birkhauser MH, Panay N, Archer DF, et al. Updated practical recom-mendations for hormone replacement therapy in the peri- andpostmenopause. Climacteric 2008;11:108–23

5. Di Carlo C, Tommaselli GA, Gargano V, Savoia F, Bifulco G, Nappi C.Transdermal estradiol and oral or vaginal natural progesterone:bleeding patterns. Climacteric 2010;13:442–6

6. Di Carlo C, Sammartino A, Di Spiezio Sardo A, et al. Bleeding pat-terns during continuous estradiol with different sequential proges-togens therapy. Menopause 2005;12:520–5

7. Allen NE, Tsilidis KK, Key TJ, et al. Menopausal hormone therapyand risk of endometrial carcinoma among postmenopausal womenin the European Prospective Investigation Into Cancer andNutrition. Am J Epidemiol 2010;172:1394–403

8. Fournier A, Dossus L, Mesrine S, et al. Risks of endometrial cancerassociated with different hormone replacement therapies in theE3N cohort, 1992–2008. Am J Epidemiol 2014;180:508–17

9. Harman SM, Black DM, Naftolin F, et al. Arterial imaging outcomesand cardiovascular risk factors in recently menopausal women: arandomized trial. Ann Intern Med 2014;161:249–60

10. Bolaji II, Mortimer G, Grimes H, Tallon DF, O’Dwyer E, Fottrell PF.Clinical evaluation of near-continuous oral micronized progesteronetherapy in estrogenized postmenopausal women. GynecolEndocrinol 1996;10:41–7

11. Bolaji II, Mortimer G, Grimes H, O’Dwyer EM. Endometrial responsein oestrogenised postmenopausal women after treatment with oralprogesterone: results of a prospective analysis. J Obstet Gynaecol1992;12:412–17

12. Darj E, Nilsson S, Axelsson O, Hellberg D. Clinical and endometrialeffects of oestradiol and progesterone in post-menopausal women.Maturitas 1991;13:109–15

13. Dupont A, Dupont P, Cusan L, et al. Comparative endocrinologicaland clinical effects of percutaneous estradiol and oral conjugatedestrogens as replacement therapy in menopausal women.Maturitas 1991;13:297–311

14. Gillet JY, Andre G, Faguer B, et al. Induction of amenorrhea duringhormone replacement therapy: optimal micronized progesteronedose. A multicenter study. Maturitas 1994;19:103–15

15. The Writing Group for the PEPI Trial. Effects of hormone replace-ment therapy on endometrial histology in postmenopausal women.The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.JAMA 1996;275:370–5

16. Hargrove JT, Maxson WS, Wentz AC, Burnett LS. Menopausal hor-mone replacement therapy with continuous daily oral micronizedestradiol and progesterone. Obstet Gynecol 1989;73:606–12

17. Holst J, Cajander S, von Schoultz B. Endometrial response in post-menopausal women during treatment with percutaneous 17 beta-oestradiol opposed by oral progesterone. Maturitas 1986;8:201–7

18. Jondet M, Maroni M, Yaneva H, Brin S, Peltier-Pujol F, Pelissier C.Comparative endometrial histology in postmenopausal womenwith sequential hormone replacement therapy of estradiol and,either chlormadinone acetate or micronized progesterone.Maturitas 2002;41:115–21

CLIMACTERIC 327

19. Lane G, Siddle NC, Ryder TA, Pryse-Davies J, King RJ, Whitehead MI.Dose dependent effects of oral progesterone on the oestrogenisedpostmenopausal endometrium. Br Med J (Clin Res Ed)1983;287:1241–5

20. Moyer DL, de Lignieres B, Driguez P, Pez JP. Prevention of endo-metrial hyperplasia by progesterone during long-term estradiolreplacement: influence of bleeding pattern and secretory changes.Fertil Steril 1993;59:992–7

21. Prestwood KM, Kenny AM, Kleppinger A, Kulldorff M. Ultralow-dosemicronized 17beta-estradiol and bone density and bone metabol-ism in older women: a randomized controlled trial. JAMA2003;290:1042–8

22. Pelissier C, Maroni M, Yaneva H, Brin S, Peltier-Pujol F, Jondet M.Chlormadinone acetate versus micronized progesterone in thesequential combined hormone replacement therapy of the meno-pause. Maturitas 2001;40:85–94

23. Suvanto-Luukkonen E, Sundstrom H, Penttinen J, Kauppila A,Rutanen EM. Insulin-like growth factor-binding protein-1: a bio-chemical marker of endometrial response to progestin during hor-mone replacement therapy. Maturitas 1995;22:255–62

24. Moyer DL, Felix JC, Kurman RJ, Cuffie CA. Micronized progesteroneregulation of the endometrial glandular cycling pool. Int J GynecolPathol 2001;20:374–9

25. Marengo M, Rodriguez Vidal V, Deza EG. Hormonal replacementtherapy (HRT). Evaluation of a novel 25 days regimen with percu-taneous estradiol (PE2) and micronized oral progesterone (MP).PAMI Institution: Sarmiento 373, Rosario, Argentina, 2000

26. Foidart JM, Dombrowicz N, Greimers R, Smet M, de Lignieres B.Endometrial tolerance of long-term combined hormone replace-ment therapy: analysis of the cell cycle. In von Schoultz B,Christiansen C, eds. Hormone Replacement Therapy: standardized orIndividually Adjusted Doses? Lancaster, UK: Parthenon Publishing,1993:47–58

27. Antoniou G, Kalogirou D, Karakitsos P, Antoniou D, Kalogirou O,Giannikos L. Transdermal estrogen with a levonorgestrel-releasingintrauterine device for climacteric complaints versus estradiol-releasing vaginal ring with a vaginal progesterone suppository: clin-ical and endometrial responses. Maturitas 1997;26:103–11

28. Ben-Chetrit A, Hochner-Celnikier D, Lindenberg T, et al. Vaginal ringdelivering estradiol and progesterone: a possible alternative torelieve climacteric symptoms. Isr Med Assoc J 2005;7:302–6

29. de Ziegler D, Ferriani R, Moraes LA, Bulletti C. Vaginal progesteronein menopause: Crinone 4% in cyclical and constant combined regi-mens. Hum Reprod 2000;1(Suppl 1):149–58

30. Fernandez-Murga L, Hermenegildo C, Tarin JJ, Garcia-Perez MA,Cano A. Endometrial response to concurrent treatment with vaginalprogesterone and transdermal estradiol. Climacteric 2012;15:455–9

31. Cicinelli E, de Ziegler D, Galantino P, et al. Twice-weekly transder-mal estradiol and vaginal progesterone as continuous combinedhormone replacement therapy in postmenopausal women: a 1-yearprospective study. Am J Obstet Gynecol 2002;187:556–60

32. Miles RA, Paulson RJ, Lobo RA, Press MF, Dahmoush L, Sauer MV.Pharmacokinetics and endometrial tissue levels of progesteroneafter administration by intramuscular and vaginal routes: a com-parative study. Fertil Steril 1994;62:485–90

33. Cicinelli E, de Ziegler D, Alfonso R, Nicoletti R, Bellavia M, ColafiglioG. Endometrial effects, bleeding control, and compliance with anew postmenopausal hormone therapy regimen based on trans-dermal estradiol gel and every-other-day vaginal progesterone incapsules: a 3-year pilot study. Fertil Steril 2005;83:1859–63

34. Noe G, Sitruk-Ware R, Zegers-Hochschild F, et al. Endometrial effectof progesterone delivered by vaginal rings in estrogen-treatedpostmenopausal women. Climacteric 2010;13:433–41

35. Suvanto-Luukkonen E, Malinen H, Sundstrom H, Penttinen J,Kauppila A. Endometrial morphology during hormone replacement

therapy with estradiol gel combined to levonorgestrel-releasingintrauterine device or natural progesterone. Acta Obstet GynecolScand 1998;77:758–63

36. Vilodre LC, Osorio Wender MC, Sisson de Castro JA, et al.Endometrial response to a cyclic regimen of percutaneous17beta-estradiol and low-dose vaginal micronized progesterone inwomen with mild-to-moderate hypertension. Gynecol Endocrinol2003;17:323–8

37. Cicinelli E, Borraccino V, Petruzzi D, Mazzotta N, Cerundolo ML,Schonauer LM. Pharmacokinetics and endometrial effects of thevaginal administration of micronized progesterone in an oil-basedsolution to postmenopausal women. Fertil Steril 1996;65:860–2

38. Ferrero S, Gerbaldo D, Fulcheri E, Cristoforoni P. Vaginal micronizedprogesterone in continuous hormone replacement therapy. A pro-spective randomized study. Minerva Ginecol 2002;54:519–30

39. Ross D, Cooper AJ, Pryse-Davies J, Bergeron C, Collins WP,Whitehead MI. Randomized, double-blind, dose-ranging study ofthe endometrial effects of a vaginal progesterone gel in estrogen-treated postmenopausal women. Am J Obstet Gynecol1997;177:937–41

40. Hodis HN, Mack WJ, Shoupe D, et al. Methods and baseline cardio-vascular data from the Early versus Late Intervention Trial withEstradiol testing the menopausal hormone timing hypothesis.Menopause 2015;22:391–401

41. Leonetti HB, Wilson KJ, Anasti JN. Topical progesterone cream hasan antiproliferative effect on estrogen-stimulated endometrium.Fertil Steril 2003;79:221–2

42. Leonetti HB, Landes J, Steinberg D, Anasti JN. Transdermal proges-terone cream as an alternative progestin in hormone therapy.Altern Ther Health Med 2005;11:36–8

43. Vashisht A, Wadsworth F, Carey A, Carey B, Studd J. Bleeding pro-files and effects on the endometrium for women using a novelcombination of transdermal oestradiol and natural progesteronecream as part of a continuous combined hormone replacementregime. BJOG 2005;112:1402–6

44. Wren BG, McFarland K, Edwards L. Micronised transdermal proges-terone and endometrial response. Lancet 1999;354:1447–8

45. Wren BG, McFarland K, Edwards L, et al. Effect of sequential trans-dermal progesterone cream on endometrium, bleeding pattern,and plasma progesterone and salivary progesterone levels in post-menopausal women. Climacteric 2000;3:155–60

46. Jane FM, Davis SR. A practitioner’s toolkit for managing the meno-pause. Climacteric 2014;17:564–79

47. Sarri G, Davies M, Lumsden MA, Guideline Development Group.Diagnosis and management of menopause: summary of NICE guid-ance. BMJ 2015;351:h5746

48. Stuenkel CA, Davis SR, Gompel A, et al. Treatment of Symptoms ofthe Menopause: An Endocrine Society Clinical Practice Guideline.J Clin Endocrinol Metab 2015;100:3975–4011

49. North American Menopause. The 2012 hormone therapy positionstatement of The North American Menopause Society. Menopause2012;19:257–71

50. Pinkerton JV, Santoro N. Compounded bioidentical hormone ther-apy: identifying use trends and knowledge gaps among USwomen. Menopause 2015;22:926–36

51. Pinkerton JV. Think twice before prescribing custom-compoundedbioidentical hormone therapy. J Womens Health (Larchmt)2014;23:631–3

52. Pinkerton JV. What are the concerns about custom-compounded‘‘bioidentical’’ hormone therapy? Menopause 2014;21:1298–300

53. Committee for Medicinal Products for Human Use EuropeanMedicines Agency. Guideline on clinical investigation of medicinalproducts for hormone replacement therapy of oestrogen deficiencysymptoms in postmenopausal women. EMEA/CHMP/021/97 Rev. 1,October 2005

328 P. STUTE ET AL.