Mikael Engman - SFOG

SFOG Kristianstad 

2012 

Mifepristone for preoperative treatment of 

uterine leiomyoma 2011-05-20 

(http://hdl.handle.net/10616/40495) 

Med dr. Mikael Engman 

Handledare: Professor Kristina Gemzell-Danielson 

Med.dr Lalit Kumar, doc Gunnar Söderqvist

ORIGINAL PUBLICATIONS 

I. Engman M, Skoog L, Soderqvist G, Gemzell-Danielsson K 2008 The effect 

of mifepristone on breast cell proliferation in premenopausal women evaluated 

through fine needle aspiration cytology. Hum Reprod 23:2072-2079 

II. 

Engman M, Granberg S, Williams AR, Meng CX, Lalitkumar PGL, Gemzell- 

Danielsson K 2009 Mifepristone for treatment of uterine leiomyoma. A 

prospective randomized placebo controlled trial. Hum Reprod 24:1870-1879 

III. Engman M, Brett G, Varhese S, Gemzell-Danielsson K, Lalitkumar P.G.L 

(2011) Ephrin and Integrin pathways in uterine leiomyoma during mifepristone 

treatment (Manuscript). 

IV. Engman M, Byström B Varghese S, Lalitkumar P.G.L, Gemzell-Danielsson 

K (2011) Glutathione pathway gene expression determines good or poor 

response to mifepristone in leiomyoma volume regression (Submitted). 

Mikael Engman 

8/28/2012 2

Hypothesis 

As cell proliferation in uterine leiomyoma and breast 

tissue is progesterone dependent, mifepristone (PRM) 

treatment should: 

• decrease volume of leiomyomas 

• reduce breast tissue proliferation 

• be suitable for preoperative treatment 

• No placebo controlled studies were available at the time 

(2004). 


8/28/2012 3

Benign monoclonal myocyt tumör 

Malignifiering 1-2/1000 

• Subserös(30%) 

• Intramural (60%) 

• Submucös(10%) 


28 augusti 2012 4

Symptom 

• Abnorm uterusblödning 

• Mekaniska besvär 

• Infertilitet 

Mikael Engman 28 augusti 2012 5


MR 

Dueholm 2002,2003 


Intracavitärt myom 


Livstidsrisk för kliniskt relevant myom 

(>4cm, submucöst, uterus>9v. graviditet) 

Age 35-39 Age 40+ 

50 

50 

45 

40 

35 

30 

25 

20 

35 

35 

15 

10 

12 

5 

0 

Baird, 2003 


pmol/g cytosol 

Steroidreceptorinnehåll 

250 

200 

150 

100 

50 

0 

Endometrium Myom Myometrium 

ER (pmol/g cytosol) 130 41 17 

PR (pmol/g cytosol) 195 104 80 

(Wilson;1980) 


• Genetisk predisposition 

• Progesteron+(PR) 

• Östradiol+(ER) 

• Growth factors 

Cyclicity 

Mutation 

Tumör 

(Rein, 2000)

Riskfaktorer-cyclicitet 

Afroamerikansk etnicitet 

(RR:3,25 0,95 CI: 2,71-3,88 ) 

Tidig menarche 

Låg paritet 

Hög ålder vid första 

förlossning 

(Marshall 1979, Baird 2003) 


Kirurgi: RR =35 (0,95 CI= 25,8-46,5) 

(Myom vs nonmyom) 

Marshall, 1997 


Kostnad/år 

• 2,6 x matchade kontroller utan myom 

• Årlig merkostnad(USD): 5081 

(Hartmann- 2006) 


28 augusti 2012 15

Myomectomi före IVF 

• Intramuralt myom>5cm 

• Patient beslut efter information 

Delivery rate: 

Op: 

25% 

P=0,001 

Ej Op: 

12% 

Bulletti; 2004 


Progesterone 

Mifepristone docked 

on PR (933/769a.a.) 

Mukherjee S, Majumder D 2009 

Computational molecular 

docking assessment of hormone 

receptor adjuvant drugs: Breast 

cancer as an example. 

Pathophysiology 16:19-29 

Mifepristone docked on 

GR (394 a.a.) 

Mifepristone 

RBA PR: mifepristone/P4 =2.4 

Heikinheimo O, Kontula K, Croxatto H, Spitz I, Luukkainen T, 

Lahteenmaki P 1987 

Plasma concentrations and receptor binding of RU 486 

and its metabolites in humans. J Steroid Biochem 26:279-284 

Relative binding affinities (RBAs) GR: 

•Mifepristone 11 

•Monodemethylated metabolite 6,7 

•Hydroxylated metabolite 5,3 

•Didemethylated metabolite 5,0 

•Dexamethasone 2,6 

•Cortisol 1 


8/28/2012 17

Kliniskt användbara PRMs 

• Mifepristone (2.5-50 mg dagligen) 

• Ulipristal (UPA) Esmya® (5mg 

dagligen) 


Antioxid 

ant 

Antiprogesteron 

Mifepristone 

(8S,11R,13S,14S, 

17S)-11-[4-(dimethylamino)phenyl]-17-hydroxy-13- 

methyl-17-prop-1-ynyl-1, 

2,6,7,8,11,12,14,15,16- 

decahydrocyclopenta[a]phenanthren-3-one 

Antiprogesteron 

Ulipristal (Ella-One 30mg, Esmya 5mg) 

[(8S,11R,13S,14S, 

17R)-17-acetyl-11-[4-(dimethylamino)phenyl]-13- 

methyl-3-oxo-1,2,6,7,8, 

11,12,14,15,16-decahydrocyclopenta[a]phenanthren-17- 

yl] acetate 

(www.preglem.com) 


28 augusti 2012 19

Chabbert-Buffet et al. Hum Reprod Update 2005;11:293–307 


18 studies 

Mifepristone treated cases (N=384), proportions after 3 and 6 months treatment, sorted after dosage. 

Eisinger reports a 12 month study with follow up. 18 studies, 15 reports, 2 Chinese reports, from abstract in 

English. Sorted according to dose. Three studies are placebo controlled *. 

Year 

N 

(Total 

384) 

Daily 

dose 

(mg) 

Residual 

leiomyo 

ma 

volume 

Amenorr 

hea after 

3 month 

Amenorr 

hea after 

6 month 

Pain relief Hot flashes Endomet 

Hyperpl 

Murphy 1993 10 50 0.5 1.0 0.4 

Murphy 1995 9 50 0.7 

Engman * 2009 14 25 0.7 1.0 0.0 0.4 0.0 

Murphy 1995 11 25 0.4 1.0 

Reinsch 1994 8 25 0.7 0.0 

Yang (in Chinese) 1996 15 20 0.4 1.0 1.0 0.7 

Zeng (in Chinese) 1998 45 12,5 0.8 1.0 1.0 0.1 

Bagaria * 2009 19 10 0.7 0.8 0.3 0.6 

Carbonell 2008 49 10 0.8 0.9 0.2 0.0 

Eisinger ut vol 2003 20 10 0.5 0.9 0.7 0.3 0.1 0.3 

Yang 1998 28 10 0.4 1.0 1.0 0.7 

Carbonell 2008 50 5 0.6 0.9 0.1 0.0 

Fiscella ut vol * 2006 20 5 0.5 0.4 0.0 

Eisinger ut vol 2003 20 5 0.5 0.9 0.6 0.3 0.1 0.2 

Murphy 1995 9 5 0.7 1.0 0.1 

Eisinger 12 months 2005 20 10 0.5 0.6 0.1 

Eisinger 12 months 2005 20 5 0.5 0.6 0 

Eisinger 2009 17 2,5 0.9 0.7 0.3 0.0 

Mean 13 0.6 0.9 0.5 0.6 0.3 0.1 

STDDEV 0.1 0.1 0.1 0.4 0.3 0.2 


28 augusti 2012 21

KBH myoma 

study: 

2004-2007 

Myoma indicating surgery 

Mammogram 

Clinical evaluation 

Randomized to 12 wk treatment 

N=30 

FNA breast Baseline at luteal phase 

Monthly myoma volumetry, Symptom diary 

(Engman;2009) 

Mifepristone 

50mg eod 

Analyzed N=14 

Control 

Analyzed N=14 

Dropouts 

N=2 

FNA breast 

assessable 

N=8 

FNA breast 

not assessable 

N=6 

FNA breast 

assessable 

N=6 

FNA breast not 

assessable 

N=8 


Surgery(N=28), biopsies for IHC, gene 

expressions 


8/28/2012 22

Fördelning av indikationer 

Mifepristone 

Placebo 

9(7) 

xxxxxx 

xxxxxx 

xxxxxx 

xxxxxx 

Drop 

outs 

6 

5 

5 

3 

2 

Mechanical Bleed Fert 


Åldersfördelning kategoriserat i 

behandlingsgrupper 

Treatment: Control Age: N = 16; Mean = 40,875; StdDv = 7,5708; Max = 55; Min = 27 

Treatment: Mifepristone Age: N = 14; Mean = 40,7857; StdDv = 4,7097; Max = 49; Min = 34 

6 

Histogram of Age; categorized by Treatment 

5 

4 

No of obs 

3 

2 

1 

0 

20 25 30 35 40 45 50 55 60 

Age 

Treatment: Control 

Treatment: Mifepristone 


Histogram of Bleeddays per cycle; categorized by Treatment 

5 

4 

3 

No of obs 

2 

1 

0 

3 4 5 6 7 8 9 

Bleeddays per cycle 




Resultat 

30 

Antal blödningsdagar under tre månader 

Grupperat efter behandling 

p

Hb utveckling 

Mellan grupper efter 3 månade: p=0.046 

Inom mifepristone gruppen: p=0.003 


8/28/2012 27

Volymförändring av största myomet 

under tre behandlingsmånader 

Histogram av volym förändring av största myomet under tre månader 

nt: Control myomvol%Šndringvis1-4: Treatment: Control myomvol%Šndringvis1-4 N = 15; Mean = 8,3354; = 15*20*normal(x; StdDv = 32,4024; 8,3354; Max 32,4024) = 76,1806; Min = -37,5598 

nt: Mifepristone Treatment: myomvol%Šndringvis1-4: Mifepristone myomvol%Šndringvis1-4 N = 12; Mean = -27,4228; 12*20*normal(x; StdDv = -27,4228; 30,1916; 30,1916) Max = 19,0897; Min = -81,1967 

6 

5 

4 

No of obs 

3 

2 

p=0,01 

1 

0 

-100 -80 -60 -40 -20 0 20 40 60 80 100 

%förändring av volym största myom 





8/28/2012 29

Brunfärgade celler är Ki-67 positiva 

i proliferationsfas 

Före behandling 

Efter 12 v behandling 


8/28/2012 30


500 

Dot-plot % change Ki-67 from baseline to end of study 

Dot plot % change Ki 67 from baseline to end of study 

400 

Percent change Ki-67 

300 

200 

100 

0 

-100 

All Groups Mann-Whitney U Test 

% change of Ki-67 index from baseline to 

end of study 

p-level 

Valid N 

Control 

Valid N 

Mifepristone 

-200 

Control 

Mifepristone 

0,024 6 8

Normalt endometrium 

PAECs 

(PRM associated endometrial changes) 


8/28/2012 33

Endometriemönster 

(0 fall av hyperplasi 

eller atypi) 

Non fysiologisksekretoriskt 

(PAECs) 

Cystisk 

glandulär 

dilatation 

Mifepristone 8/9 5/8 

Placebo 4/11 1/11 

P= 0.03 0.04 


Bieffekter av PRMs 

• Endometrium visar PAEC, atrofi och apoptos i endometrieceller, 

non fysiologiska sekretoriska förändringar 

• Brösten minskar i volym med mindre svullnad och smärta 

• Diskreta klimakteriebesvär 

• 

(Engman M, 2008, 2009, Horne FM, Blithe DL 2007) 


Effekter av PR blockad med mifepristone 

• Blödningar försvinner inom en vecka 

• Myom krymper 27% på 3 månaders behandling 

• Minskad proliferation i normal bröstvävnad 

(Engman; 2008,2009) 


Genuttryck i myom korrelerades till 

klinisk myomvolymkrympning 

• RNA extraktion 

• Microarray 

• IPA (Ingenuity pathway analysis) 

• cDNA syntes 

• Real Time-PCR 


IPA, Integrin och Efrin pathway 


8/28/2012 38

EFNB2 

(subfamily of receptor protein-tyrosine kinases (RTKs) 



Ingenuity Canonical 

Pathways 

Integrin Signaling 

EGF Signaling 

NRF2-mediated 

Oxidative Stress 

Response 

Ephrin Receptor Signaling 

FGF Signaling 

p53 Signaling 

IL-2 Signaling 

ERK/MAPK Signaling 

Calcium Signaling 

JAK/Stat Signaling 

T Cell Receptor Signaling 

PTEN Signaling 

Wnt/Î²-catenin Signaling 

(ROR1 ) 

-log(pvalue) 

p-value Ratio Downregulated Upregulated 

7,24E- 

3,14E+00 04 4,27E-02 4/211 (2%) 5/211 (2%) 

2,09E- 

2,68E+00 03 8,51E-02 4/47 (9%) 0/47 (0%) 

2,35E+00 

2,17E+00 

1,79E+00 

1,74E+00 

1,66E+00 

1,55E+00 

1,55E+00 

1,53E+00 

1,51E+00 

1,47E+00 

1,43E+00 

4,47E- 

03 4,23E-02 3/142 (2%) 3/142 (2%) 

6,76E- 

03 3,38E-02 6/207 (3%) 1/207 (1%) 

1,62E- 

02 4,76E-02 4/84 (5%) 0/84 (0%) 

1,82E- 

02 4,60E-02 3/87 (3%) 1/87 (1%) 

2,19E- 

02 5,66E-02 3/53 (6%) 0/53 (0%) 

2,82E- 

02 2,97E-02 5/202 (3%) 1/202 (1%) 

2,82E- 

02 2,84E-02 5/211 (3%) 1/211 (1%) 

2,95E- 

02 5,08E-02 2/59 (3%) 1/59 (2%) 

3,09E- 

02 3,85E-02 2/104 (2%) 2/104 (2%) 

3,39E- 

02 3,67E-02 4/109 (4%) 0/109 (0%) 

3,72E- 

02 3,09E-02 3/162 (2%) 2/162 (1%) 


Fold change 

Fold change 

4,0 

3,0 

2,0 

1,0 

0,0 

-1,0 

-2,0 

-3,0 

-4,0 

-5,0 

ROR1* 

ARGHAP 

26 

Integrin pathway 

ITGB5 ITGAD PIK3C2G ITGA3 PAK3 CDKN1 PIK3R1* 

PCR 3,1 1,5 1,4 1,4 1,1 1,1 -1,0 -1,7 -1,8 

Array 3,6 3,3 2,3 2,0 -3,9 -2,4 -1,9 1,6 -2,9 

6,0 

Ephrin pathway 

4,0 

2,0 

0,0 

-2,0 

-4,0 

-6,0 

-8,0 

PAK3 ROR1 ITGA3 CREB5 EFNB2 PIK3C2G GRIN2A 

PCR 3,0 2,5 1,1 -2,3 -2,3 -2,6 -5,6 

Microarray -1,9 3,6 -2,4 -2,5 -2,8 -3,9 -3,3 

Mikael Engman 8/28/2012 42

The difference between treatment groups was significant upon 

ANCOVA, analysis of slopes for correlation curves (p=0.048). 


8/28/2012 43

Vad bestämmer respons på mifepristone 

behandling (SD=±30%) 


8/28/2012 44

Myomvolym (ml) 

Genuttryck bakom skillnad i respons 

Subgruppsanalys (GR 4- IR 3- PR 4) 

140,0 

Respons på mifepristone 

120,0 

100,0 

80,0 

60,0 

40,0 

20,0 

0,0 

Good responders 

Poor responders 

Volume baseline 126,7 112,5 

Volume at 12 weeks 71,4 121,6 


Categorization 

Categorization: Response to mifepristone treatment 

Poor ( N=4) 

Good (N=4) 

Myoma 

volume 

change 

Medi 

an 

Min Max (IQR) 

Media 

n 

Min Max (IQR) 

(% ) 

4.2* -16.8 19.1 31.1 -48.6* -63.8 -30.9 26.5 

•Microarray and confirmation with Real time PCR 

•TUNEL analysis 

•Correlations to: 

•Clinical myoma volume regression, gene expressions of 

TP53 and MKI67 


8/28/2012 46


Good versus Poor responders 

Microarray fold Changes are: 

Glutathione, Nrf2, NF-kB pathways 

10 

8 

Good Responders: 

GSTM1: + 8 fold 

6 

4 

Fold Change 

2 

0 

-2 

GPX2 GSTM2 TNFAIP3 TLR1 IL18 TLR4 GSTM5 GSTM3 

(includes 

EG:2947) 

GSTM1 

-4 


8/28/2012 48

GSTM1 

GSTM1 positiva 50% 

Detoxifiering av: 

Carcinogener 

Droger 

Steroid hormoner 

Fria syre radikaler 

Miljö toxiner 

GSTM1 negativa 50% 

Cancer 

Myoma 

Endometrios 


GR6 GR20 GR21 GR23 PR5 PR7 PR9 PR16 ID 

1.15 0.37 5.12 1.86 0.60 0.10 0.05 0.05 G/β 

-64 -31 -59 - 39 -9 +19 -17 +17 % vol 

Western Blotting 

GSTM1 proteinuttryck 

visar högre värden för 

Good responders 

jämfört med Poor 

responders 

Box plot by Group 

WB G STM1/b-ac tin 

6 

5 

4 

3 

2 

Variable: WB GSTM 1/b-ac tin 

P=0,052 R= -0,82 

P=0,004 

Korrelation: 

%volume change vs. 

GSTM1 uttryck 

1 

0 

-1 

Poor 

Res pons e 

Good 

M edian 

25%-75% 

M in-M ax 


GSTM1: möjlig biomarker 

Uttryck av GSTM1 

Indikerar förväntat svar på mifepristone i form av 

myomvolymkrympning 

Nytt verktyg för design av optimal terapi 


SFOG 2012 

Mifepristone for 

preoperative 

treatment of uterine 

leiomyoma 

(http://hdl.handle.net/ 

10616/40495) 


Median % Volume Reduction in the largest fibroids 

PEARL II: 

EFFECT ON FIBROIDS VOLUME REDUCTION 

No statistical difference between GnRH-a and UPA 

Week 13 

0 

-10 

Change from 

baseline at 

Week 13 (%) 

PP Population 

-20 

-30 

-35.55 

-40 

-42.05 

-50 

-53.45 

-60 

UPA 

5 mg 

UPA 

10 mg 

Lupron

PEARL II: 

MEDIAN % VOLUME REDUCTION IN 3 LARGEST 

FIBROIDS AT WEEK 13, 26 & 38 

0 

EOT 

Follow-up 

Follow-up 

Follow-up 

3 mo 6 mo EOT 3 mo 6 mo EOT 3 mo 6 mo EOT : Week 13 

Mo: Months 

-10 

6mo 

3mo 

- 16.5 

-20 

-30 

-40 

-45.5 

- 44.8 

-43.3 

-50 

-50.0 

-56.7 - 54.8 

-55.7 

-60 

-62.5 

-70 

● 

● 

UPA 5 mg 

UPA 10 mg 

Lupron 

Subpopulation of subjects where no surgery/UAE was performed 

Change from EOT (Week 13) to 6 months follow up for UPA 5 mg and UPA 10 mg 

versus Lupron - p< 0.05

PEARL I: 

BLEEDING CONTROL IN 91.5% OF PATIENTS FOR 

UPA 5 MG (PRIMARY ENDPOINT) 

100 

90 

80 

70 

60 

50 

40 

30 

20 

10 

0 

91.5% 92.5% 

18.8% 

Placebo UPA 5 mg UPA 10 mg 

Patients 

with 

PBAC

PEARL I: 

UPA CONTROLLED BLEEDING (PBAC

Median Serum oestradiol (pg/ml) 

Patients with moderate and severe 

hot flushes (%) 

PEARL II: 

UPA SUPERIOR SAFETY PROFILE TO GNRH AGONIST 

CONFIRMED AS IT DOES NOT INDUCE MENOPAUSAL 

SYMPTOMS 

70 

60 

50 

40 

30 

20 

10 

0 

UPA 

5 mg 

Oestradiol, Week 13 

UPA 

10 mg 

Lupron 

Co-Primary 

Safety 

Endpoints 

(superiority) 

● UPA shows a superior safety profile to GnRH-a 

● UPA does not induce menopausal symptoms 

45 

40 

35 

30 

25 

20 

15 

10 

5 

0 

Hot flushes, Week 13 

UPA 

5 mg 

UPA 

10 mg 

Lupron

PEARL I: 

ENDOMETRIAL THICKNESS > 16 MM 

(PART B RESULTS) 

12% 

10% 

10% 

8% 

7.0% 

6% 

5.3% 

5.0% 

4% 

3.3% 

3.3% 

3.3% 

2% 

1.7% 

1.8% 

0% 

0% 0% 

0% 

Baseline Week 13 Week 26 Week 38 

Placebo UPA 5 mg UPA 10 mg

400 

Mean myoma volume development over time 

Good versus Poor responders 

Vertical bars denote 0,95 confidence intervals 

300 

200 

100 

ml 

0 

-100 

-200 

-300 

Dom myoma vol. baseline Dom my vol. 8 weeks 

Dom. myoma vol. 4 weeks Dom my. vol. 12 weeks 

WEEKS 

Response 

Good 

Response 

Poor 



8/28/2012 60

KBH myomstudie: 2004-2007 

• Dubbel blind randomisering till: 

• Mifepristone (50mg vad) N=14, eller placebo, N=16. 

• 3 månaders preoperativ behandling 

• Bröstbiopsi vid start och efter 3 månaders behandling 


• Endometriebiopsi före och efter (vid op) 

• Ultraljud för volumetri varje månad (Engman;2009) 

• Patienthanterade symptomprotokoll, dagbok och Likert scale 


• Vid op biopsier för IHC och analys av genuttryck i myom 


GSTM1 

GSTM1 positiva 50% 

Detoxifiering av: 

Carcinogener 

Droger 

Steroid hormoner 

Fria syre radikaler 

Miljö toxiner 

GSTM1 negativa 50% 

Överrepresentation av : 

Cancer 

Leiomyoma 

Endometrios 



The pharmacokinetics of mifepristone is characterized by rapid absorption, a long half-life of 25–30 h, and high 

micromolar serum 

concentrations following ingestion of doses of 100 mg of the drug. The serum transport protein α1-acid 

glycoprotein (AAG)—regulates the serum kinetics of mifepristone in man. Binding to AAG limits the tissue availability 

of mifepristone, explaining its low volume of distribution and low metabolic clearance rate of 0.55 L/kg per day. In 

addition, the similar serum levels of mifepristone following ingestion of single doses exceeding 100 mg can be explained 

by saturation of the binding capacity of serum AAG. Mifepristone is extensively metabolized by demethylation and 

hydroxylation, the initial metabolic steps being catalyzed by the cytochrome P-450 enzyme CYP3A4.The three most 

proximal metabolites, namely, monodemethylated, didemethylated and hydroxylated metabolites of mifepristone, all 

retain considerable affinity toward human progesterone and glucocorticoid receptors. Also, the serum levels of these 

three metabolites are in rangessimilar to those of the parent mifepristone. Thus, the combined pool of mifepristone—plus 

its metabolites—seems to be responsible for thebiological actions of mifepristone. Recent clinical studies on pregnancy 

termination and emergency contraception have focused onoptimization of the dose of mifepristone. In these studies it has 

become apparent that the doses efficient for pregnancy termination differfrom those needed in emergency 

contraception—mifepristone is effective in emergency contraception at a dose of 10 mg, which results inlinear 

pharmacokinetics. However, the 200 mg doses of mifepristone needed for optimal abortifacient effects of 

mifepristone result insaturation of serum AAG and thus nonlinear pharmacokinetics. In view of the 

pharmacokinetic data, it may be speculated that dosing ofmifepristone for pregnancy termination and for 

emergency contraception could be reduced to approximately 100 mg and 2–5 mg,respectively. It remains to be seen 

whether the newly synthesized, more selective antiprogestins will prove more efficacious in the clinicalarena. 


Myoma prevalence, age 33-40 Sweden 

(Borgfeldt 2000, N=335) 

8% 

No myomas 

92% 



Myom prevalens, age 35-49 

African americans (Baird 2003) 

No myomas 

47% 

53% 

Focal fibroids 


Myom prevalens, age 35-49 

White (Baird 2003) 

37% 

Focal fibroids 

No myomas 

63% 


Esmya® 

successfully completed two Phase III clinical trials 

in Europe in June 2010 and was filed in late 2010 for 

European registration for the treatment of uterine 

fibroids 


28 augusti 2012 69

Risk för bröstcancer vid HT 

Schairer, 2000 BCDDP (N=46355) 

RR(E2 vs no treatment ):1.2, RR(E2+P4 vs no treatm):1.4 

Cheblowski , 2003 WHI study (N=16608) 

RR(E2+P4 vs placebo) :1.24 

E2 versus non-users 

E2+P4 versus non-users

Mikael Engman - SFOG

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