Applicability of selective progesterone receptor modulators in the treatment of uterine leiomyomata and their future role in the field of gynecology

Zastosowanie selektywnych modulatorów receptora progesteronowego w leczeniu mięśniaków macicy oraz ich przyszłość w ginekologii

Applicability of selective progesterone receptor modulators in the treatment of uterine leiomyomata and their future role in the field of gynecology

0DFLHM%Uą]HUW0DUFLQ3.RUPDQ/HV]HN$3DZHOF]\N

Klinika Niepłodności i Endokrynologii Rozrodu Uniwersytetu Medycznego im. K. Marcinkowskiego w Poznaniu, Polska

Streszczenie

Mięśniaki macicy to łagodne, monoklonalne guzy wywodzące się z komórek mięśni gładkich należące do najczęstszych patologii układu rozrodczego kobiet. Ich etiologia pozostaje ciągle tematem otwartej debaty, jakkolwiek wydaje się, iż kluczową rolę w ich rozwoju odgrywa progesteron oraz receptor progesteronowy. Dotychczasowe zachowawcze metody leczenia mięśniaków (doustna antykoncepcja, gestageny lub analogi GnRH) są nieskuteczne bądź niemożliwe do stosowania w długotrwałej terapii.

Pojawienie się selektywnych modulatorów receptora progesteronowego (SPRM) otworzyło nowe możliwości terapeutyczne. Obecnie preparaty te są zarejestrowane w doraźnej antykoncepcji, terminacji ciąży i w leczeniu mięśniaków. Ponadto na etapie badań klinicznych trwają próby zastosowania SPRM w leczeniu endometriozy, raka endometrium, choroby Cushinga, choroby Alzheimera czy w długotrwałej antykoncepcji.

Słowa kluczowe: SPRM / selektywne modulatory receptora progesteronowego / / mLĊĞnLakL macLcy / antykoncepcja /

Otrzymano: 12.12.2012

Zaakceptowano do druku: 30.07.2013 Adres do korespondencji:

Maciej Brązert

Klinika Niepłodności i Endokrynologii Rozrodu Uniwersytetu Medycznego im. K. Marcinkowskiego w Poznaniu Polska, 60-535 Poznań, Ul. Polna 33,

tel: (61) 8419 412 e-mail: maciejbrazert@interia.pl

0LĊĞQLDNLPDFLF\WRáDJRGQHPRQRNORQDOQHJX]\Z\ZRG]ą

FHVLĊ]NRPyUHNPLĊĞQLJáDGNLFKNWyUHQDOHĪąGRQDMF]ĊVWV]\FK

SDWRORJLLXNáDGXUR]URGF]HJRNRELHW:\VWĊSXMąRQHXRNRáR

ELDá\FKNRELHWZZLHNXODWGRQDZHWZĞUyGSLĊüG]LHVLĊ

FLRODWHN>@

'RF]\QQLNyZU\]\NDUR]ZRMXPLĊĞQLDNyZQDOHĪąUDVDF]DU

QDZF]HVQ\ZLHNmenarche,SUHG\VSR]\FMDURG]LQQDRUD]QDG

ZDJD >  @ 3RQLHZDĪ F]ĊVWR QLH SRZRGXMą REMDZyZ ZLHOH

]QLFKSR]RVWDMHGáXJRQLHUR]SR]QDQ\FK.OLQLF]QLHPDQLIHVWXMą

VLĊ]DĞQLHSUDZLGáRZ\PLSU]HGáXĪDMąF\PLVLĊNUZDZLHQLDPLPD

FLF]Q\PL>@QLH]ZLą]DQ\PL]F\NOHPGROHJOLZRĞFLDPLEyORZ\

PLOXEG\VSDUHXQLą>@NWyUH]QDF]QLHSRJDUV]DMąMDNRĞüĪ\FLD

RUD]F]ĊVWRSURZDG]ąGRQLHGRNUZLVWRĞFL3RQDGWRQLHNWyUHGXĪH

OXESRGĞOX]yZNRZRXPLHMVFRZLRQHPLĊĞQLDNLQHJDW\ZQLHZSá\

ZDMąQDSRWHQFMDáUR]URGF]\NRELHW

(WLRORJLD W\FK áDJRGQ\FK JX]yZ SR]RVWDMH FLąJOH WHPDWHP

RWZDUWHM GHEDW\ GRW\F]ąFHM ZSá\ZX F]\QQLNyZ JHQHW\F]Q\FK

LKRUPRQDOQ\FK2EHFQLHZ\GDMHVLĊLĪNOXF]RZąUROĊZLFKUR]

ZRMXRGJU\ZDSURJHVWHURQRUD]UHFHSWRUSURJHVWHURQRZ\35

Z\ND]DQRERZLHPĪH]ZLą]DQ\]OLJDQGHP35SREXG]DSUROL

IHUDFMĊ RUD] ]PQLHMV]D VWRSLHĔ DSRSWR]\ NRPyUHN P\RPHWULXP

>@

:LĊNV]RĞü GRVWĊSQ\FK RSFML WHUDSHXW\F]Q\FK PLĊĞQLD

NyZPDFLF\SRVLDGDOLF]QHRJUDQLF]HQLDZ\QLNDMąFH]HIHNWyZ

XERF]Q\FKVWRVRZDQ\FKOHNyZLSURFHGXUEąGĨ]UDG\NDOQRĞFL

]DELHJX  7UDG\F\MQH PHWRG\ OHF]HQLD REHMPXMą KLVWHUHNWRPLĊ

OXE P\RPHNWRPLĊ RVWDWQLR FRUD] F]ĊĞFLHM Z\NRQ\ZDQą Z OD

SDURVNRSLL RUD] HQGRVNRSRZą DEODFMĊ HQGRPHWULXP 2VWDWQLR

ZSURZDG]DVLĊEDUG]LHM]DDZDQVRZDQHLPQLHMLQZD]\MQHSURFH

GXU\MDNQSHPEROL]DFMDQDF]\ĔPDFLF]Q\FK>@

:OHF]HQLX]DFKRZDZF]\PQLHSUDZLGáRZ\FKNUZDZLHĔVWR

VXMH VLĊ GRXVWQą DQW\NRQFHSFMĊ RUD] JHVWDJHQ\ MDNNROZLHN QLH

XGRZRGQLRQR LFK VNXWHF]QRĞFL Z OHF]HQLX PLĊĞQLDNyZ PDFLF\

>@1DMZLĊFHMGDQ\FKGRW\F]\XĪ\FLDDQDORJyZ*Q5+6ąVNX

WHF]QHZ]PQLHMV]DQLXREMĊWRĞFLPLĊĞQLDNyZRUD]RJUDQLF]DQLX

NUZDZLHĔ-HGQDN]HZ]JOĊGXQDNOLQLF]QHNRQVHNZHQFMHKLSR

HVWURJHQL]PX XQLHPRĪOLZLDMąFH LFK GáXJLH VWRVRZDQLH ZVND]D

QLDGROHF]HQLDPLĊĞQLDNyZDQDORJDPL*Q5+VąRJUDQLF]RQHGR

WHUDSLLSU]HGRSHUDF\MQHM>@3RMDZLHQLHVLĊVHOHNW\ZQ\FKPR

GXODWRUyZ UHFHSWRUD SURJHVWHURQRZHJR 6350 RWZLHUD QRZH

PRĪOLZRĞFLWHUDSHXW\F]QH2EHFQLHSUHSDUDW\WH]DUHMHVWURZDQH

VąZGRUDĨQHMDQW\NRQFHSFMLRUD]WHUPLQDFMLFLąĪ\DRVWDWQLR.R

PLVMD(XURSHMVNDGRSXĞFLáDRFWDQXOLSU\VWDOX83$ZOHF]HQLX

PLĊĞQLDNyZ PDFLF\ > @ 3RQDGWR QD HWDSLH EDGDĔ NOLQLF]

Q\FKWUZDMąSUyE\]DVWRVRZDQLD6350ZOHF]HQLXHQGRPHWULR]\

UDNDHQGRPHWULXPFKRURE\&XVKLQJDFKRURE\$O]KHLPHUDF]\

ZGáXJRWUZDáHMDQW\NRQFHSFML>@

Progesteron i receptor progesteronowy 'R NOXF]RZ\FK ]DGDĔ SURJHVWHURQX QDOHĪ\ NRQWUROD LP

SODQWDFML L XWU]\PDQLH FLąĪ\ > @ ']LDáDQLH MHJR MHVW MHG

QDN ZLHORNLHUXQNRZH SRQLHZDĪ MHVW UyZQLHĪ RGSRZLHG]LDOQ\

]D UyĪQLFRZDQLH QDEáRQND JUXF]RáyZ SLHUVLRZ\FK KDPRZDQLH

SUROLIHUDF\MQHJR G]LDáDQLD HVWURJHQyZ QD HQGRPHWULXP Z]URVW

NRPyUHN PLĊĞQL JáDGNLFK PDFLF\ PRGXORZDQLH SXOVDF\MQHJR

Z\G]LHODQLD*Q5+MDNLSURFHVXZDOQLDQLDRRF\WX]MDMQLND>

@']LDáDQLHSURJHVWHURQXDWDNĪHVHOHNW\ZQ\FKPRGXOD

WRUyZMHJRUHFHSWRUD6350ZWNDQNDFKGRFHORZ\FKRGE\ZD

VLĊJáyZQLH]DSRĞUHGQLFWZHP35QDOHĪąFHJRGRURG]LQ\UHFHS

WRUyZ MąGURZ\FK L Z\VWĊSXMąFHJR SRG SRVWDFLą GZyFK L]RIRUP

Abstract

Uterine leiomyomata are benign, monoclonal tumors arising from smooth muscle cells, which belong to one of the most common pathologies of the female genital system. Current pharmacotherapies (oral contraceptives, progestins, GnRH analogs) are ineffective or of limited use for long-term treatment. Although there is still much debate regarding their etiology, it is very likely that progesterone and progesterone receptor play a key role in their development. Profound importance of progesterone in the female reproductive system has led to discovery of synthetic progesterone receptor ligands, which can poses the activity ranging from pure agonist activity, trough mixed agonist/antagonist activity, to pure antagonist activity. Development of selective progesterone receptor modulators (SPRM) has created new therapeutic options and has great potential in a number of gynecologic indications. So far, ulipristal acetate has been approved for emergency contraception, mifepristone as a progesterone receptor antagonist because of the unique property of this compound for termination of pregnancy.

Recently, the European Commission has authorized ulipristal acetate for the pre-operative treatment of uterine fibroids. Superior efficacy of ulipristal acetate versus placebo, to reduce excessive uterine bleeding and to reduce total fibroid volume prior to surgery was demonstrated. Moreover, non-inferior efficacy of ulipristal acetate versus Gonadotropin Releasing Hormone (GnRH)-agonist to reduce excessive uterine bleeding prior to surgery of uterine fibroids has been documented. Ulipristal acetate is also characterized by a superior side-effect profile in comparison to leuprolide acetate in terms of serum estradiol levels and the proportion of patients with moderate-to-severe hot flashes during treatment. Regarding safety profile, except elevation of liver enzymes after telapristone and onapristone treatment, to date no serious untoward effects of other SPRM have been reported.

The issue of endometrial effects of these compounds remains to be resolved, although observation that intrinsic agonist activity of SPRM prevents endometrial proliferation may suggest future use of these agents in prevention of endometrial hyperplasia. Other promising applications, including endometriosis, endometrial cancer, Cushing’s disease, Alzheimer disease or long-term contraception, are currently in development.

Key words: SPRM / selective progesterone receptor modulators / uterine leiomyoma / / contraception /

$L%35$35%2ELHL]RIRUP\VąNRGRZDQHSU]H]WHQVDP

JHQ]GZRPDUyĪQ\PLPLHMVFDPLSRF]ąWNXWUDQVNU\SFML5\FLQD

>@DL]RIRUPD35$MHVWNUyWV]DRG35%RDPLQRNZD

V\]NRĔFD1áDĔFXFKDSROLSHSW\GRZHJR,]RIRUP\WHUyĪQLąVLĊ

SRGZ]JOĊGHPDNW\ZQRĞFLELRORJLF]QHMRUD]GRFHORZ\FKJHQyZ

35%MHVW]QDF]QLHVLOQLHMV]\PDNW\ZDWRUHPWUDQVNU\SFMLQDWR

PLDVWMHJRJáyZQ\PLQKLELWRUHPZ\GDMHVLĊE\ü35$3RGF]DV

JG\ 35$ NRQWUROXMH LQGXNRZDQą SU]H] HVWURJHQ\ SUROLIHUDFMĊ

HQGRPHWULXP35%XF]HVWQLF]\ZUHJXORZDQLXZ]URVWXLUyĪQL

FRZDQLDQDEáRQNDJUXF]RáyZSLHUVLRZ\FK>@3URJHVWHURQSR

]ZLą]DQLX ] UHFHSWRUHP SRZRGXMH ]PLDQ\ MHJR VWUXNWXU\ SROH

JDMąFH QD RGáąF]HQLX ELDáHN V]RNX WHUPLF]QHJR RUD] GLPHU\]D

FMĊ PROHNXá\ 1DVWĊSQLH DNW\ZRZDQH GLPHU\ 35 ZLąĪą VLĊ ]H

VSHF\¿F]Q\PLVHNZHQFMDPL'1$ZUHJLRQDFKSURPRWRURZ\FK

Z\EUDQ\FKJHQyZ35(±Progesterone Response Element) LDN

W\ZXMąSURFHVWUDQVNU\SFMLELDáHNEH]SRĞUHGQLROXESRĞUHGQLRSR

]ZLą]DQLX]NRDNW\ZDWRUDPL5\FLQD

-HVWOLF]QDJUXSDELDáHNNWyUHSRSU]H]]PLDQ\VWUXNWXUDOQH

OXEHQ]\PDW\F]QHRGG]LDáXMą]SURPRWRUHP]ZLĊNV]DMąFSR]LRP

WUDQVNU\SFML QD SR]LRPLH NRPyUNRZ\P MDN L WNDQNRZ\P 'R

QDMOHSLHM SR]QDQ\FK QDOHĪą NRDNW\ZDWRU UHFHSWRUD VWHURLGRZH

JR65&±Steroid Receptor Co-activator)RUD]ELDáNR5,3

(Receptor-Interacting Protein  >  @ 3RQDGWR UHFHSWR

U\ KRUPRQyZ VWHURLGRZ\FK PRJą UyZQLHĪ DNW\ZRZDü SR]DJHQR

PRZH V]ODNL V\JQDáRZH WDNĪH Z SU]\SDGNX EUDNX OLJDQGX >@

Selektywne modulatory receptora progesteronowego

2G F]DVX ]V\QWHW\]RZDQLD SLHUZV]HJR DQWDJRQLVW\ 35 PL

IHSULVWRQX Z  URNX XGDáR VLĊ ]LGHQW\¿NRZDü VHWNL LQQ\FK ]ZLą]NyZ EĊGąF\FK OLJDQGDPL WHJR UHFHSWRUD >@ *UXSD WD REHMPXMH V]HURNLH VSHNWUXP ]ZLą]NyZ RG F]\VW\FK DJRQLVWyZ

GR VXEVWDQFML R DNW\ZQRĞFLDFK Z\áąF]QLH DQWDJRQLVW\F]Q\FK 3$ 6350 FKDUDNWHU\]XMą VLĊ PLHV]DQą DNW\ZQRĞFLą V\WXXMąFą MH Z ĞURGNX WHJR VSHNWUXP D Z\ZRá\ZDQ\ SU]H] QLH HIHNW UyĪ

QL VLĊ Z ]DOHĪQRĞFL RG WNDQNL GRFHORZHM 3RGREQLH GR QDWXUDO

QHJR SURJHVWHURQX PROHNXá\ 6350 ZLąĪą VLĊ ] 35 SRZRGXMąF LFK GLPHU\]DFMĊ D QDVWĊSQLH ]ZLą]DQLH ] VHNZHQFMDPL SURPR

WRURZ\PL GRFHORZ\FK JHQyZ -HGQDNĪH ]PLDQ\ NRQIRUPDF\MQH SREXG]RQHJR Z WHQ VSRVyE 35 XPRĪOLZLDMą MHJR LQWHUDNFMĊ QLH W\ONR ] NRDNW\ZDWRUDPL OHF] UyZQLHĪ ] NRUHSUHVRUDPL WDNLPL MDN UHSUHVRU UHFHSWRUD MąGURZHJR 1&R5 ± Nuclear Receptor Co- repressor) OXE PHGLDWRU UHFHSWRUD NZDVX UHWLQRZHJR L UHFHSWRUD KRUPRQX W\URLGRZHJR 6057 ± Silencing Mediator for Retinoid

Rycina 1. Początkowa struktura dwóch głównych izoform receptora progesteronowego A i B (PR A, PR B), AF = domena aktywacji, ID = domena inhibitorowa, DBD = domena wiążąca DNA, LBD = domena wiążąca ligand, RZ = region zawiasowy odpowiedzialny za translokacje receptora do jądra komórkowego, ATG = kodon początku transkrypcji.

Rycina 2. Mechanizm działania progesteronu poprzez swoiste receptory progesteronowe A lub B. PRE = progesterone response element, PR-A/B = receptor progesteronowy A lub B [15].

Acid Receptor and Thyroid Hormone Receptor). 3RGREQLH MDN DN

W\ZDWRU\ NRUHSUHVRU\ Vą V]HURNą JUXSą ELDáHN R ZáDĞFLZRĞFLDFK HQ]\PDW\F]Q\FK QS R DNW\ZQRĞFL GHDFHW\OD]\ KLVWRQRZHM NWy

UH PRGXOXMą VWUXNWXUDOQLH '1$ L KDPXMą SURFHV WUDQVNU\SFML >@

:HZQąWU]NRPyUNRZD UyZQRZDJD SRPLĊG]\ NRDNW\ZDWRUDPL D NRUHSUHVRUDPL Z\GDMH VLĊ E\ü WNDQNRZR VZRLVWD : ]DOHĪQRĞFL ZLĊF RG UyĪQLF Z EXGRZLH NRQNUHWQ\FK 6350 MDN UyZQLHĪ WNDQ

NRZ\FK VWĊĪHĔ Z\PLHQLRQ\FK ZF]HĞQLHM NRPRGXODWRUyZ HIHNW LFK G]LDáDQLD EĊG]LH DJRQLVW\F]Q\ EąGĨ DQWDJRQLVW\F]Q\ Z VWR

VXQNX GR SURJHVWHURQX >@ 5\FLQD 

=DUyZQR $3 MDN L 6350 QLH KDPXMą ]PLDQ NRQIRUPDF\M

Q\FK 35 RGáąF]HQLD ELDáHN V]RNX WHUPLF]QHJR RUD] GLPHU\]D

FML D JáyZQ\PL F]\QQLNDPL GHF\GXMąF\PL R URG]DMX DNW\ZQRĞFL 6350 Vą UHNUXWDFMD L SRWUDQVODF\MQH PRG\¿NDFMH NRUHJXODWRUyZ RUD] VDPHJR 35 >  @ 'RGDWNRZR SHZQą UROĊ RGJU\ZDMą UyZQLHĪ Z]DMHPQH RGG]LDá\ZDQLD ] LQQ\PL V]ODNDPL ZHZQąWU]

NRPyUNRZ\PL PLQ F$03]DOHĪQ\PL RUD] VWRVXQHN SRV]F]H

JyOQ\FK L]RIRUP 35 >@ 1LHNWyUH 6350 SRVLDGDMą Z\MąWNRZH ZáDĞFLZRĞFL ZLąĪą VLĊ ERZLHP QLH W\ONR ] UHFHSWRUHP SURJHVWH

URQRZ\P 3U]\NáDGHP WDNLHJR ]ZLą]NX MHVW PLIHSULVWRQ NWyU\

MDNR F]\VW\ DQWDJRQLVWD 35 SRVLDGD  GR  UD]\ ZLĊNV]H SRZLQR

ZDFWZR GR UHFHSWRUD JOXNRNRUW\NRLGRZHJR *5 QLĪ GHNVDPH

WD]RQ >@

6WDQGDUGRZR Z FHOX RNUHĞOHQLD DNW\ZQRĞFL SURJHVWDJHQQHM

VWRVXMH VLĊ WHVW 0F3KDLOD Z NWyU\P RFHQLH SRGGDZDQ\ MHVW VWR

SLHĔ SUROLIHUDFML RUD] WUDQVIRUPDFML HQGRPHWULXP X QLHGRMU]Dá\FK NUyOLNyZ SRGGDQ\FK ZF]HĞQLHM VW\PXODFML HVWURJHQRZHM D QD

VWĊSQLH G]LDáDQLX EDGDQHM VXEVWDQFML > @

0LPR LĪ in vivo 6350 SRVLDGDMą ZLHOH SRNUHZQ\FK FHFK EORNXMą RZXODFMĊ SRGREQLH RGG]LDá\ZXMą QD PLĊĞQLDNL PDFL

F\ RUD] HQGRPHWULXP WR WHVW 0F3KDLOD QLH RSLVXMH VXEWHOQ\FK UyĪQLF Z G]LDáDQLX DQWDJRQLVW\F]Q\P Z]JOĊGHP 35 SRPLĊG]\

SRV]F]HJyOQ\PL PROHNXáDPL 3RVWXOXMH VLĊ ZLĊF ZSURZDG]HQLH QRZHM EDUG]LHM ]DDZDQVRZDQHM NODV\¿NDFML NWyUD ED]XMąF QD

DNW\ZQRĞFL WUDQVNU\SF\MQHM RSLV\ZDáDE\ QLHSRZWDU]DOQH ZáDĞFL

ZRĞFL NDĪGHJR 6350 ] RVREQD >@

-HGQDN PLPR ]LGHQW\¿NRZDQLD EDUG]R OLF]QHM JUXS\ ]ZLą]

NyZ RSLV\ZDQ\FK MDNR 6350 ]DOHGZLH NLOND ] QLFK WHVWRZDQR NOLQLF]QLH D W\ONR GZD Vą ]DUHMHVWURZDQH Z SUDNW\FH JLQHNROR

JLF]QHM 7DEHOD ,

0LIHSULVWRQ MHVW VWRVRZDQ\ Z SRQDG  NUDMDFK Z FHOX WHUPL

QDFML FLąĪ\ QDWRPLDVW 83$ ZF]HĞQLHM ]DWZLHUG]RQ\ MDNR GRUDĨQD DQW\NRQFHSFMD ]RVWDá GRSXV]F]RQ\ SU]H] .RPLVMĊ (XURSHMVNą GR SU]HGRSHUDF\MQHJR OHF]HQLD PLĊĞQLDNyZ >@

Tabela I. Zarejestrowane oraz będące w trakcie badań możliwe zastosowania wybranych selektywnych modulatorów receptora progesteronowego [15].

=ZLą]HNFKHPLF]Q\ %DGDQH]DVWRVRZDQLH

WHUDSHXW\F]QH

0LIHSULVWRQ58

7HUPLQDFMDFLąĪ\

'RUDĨQDDQW\NRQFHSFMD

&KRURE\SV\FKRW\F]QH

&KRURED&XVKLQJD

'áXJRWHUPLQRZDDQW\NRQFHSFMD 0LĊĞQLDNLPDFLF\

(QGRPHWULR]D

&KRURED$O]KHLPHUD 5DNHQGRPHWULXP

2FWDQXOLSU\VWDOX

&'%

'RUDĨQDDQW\NRQFHSFMD 0LĊĞQLDNLPDFLF\

'áXJRWUZDáDDQW\NRQFHSFMD

2FWDQWHODSULVWRQX

&'%

0LĊĞQLDNLPDFLF\

1LHGRNUZLVWRĞü (QGRPHWULR]D /RQDSULVDQ=. 5DN

&3L&3 =DEXU]HQLDJLQHNRORJLF]QH

:$< $QW\NRQFHSFMD

Rycina 3. Mechanizm działania selektywnych modulatorów receptora progesteronowego (SPRM). PRE = progesterone response element, PR-A/B = receptor progesteronowy A lub B [15].

Działanie antykoncepcyjne SPRM

-XĪ GDZQR XGRZRGQLRQR ĪH PLIHSULVWRQ RSyĨQLD SU]HPLD

Q\ HQGRPHWULDOQH XQLHPRĪOLZLDMąF LPSODQWDFMĊ ]DĞ Z Z\ĪV]\FK GDZNDFK KDPXMH UyZQLHĪ GRMU]HZDQLH RRF\WyZ RUD] LQGXNXMH DWUH]MĊ SĊFKHU]\NyZ > @ 3URFHV ]DJQLHĪGĪHQLD VLĊ EODVWRF\

VW\ ]RVWDMH WDNĪH ]DEXU]RQ\ SU]H] SRMHG\QF]ą GDZNĊ 83$ 25*

 RUD] =.  >  @

: FKZLOL REHFQHM SRMHG\QF]D GDZND  PJ 83$ X]\VNDáD UHMHVWUDFMĊ Z DQW\NRQFHSFML GRUDĨQHM SRVWNRLWDOQHM GR  JRG]LQ SR ZVSyáĪ\FLX %DGDQLD QDG ]DVWRVRZDQLHP 6350 Z GáXJRWUZD

áHM DQW\NRQFHSFML Vą PQLHM ]DDZDQVRZDQH MDNNROZLHN NLOND SUDF Z\ND]DáR ĪH FRG]LHQQH QLVNLH GDZNL PLIHSULVWRQX  PJ OXE 83$  PJ VNXWHF]QLH EORNXMą RZXODFMĊ X ZLĊNV]RĞFL NRELHW

>@

3RQDGWR PLIHSULVWRQ NWyUHJR G]LDáDQLH DQWDJRQLVW\F]QH Z]JOĊGHP 35 MHVW Z\MąWNRZH SR]RVWDMH MHG\Q\P RGNU\W\P 6350 ]GROQ\P GR SU]HUZDQLD FLąĪ\ 2SXEOLNRZDQH GR WHM SRU\

GDQH ZVND]XMą LĪ PLIHSULVWRQ Z GDZFH  GR  PJ Z NRP

ELQDFML ] SURVWDJODQG\QDPL MHVW Z\VRFH VNXWHF]Q\ Z WHUPLQDFML FLąĪ\ >@

SPRM w leczeniu endometriozy

2SLHUDMąF VLĊ QD DQW\SUROLIHUDF\MQ\P RUD] SURPXMąF\P DSR

SWR]Ċ NRPyUHN HQGRPHWULXP G]LDáDQLX 6350 >@

]DREVHUZRZDQR Z PRGHODFK ]ZLHU]ĊF\FK X NWyU\FK ZF]HĞQLHM Z\ZRáDQR FKLUXUJLF]QLH HQGRPHWULR]Ċ ]PQLHMV]HQLH ZLHONRĞFL RJQLVN HQGRPHWULR]\ RG  GR  SR WHUDSLL RQDSULVWRQHP =.

  RUD] PLIHSULVWRQHP > @ 0LIHSULVWRQ Z PRQRWHUD

SLL RND]Dá VLĊ EDUG]LHM VNXWHF]Q\ QLĪ Z OHF]HQLX VNRMDU]RQ\P ] DQDORJLHP *Q5+ OXE VDP\P DQDORJLHP *Q5+ >@ :\ND

]DQR SRQDGWR UHGXNFMĊ SURGXNFML SURVWDJODQG\Q SU]H] WNDQNĊ HQGRPHWULDOQą FR PRĪH ZSá\ZDü QD ]PQLHMV]HQLH GROHJOLZRĞFL EyORZ\FK ]ZLą]DQ\FK ] W\P VFKRU]HQLHP > @ FR ]QDOD]áR SRWZLHUG]HQLH Z EDGDQLDFK NOLQLF]Q\FK Z NWyU\FK X]\VNDQR SR

SUDZĊ Z ]DNUHVLH GROHJOLZRĞFL EyORZ\FK RUD] LQQ\FK NOLQLF]Q\FK Z\NáDGQLNyZ HQGRPHWULR]\ >  @ :\QLNL EDGDĔ ]ZáDV]

F]D QDG PLIHSULVWRQHP Z\GDMą VLĊ E\ü EDUG]R RELHFXMąFH SU]HGH ZV]\VWNLP ]H Z]JOĊGX QD EUDN REMDZyZ KLSRHVWURJHQL]PX

SPRM w chorobach nowotworowych

)L]MRORJLF]\ SR]LRP HNVSUHVML REX L]RIRUP 35 ]RVWDMH ]DEX

U]RQ\ SU]H] SURFHV NDUF\QRJHQH]\ > @ 1DGHNVSUHVMD 35%

NRUHORZDáD ]H VWRSQLHP ]áRĞOLZRĞFL QRZRWZRUyZ HQGRPHWULXP RUD] UDNyZ HQGRPHWULDOQ\FK L QDEáRQNRZ\FK MDMQLND > @

]DĞ Z]JOĊGQ\ QLHGREyU 35$ ]DREVHUZRZDQR Z SU]HZRGRZ\FK UDNDFK JUXF]RáX VXWNRZHJR >@ 3LHUZV]H EDGDQLD VXJHUXMą ĪH 6350 PRJą ]QDOHĨü ]DVWRVRZDDQLH Z OHF]HQLX UDND JUXF]RáX VXWNRZHJR VDPH OXE Z VNRMDU]HQLX ] DQW\HVWURJHQDPL >@ 0L

IHSULVWRQ Z\ZLHUD UyZQLHĪ DQW\SUROLIHUDF\MQ\ HIHNW QD 35GR

GDWQLH NRPyUNL UDND QDEáRQNRZHJR MDMQLND >@ &R FLHNDZH

QRZV]H SUDFH ZVND]XMą LĪ PLIHSULVWRQ KDPXMH Z]URVW NRPyUHN QRZRWZRURZ\FK SRFKRG]HQLD UR]URGF]HJR RUD] SR]DUR]URGF]H

JR QLH]DOHĪQLH RG HNVSUHVML 35 FR PRĪH GRGDWNRZR SRV]HU]Dü ]DNUHV HZHQWXDOQ\FK ]DVWRVRZDĔ WHJR DQWDJRQLVW\ >@

SPRM w leczeniu mięśniaków macicy : ODWDFK RVLHPG]LHVLąW\FK XELHJáHJR VWXOHFLD ]DREVHUZRZD

QR D Z G]LHZLĊüG]LHVLąW\FK SRWZLHUG]RQR LĪ NRPyUNL PLĊĞQLD

NyZ PDFLF\ ]DZLHUDMą ZLĊFHM P51$ GOD UHFHSWRUyZ HVWURJHQR

Z\FK L SURJHVWHURQRZ\FK (5 L 35 QLĪ SREUDQH ]H ]GURZHJR P\RPHWULXP > @ : Z\QLNX SRZ\ĪV]\FK VSRVWU]HĪHĔ ]DSUR

SRQRZDQR KLSRWH]Ċ R KRUPRQR]DOHĪQ\P SRZVWDZDQLX L Z]URĞFLH W\FK JX]yZ 3LHUZRWQLH WR HVWUDGLRO Z\GDZDá VLĊ VW\PXORZDü Z]URVW NRPyUHN PLĊĞQLDNyZ Z PHFKDQL]PDFK EH]SRĞUHGQLFK RUD] SRSU]H] F]\QQLNL Z]URVWX MDN (*) ,*) >@ /HF]QLF]H ]DVWRVRZDQLH SURJHVWDJHQyZ PLDáR ZLĊF SU]\QLHĞü NRU]\ĞFL QD ]DVDG]LH SU]HFLZG]LDáDQLD HIHNWRP HVWUDGLROX 2ND]DáR VLĊ MHG

QDN LĪ SR]D ]PQLHMV]HQLHP QDWĊĪHQLD NUZDZLHĔ PDFLF]Q\FK ]D

REVHUZRZDQR UyZQLHĪ Z]URVW PDV\ JX]yZ >@ : SyĨQLHMV]\FK EDGDQLDFK Z\ND]DQR LĪ SURJHVWHURQ VW\PXOXMH SUROLIHUDFMĊ OLQLL NRPyUNRZ\FK PLĊĞQLDNyZ SRSU]H] G]LDáDQLH DQW\DSRSWRW\F]QH

>@ L SUDZGRSRGREQLH DQDORJLF]QLH GR HVWUDGLROX SU]H] ,*)

L (*) >@ :\NRU]\VWXMąF SRZ\ĪV]H GDQH ]DSURSRQRZDQR PRGHO WHUDSLL RSDUW\ QD ]ZLą]NDFK FKHPLF]Q\FK NWyUH SU]\áą

F]DMą VLĊ GR UHFHSWRUD 35

=DVWRVRZDQR ]DWHP DQWDJRQLVWĊ 3$ FR RND]DáR VLĊ VNX

WHF]QH Z ]PQLHMV]HQLX PDV\ PLĊĞQLDNyZ L GROHJOLZRĞFL EyOR

Z\FK SRGEU]XV]D RUD] DQHPLL 8GRZRGQLRQR WR Z ZLHOX EDGD

QLDFK NOLQLF]Q\FK ] ]DVWRVRZDQLHP PLIHSULVWRQX Z ODWDFK 

 VWRVXMąF GDZNRZDQLH RG  GR  PJ SU]H] F]DV  GR  PLHVLĊF\ Z UyĪQ\FK SURWRNRáDFK >@

$QDORJLF]QLH ]DVWRVRZDQLH JUXS\ 6350 ± 83$ L WHODSUL

VWRQX RUD] DVRSULVQLOX Z EDGDQLDFK QDG KRGRZODQ\PL OLQLDPL NRPyUNRZ\PL leiomyoma, Z\ND]DáR LVWRWQH ]DKDPRZDQLH SUR

OLIHUDFML RUD] QDVLOHQLH ]DOHĪQ\FK RG VWUHVX ZHZQąWU] L ]HZQąWU]

SRFKRGQ\FK GUyJ DSRSWR]\ >@ &R FLHNDZH WDNLFK HIHNWyZ QLH RGQRWRZDQR ZREHF NRPyUHN ]GURZHJR P\RPHWULXP 83$ SR

QDGWR KDPRZDá V\QWH]Ċ NRODJHQX F]\QQLNyZ Z]URVWX L LFK UHFHS

WRUyZ Z OLQLDFK NRPyUNRZ\FK PLĊĞQLDNyZ >@

3XEOLNRZDQH Z ODWDFK  EDGDQLD NOLQLF]QH SRWZLHU

G]DMą LĪ 6350 Vą HIHNW\ZQH Z OHF]HQLX PLĊĞQLDNyZ PDFLF\

SRG NąWHP ]PQLHMV]HQLD REMĊWRĞFL JX]yZ RG  REMĊWRĞFL 3RQDGWR Z RGUyĪQLHQLX GR WHUDSLL DJRQLVWDPL *Q5+ 6350 ]PQLHMV]DMą VSRZRGRZDQH REHFQRĞFLą PLĊĞQLDNyZ NUZDZLHQLH EH] KDPRZDQLD VHNUHFML HVWURJHQyZ 83$ DVRSULVQLO L PLIHSUL

VWRQ WDNĪH SR]\W\ZQLH ZSá\ZDMą QD MDNRĞü Ī\FLD NRELHW SRGGD

Q\FK EDGDQLRP >@

: URNX  .RPLVMD (XURSHMVND R¿FMDOQLH ]DUHMHVWURZDáD 83$ Z GDZFH PJG]LHĔ MDNR PHWRGĊ SU]HGRSHUDF\MQHJR OHF]H

QLD PLĊĞQLDNyZ PDFLF\ X NRELHW Z ZLHNX UR]URGF]\P :VND

]DQLD GRW\F]ą SDFMHQWHN X NWyU\FK Z\VWĊSXMą REMDZ\ R XPLDU

NRZDQ\P OXE FLĊĪNLP QDVLOHQLX D RNUHV OHF]HQLD QLH SRZLQLHQ SU]HNUDF]Dü  PLHVLĊF\ >@ 3UHSDUDW RFHQLDQ\ E\á Z GZyFK EDGDQLDFK NOLQLF]Q\FK 3($5/ , L 3($5/ ,, NWyU\FK Z\QLNL ]RVWDá\ RSXEOLNRZDQH Z OXW\P  URNX >@ D WDNĪH ]DZDUWH Z 6WDQRZLVNX =HVSRáX (NVSHUWyZ 37* Z VSUDZLH ]DVWRVRZDQLD 6350 Z OHF]HQLX PLĊĞQLDNyZ PDFLF\ >@ :\QLNL EDGDQLD 3(

$5/ , XND]Dá\ LĪ 83$ VWRVRZDQ\ ]DUyZQR Z GDZFH PJ MDN L PJ  GREĊ MHVW VNXWHF]QLHMV]\ RG SUHSDUDWX SODFHER Z NRQWUROL NUZDZLHĔ PDFLF]Q\FK  YV  RUD] ]PQLHMV]HQLD REMĊWRĞFL PLĊĞQLDND  > PJ@  > PJ@  >SODFHER@ > @

2SXEOLNRZDQH GDQH EDGDQLD 3($5/ ,, ZVND]Dá\ MHGQR]QDF]QLH

LĪ 83$ ]DUyZQR Z GDZFH  PJ MDN L  PJ G]LHQQLH MHVW UyZ

QLH VNXWHF]Q\ FR RFWDQ OHXSUROLGX Z DVSHNFLH NRQWUROL NUZDZLHĔ PDFLF]Q\FK QLH Z\ND]XMąF SU]\ W\P HIHNWyZ QLHGRERUX HVWUR

JHQyZ

5DSRUW\ SRZ\ĪV]\FK EDGDĔ RNUHĞORQH ]RVWDá\ PLDQHP ÄZDĪ

QHJR NURNX´ Z DVSHNFLH HIHNW\ZQHJR QLHRSHUDF\MQHJR OHF]HQLD

PLĊĞQLDNyZ PDFLF\ REQDĪDMąF MHGQDN SUREOHP WUXGQHJR GR LQ

WHUSUHWDFML UR]URVWX EáRQ\ ĞOX]RZHM HQGRPHWULXP

3RGGDMąF V]F]HJyáRZHM DQDOL]LH ]DUyZQR EDGDQLD 3($5/ ,

MDN L 3($5/ ,, OHF] WDNĪH ELRUąF SRG XZDJĊ ZF]HĞQLHMV]H GRQLH

VLHQLD GRW\F]ąFH VWRVRZDQLD PLIHSULVWRQX L DVRSU\VQLOX Z\ND]D

QR ĪH HQGRPHWULXP XOHJD PDáR VZRLVW\P ]PLDQRP KLVWRORJLF]

Q\P NWyUH QD]ZDQR 3$(&V (Progesterone Receptor Modulator – Associated Endometrial Changes) >@ =PLDQ\ WH FKDUDNWHU\]XMą VLĊ QLVNą DNW\ZQRĞFLą SUROLIHUDF\MQą NRPyUHN QDEáRQND ] MHGQR

F]HVQ\P DV\PHWU\F]Q\P UR]URVWHP SRGĞFLHOLVND L SRV]HU]HQLHP JUXF]RáyZ >@ 3UDFD RSXEOLNRZDQD Z  URNX SU]H] +RUQH L ZVS >@ SU]HGVWDZLáD VWDQRZLVNR SDQHOX HNVSHUWyZ SDWRORJyZ

NWyUH X]QDáR ]PLDQ\ Z HQGRPHWULXP SRG ZSá\ZHP 6350 ]D QLH]DJUDĪDMąFH EH]SLHF]HĔVWZX SDFMHQWD (NVSHUFL ]DVWU]HJOL MHG

QDN LĪ HIHNW G]LDáDQLD 6350 QD HQGRPHWULXP SRZLQLHQ ]RVWDü GRNáDGQLHM RSLVDQ\ XV\VWHPDW\]RZDQ\ L SRGOHJDü VWDQGDU\]DFML

DE\ RNUHĞOLü HZHQWXDOQH V\JQDá\ KLVWRORJLF]QH Z\PDJDMąFH SRG

MĊFLD G]LDáDĔ GLDJQRVW\F]QRWHUDSHXW\F]Q\FK

2EHFQLH 3$(&V QLH SRGOHJDMą GH¿QLFML UR]URVWX HQGRPH

WULXP SR WU]\PLHVLĊF]QHM WHUDSLL 6350V 8]\VNDQLH GRNáDGQ\FK GDQ\FK Z\PDJD MHGQDN GáXJRIDORZ\FK EDGDĔ QDG EH]SLHF]HĔ

VWZHP W\FK SUHSDUDWyZ

Bezpieczeństwo SPRM

5DSRUW\ ]  URNX NWyUH GRSURZDG]Lá\ GR ]DZLHV]HQLD ED

GDĔ ,,, ID]\ QDG QLHNWyU\PL 6350 Z\ND]Dá\ KHSDWRWRNV\F]QRĞü GZyFK SUHSDUDWyZ RQDSULVWRQX L RFWDQX WHODSULVWRQX PJ SUDZGRSRGREQLH Z\QLNDMąFą ]H VWUXNWXU\ F]ąVWHF]HN RUD] GUyJ LFK PHWDEROL]PX 1RWRZDQR WDNĪH QLHZLHONLHJR VWRSQLD SRGZ\Ī

V]HQLH VXURZLF]HJR VWĊĪHQLD SURODNW\Q\ :REHF 83$ QLH RSLVDQR ĪDGQ\FK ] SRZ\ĪV]\FK G]LDáDĔ XERF]Q\FK >@

%DGDQLD 3($5/ QLH Z\ND]Dá\ FLĊĪNLFK G]LDáDĔ QLHSRĪą

GDQ\FK D WH REVHUZRZDQH QDMF]ĊĞFLHM SRG SRVWDFLą EyOyZ JáR

Z\ L WNOLZRĞFL JUXF]RáyZ VXWNRZ\FK PLDá\ FKDUDNWHU áDJRGQ\

L XPLDUNRZDQ\ GR VLOQ\FK Z SU]\SDGNX XGHU]HĔ JRUąFD 

>83$@ YV  >/XSURQ@ >@

6350 WR OLJDQG\ UHFHSWRUD 35 NWyUH ZFKRG]ąF Z LQWHUDN

FMH ] NRDNW\ZDWRUDPL L NRUHSUHVRUDPL X]\VNXMą PLHV]DQH HIHNW\

DQWDJRQLVW\F]QH OXE DJRQLVW\F]QH 3RVLDGDMą SRWHQFMDá KDPRZD

QLD RZXODFML L NUZDZLHQLD ]PQLHMV]DQLD REMĊWRĞFL PLĊĞQLDNyZ PDFLF\ RUD] SRZRGXMą QLHW\SRZH ]PLDQ\ KLVWRORJLF]QH Z HQGR

PHWULXP 6350V REHFQLH ]DUHMHVWURZDQH Vą Z GRUDĨQHM DQW\NRQ

FHSFML SU]HU\ZDQLX FLąĪ\ L RG WHJR URNX Z OHF]HQLX SU]HGRSHUD

F\MQ\P V\PSWRPDW\F]Q\FK PLĊĞQLDNyZ PDFLF\ 7UZDMą EDGDQLD QDG VWRVRZDQLHP W\FK SUHSDUDWyZ Z GáXJRWUZDáHM DQW\NRQFHSFML

OHF]HQLX HQGRPHWULR]\ L QRZRWZRUyZ : FHOX SR]QDQLD SHáQHM V]HURNRĞFL VSHNWUXP G]LDáDQLD 6350 Z RUJDQL]PLH OXG]NLP SR

WU]HEQH Vą GDOV]H GáXJRIDORZH EDGDQLD XGRZDGQLDMąFH ]DUyZQR HIHNW\ZQRĞü MDN L EH]SLHF]HĔVWZR W\FK SUHSDUDWyZ

P i ś m i e n n i c t w o

1. Baird D, Dunson D, Cousins D, [et al.]. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003, 188, 100-107.

2. Zimmermann A, Bernuit D, Gerlinger C, [et al.]. Prevalence, symptoms and management of uterine fibroids: an international internet-based survey of 21,746 women. BMC Womens Health.

2012, 12, 6.

3. Marshall L, Spiegelman D, Goldman M, [et al.]. A prospective study of reproductive factors and oral contraceptive use in relation to the risk of uterine leiomyomata. Fertil Steril. 1998, 70, 432–439.

4. Vikhlyaeva E, Khodzhaeva Z, Fantschenko N. Familial predisposition to uterine leiomyomas. Int J Gynaecol Obstet. 1995, 51, 127–131.

5. Shikora S, Niloff J, Bistrian B, [et al.]. Relationship between obesity and uterine leiomyomata.

Nutrition. 1991, 7, 251–255.

6. Ryan G, Syrop C, Van Voorhis B. Role, epidemiology, and natural history of benign uterine mass lesions. Clin Obstet Gynecol. 2005, 48, 312–324.

7. Lippman S, Warner M, Samuels S, [et al.]. Uterine fibroids and gynecologic pain symptoms in a population-based study. Fertil Steril. 2003, 80, 1488–1494.

8. Catherino W, Parrot E, Segars J. Proceedings from the National Institute of Child Health and Hu- man Development conference on the Uterine Fibroid Research Update Workshop. Fertil Steril.

2011, 95, 9-12.

9. Ishikawa H, Ishi K, Serna V, [et al.]. Progesterone is essential for maintenance and growth of uterine leiomyoma. Endocrinology. 2010, 151, 2433-2442.

10. Pietura R, Kotarski J, Janczarek M, [et al.]. Uterine artery embolization as a treatment of uterine leiomyomas. Ginekol Pol. 2003, 74, 79-84.

11. Levy B. Modern management of uterine fibroids. Acta Obstet Gynecol Scand. 2008, 87, 812–

823.

12. Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterecto- my or myomectomy for uterine fibroids. Cochrane Database Syst Rev. 2001, 2: CD000547 13. Donnez J, Tatarczuk T, Bouchard P, [et al.]. Ulipristal acetate versus placebo for fibroid treatment

before surgery. N Eng J Med. 2012, 366, 409-420.

14. Donnez J, Tomaszewski J, Vazquez F, [et al.]. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Eng J Med. 2012, 366, 421-432.

15. Bouchard P, Chabert-Buffet N, Fauser B. Selective progesterone receptor modulators in repro- ductive medicine : pharmacology, clinical efficacy and safety. Fertil Steril. 2011, 96, 1175-1189.

16. Conneely O, Jericevic B, DeMayo F, [et al.]. Reproductive functions of progesterone receptor.

Recent Prog Horm Res. 2002, 57, 339-355.

17. Mesiano S, Welsh T. Steroid hormone control of myometrial contractility and parturition. Semin Cell Dev Biol. 2007, 18, 321-331.

18. Conneely O, Jericevic B, Lydon J. Progesterone receptors in mammary gland development and tumorigenesis. J Mammary Gland Biol Neoplasia. 2003, 8, 205-214.

19. Li Q, Kannan A, DeMayo F, [et al.]. The antiprolifarative action of progesterone in uterine epithe- lium is mediated by Hand2. Science. 2011, 331, 912-916.

20. Scarpin K, Graham J, Mote P, [et al.]. Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression.

Nucl Recept Signal. 2009, 7, e009.

21. Kastner P, Krust A, Turcotte B, [et al.]. Two distinct estrogen-regulated promoters generate tran- scripts encoding the two functionally different human progesterone receptor forms A and B.

EMBO J. 1990, 9, 1603-1614.

22. Conneely O, Jericevic B, Lydon J, [et al.]. Reproductive functions of progesterone receptor isoforms: lessons from knock-out mice. Mol Cell Endocrinol. 2001, 179, 97-103.

23. Chabbert-Buffet N, Meduri G, Bouchard P, [et al.]. Selective progesterone receptor modulators and progesterone antagonists: mechanism of action and clinical application. Hum Reprod Up- date. 2005, 11, 293-307.

24. Smith C, O’Malley B. Coregulator functions: a key to understanding tissue specifity of selective receptor modulators. Endocr Rev. 2004, 25, 45-71.

25. Boonyaratanakornkit V, Edwards D. Receptor mechanism mediating non-genomic actions of sex steroids. Semin Reprod Med. 2007, 25, 139-153.

26. Philibert D. RU 38486: an original multifaced antihormone in vivo. In: Adrenal steroid antago- nism. Ed. Agarwal M. Berlin: Walter de Gruyter.1984, 77-101.

27. Madauss K, Grygielko E, Deng S, [et al.]. A structural and in vitro characterization of asoprisnil:

a selective progesterone receptor modulator. Mol Endocrinol. 2007, 21, 1066-1081.

28. Liu Z, Auboeuf D, Wong J, [et al.]. Coactivator/corepressor ratios modulate PR-mediated tran- scripction by the selective receptor modulator RU486. Proc Natl Acad Sci USA 2002, 99, 7940- 7944.

29. Hermanson O, Glass C, Rosenfeld M. Nuclear receptor coragulators: multiple modes of modifi- cation. Trends Endocrinol Metabol. 2002, 13, 55-60.

30. Gellersen B, Brosens J. Cyclic AMP and progesterone receptor cross-talk in human endome- trium: a decidualizing affair. J Endocrinol. 2003, 178, 357-372.

31. Madauss K, Stewart E, Williams S. The evolution of progesterone receptor ligands. Med Res Rev. 2007, 27, 374-408.

32. McPhail M. The assay of progestin. J Physiol. 1934, 83, 145-156.

33. Elger W, Bartley J, Schneider B, [et al.]. Endocrine pharmacological characterization of proge- sterone antagonists and progesterone receptor modulators with respect to PR agonistic and antagonistic activity. Steroids. 2000, 65, 713-723.

34. Afhüppe W, Sommer A, Miller J, [et al.]. Global gene expression profiling of progesterone recep- tor modulators in T47D cells provides a new classification system. J Steroid Biochem Mol Biol.

2009, 113, 105-115.

35. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/ medicines/002041/

human_med_001542.jsp&mid=WC0b01ac058001d124

36. Croxatto H, Salvatierra A, Croxatto H, [et al.]. Effects of continous treatment with low dose mifepristone throughout one menstrual cycle. Hum Reprod. 1993, 8, 201-207.

37. Liu J, Garzo G, Morris S, [et al.]. Disruption of follicular maturation and delay of ovulation after administration of antiprogesterone RU486. J Clin Endocrinol Metabol. 1987, 65, 1135-1140.

38. Stratton P, Levens E, Hartog B, [et al.]. Endometrila effects of a single early luteal dose of the selective progesterone receptor modulator CDB-2914. Fertil Steril. 2009, 93, 2035-2041.

39. Banaszak S, Brudney A, Donnelly K, [et al.]. Modulation of the action of chorionic gonadotropin in the baboon (Papio anubis) uterus by progesterone receptor antagonist (ZK 137-316). Biol Reprod. 2000, 63, 820-825.

40. Petersen A, Bentin-Ley U, Ravn V, [et al.]. The antiprogesterone ORG 31710 inhibits human blastocyst-endometrial interactions in vitro. Fertil Steril. 2005, 85, (Suppl 1), 1255-1263.

41. Baird D, Thong K, Hall C, [et al.]. Failure of oestrogen induced luteinizing hormone surge in women treated with mifepristone (RU 486) every day for 30 days. Hum Reprod. 1995, 10, 2270-2276.

42. Chabbert-Buffet N, Pintiaux-Kairis A, Bouchard P. Effects of progesterone receptor modulator VA2914 in a continous low dose on the hypothalamic-pituitary-ovarian axis and endometrium in normal women: a prospective, randomized, placebo-controlled trial. J Clin Endocrinol Metabol.

2007, 92, 3582-3589.

43. Fiala C, Gemzel-Danielsson K. Review of medical abortion using mifepristone in combination with a prostaglandin analogue. Contraception. 2006, 74, 66-86.

44. Han S, Sidell N. RU486-induced growth inhibition of human endometrial cells involves the nuc- lear factor-kappa B signaling pathway. J Clin Endocrinol Metabol. 2003, 88, 713-719.

45. Brenner R, Slayden O, Nath A, [et al.]. Intrauterine administration of CDB-2914 (Ulipristal) sup- presses the endometrium in rhesus macaques. Contraception. 2010, 81, 336-342.

46. Gopalkrishnan K, Katkam R, Sachdeva G, [et al.]. Effects of antiprogestin onapristone on the endometrium of bonnet monkeys: morphometric and ultrastructural studies. Biol Reprod. 2003, 68, 1959-1967.

47. Zhang Z, Lundeen S, Slayden O, [et al.]. In vitro and in vivo characterization of a novel nonstero- idal, species specific progesterone receptor modulator, PRA-910. Ernst Schering Found Symo Proc. 2007,171-197.

48. Grow D, Williams R, Hsiu J, [et al.]. Antiprogestin and/or gonadotropin-releasing hormone ago- nist for endometriosis treatment and bone maintenance: a 1-year primate study. J Clin Endocri- nol Metab. 1996, 81, 1933-1939.

49. Stoeckemann K, Hegele-Hartung C, Chwalisz K. Effects of the progesterone antagonist ona- pristone (ZK 98 299) and ZK 136 799 on surgically induced endometriosis in intact rats. Hum Reprod. 1995,10, 3264-3271.

50. Elger W, Ivell R, Nandy A, [et al.]. Modulation of uterine prostaglandin secretion by the selective progesterone receptor modulator (SPRM) asoprisnil, progestins, and antiprogestins in cycling and ovariectomized guinea pigs. Fertil Steril. 2004, 82, (Suppl), 316.

51. Gemzell-Danielsson K, Hamberg M. The effect of antiprogestin (RU 486) and prostaglandin synthesis inhibitor (naproxen) on uterine fluid prostaglandin F2 concentrations. Hum Reprod.

1994, 9, 1626-1630.

52. Kettel L, Murphy A, Morales A, [et al.]. Treatment of endometriosis with the antiprogesterone mifepriston (RU 486). Fertil Steril. 1996, 65, 23-28.

53. Mei L, Bao J, Tang L, [et al.]. A novel mifepriston-loaded implant for long-term treatment of endometriosis: in vitro and in vivo studies. Eur J Pharm Sci. 2010, 39, 421-425.

54. Chwalisz K, Mattia-Goldberg C, Elger W, [et al.]. Treatment of endometriosis with the novel selective progesterone receptor modulator (SPRM) asoprisnil. Fertil Steril. 2004, 82, 83-84.

55. De Vivo I, Huggins G, Hankinson S, [et al.]. A functional polymorphism in the promoter of the progesterone receptro gene associated with endometrial cancer risk. Proc Natl Acad Sci USA.

2002, 99, 12263-12268.

56. Arnett-Mansfield R, DeFazio A, Mote P, [et al.]. Subnuclear distributions of progesterone re- ceptors A and B in normal and malignant endometrium. J Clin Endocrinol Metabol. 2004, 89, 1429-1442.

57. Akahira J, Inoue T, Suzuki T, [et al.]. Progesterone receptor isoforms A and B in human epithelial ovarian carcinoma : immunohistochemical and RT-PCR studies. Br J Cancer. 2000, 83, 1488- 1494.

58. Fujimoto J, Ichigo S, Hori M, [et al.]. Expression of progesterone receptor form A and B mRNAs in gynecologic malignant tumors. Tumor Biol. 1995, 16, 254-260.

59. Ariga N, Suzuki T, Moriya T, [et al.]. Progesterone receptor A and B isoforms in the human breast and its disorders. Jpn J Cancer Res. 2001, 92, 302-308.

60. Klijn J, Setyono Han B, Foekens J. Progesterone antagonists and progesterone receptor modu- lators in the treatment of breast cancer. Steroids. 2000, 65, 825-830.

61. Rose F, Barnea E. Response of human ovarian carcinoma cell lines to antiprogestin mifepriston.

Oncogene. 1996, 7, 999-1003.

62. Tieszen C, Goyeneche A, Brandhagen B, [et al.]. Antiprogestin mifepristone inhibit the growth of cancer cells of reproductive and non-reproductive origin regardless of progesterone receptor expression. BMC Cancer. 2011, 27: doi: 10.1186/1471-2407-11-207

63. Brandon D, Erickson T, Keenan E, [et al.]. Estrogen receptor gene expression in human uterine leiomyomata. J Clin Endocrinol Metab. 1995, 80, 1876-1881.

64. Englund K, Blanck A, Gustavsson I, [et al.]. Sex steroid receptors in human myometrium and fibroids: changes during the menstrual cycle and gonadotropin-releasing hormone treatment. J Clin Endocrinol Metab. 1998, 83, 4092-4096.

65. Huet-Hudson Y, Chakraborty C, De S, [et al.]. Estrogen regulates the synthesis of epidermal growth factor in mouse uterine epithelial cells. Mol Endocrinol. 1990, 4, 510-523.

66. Harrison-Woolrych M, Robinson R. Fibroid growth in response to high-dose progestogen. Fertil Steril. 1995, 64, 191-192.

67. Maruo T. Progesterone and progesterone receptor modulator in uterine leiomyoma growth. Gy- necol Endocrinol. 2007, 23, 186-187.

68. Chabbert-Buffet N, Meduri G, Bouchard P, Spitz I. Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications. Hum Reprod Update. 2005, 11, 293-307.

69. Bouchard P, Chabbert-Buffet N, Fauser B. Selective progesterone receptor modulators in repro- ductive medicine: pharmacology, clinical efficacy and safety. Fertil Steril. 2011, 96, 1175-1189.

70. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002041/

human_med_001542.jsp&mid=WC0b01ac058001d124

71. Donnez J, Tetyana F, Tatarchuk K, [et al.]. for the PEARL I Study Group Ulipristal Acetate versus Placebo for Fibroid Treatment before Surgery. N Engl J Med. 2012, 366, 409-420.

72. Donnez J, Tomaszewski J, Vázquez F, for the PEARL II Study Group Ulipristal Acetate versus Leuprolide Acetate for Uterine Fibroids. N Engl J Med. 2012, 366, 421-432.

73. Stanowisko Zespołu Ekspertów Polskiego Towarzystwa Ginekologicznego w sprawie zastoso- wania selektywnych modulatorów receptora progesteronowego (SPRM) w leczeniu mięśniaków macicy. Ginekol Pol. 2012, 83, 555-557.

74. Horne F, Blithe D. Progesterone receptor modulators and the endometrium: changes and con- sequences. Hum Reprod Update. 2007, 13, 567-580.