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DAMAS CUS UNI VE RS I T Y
Marwan&Alhalabi&&MD&PhD&Professor&in&Reproduc7ve&Medicine&Faculty&of&Medicine&&Damascus&University&&&Clinical&Medical&Director&&Orient&Hospital&&Assisted&Reproduc7on&Center&&Damascus,&Syria.&
DAMAS CUS UNI VE RS I T Y
• Is&luteal&phase&support&necessary&?&• If&so…&Progesterone&or&HCG&?&• Are&they&equally&effec7ve&?&• Which&progesterone&to&use&?&• By&which&route&–&oral,&IM&or&vaginal&?&• Are&there&pa7ent&preferences&?&
DAMAS CUS UNI VE RS I T Y
DAMAS CUS UNI VE RS I T Y
DAMAS CUS UNI VE RS I T Y
DAMAS CUS UNI VE RS I T Y 6
DAMAS CUS UNI VE RS I T Y
7
DAMAS CUS UNI VE RS I T Y
&
&&
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DAMAS CUS UNI VE RS I T Y
• Progesterone)was) independently& discovered&by) four) research) groups) in&1933.))
• The) name) PROGESTERONE) derived) from& PROGEsta:onal) STERoidal)ketONE.)
• The)molecular&weight&of)progesterone)is)100)x)π)=)314)dalt.)
• Like) other) steroids,) progesterone) consists) of& four& interconnected& cyclic&hydrocarbons.&&
• Progesterone)contains&ketone&and)oxygenated)func:onal)groups,)as)well)as)two)methyl&branches.)
• Like)all)steroid)hormones,)it)is)hydrophobic.&
DAMAS CUS UNI VE RS I T Y
Exerts& its& ac7on& primarily& through& the& intracellular& membrane& bound&progesterone&receptor&&
• Reproduc7ve&system&&o Endometrium&o Cervical)endothelium)and)mucus))o Immune&system&during&implanta7on&and&early&pregnancy&o Decreases&contrac7lity&of&the&uterine&smooth&muscles&&o Inhibits)lacta:on))o Drop& in& progesterone& levels& is& possibly& one& step& that& facilitates&
the&onset&of&labor.&&
• Regula7ng&the&effects&of&estrogen.&&
DAMAS CUS UNI VE RS I T Y
Exerts& its& ac7on& primarily& through& the& intracellular& membrane& bound&progesterone&receptor&&
• The& fetus& metabolises& placental& progesterone& in& the&produc7on&of&adrenal&mineraloW&and&glucosteroids.&
• Nervous&System&o Neuroprotec7ve&o ?&Memory&and&cogni7ve&ability.&
• Other&systems:&&o Core&temperature&&o Reduces&spasm&and&relaxes&smooth&muscle&&o Prevent&endometrial&cancer&by®ula7ng&the&effects&of&estrogen&
(as&in&PCOS).&&
DAMAS CUS UNI VE RS I T Y
• Control&anovulatory&bleeding&• In&infer7lity&therapy&&
• To&support&early&pregnancy&(?)&
• Pa7ents& with& recurrent& pregnancy& loss& due& to& inadequate&progesterone&produc7on&
• Hormone&replacement&therapy&&
• Preterm&Labor&
• Progesterone& receptor& antagonists,& or& selec7ve& progesterone&receptor&modulators&(SPRM)s&&
• Hormonal& contracep7on& do& not& contain& progesterone& but& a&proges7n&&&&
• Trea7ng&mul7ple&sclerosis&??&
• Aging&??&
• Brain&Damage&&???&&
DAMAS CUS UNI VE RS I T Y
• P& induces&a&secretory&transforma7on&of& the&endometrium…&
…&Which&improves&endometrial&recep7vity&…&
…&Which&allows&blastocyst&impanta7on.&
• P&also&causes&local&endometrial&vasodila7on.&
• P& reduces& the& contrac7lity& of& uterine&muscle.&
DAMAS CUS UNI VE RS I T Y
DAMAS CUS UNI VE RS I T Y
2
2.5
3
3.5
4
4.5
Day 15 Day 16 Day 17 Day 18 Day 19 Day 20
(De Ziegler et al. J Soc Gynecol Invest 1996;3(2):141A)
UC F
requ
ency
/M
in
Crinone 8% administered every other day (EOD) in women with ovarian premature failure
DAMAS CUS UNI VE RS I T Y
0%5%10%
15%20%25%
<3.0 3.1-4.0 4.1-5.0 >5.0
(Fanchin et al. Human Reprod 1998;13(7):1968-74)
P <0.0001,ANOVA UC/Min
Impl
anta
tion
Rate
DAMAS CUS UNI VE RS I T Y
• Studies&with&Progesterone&vs.&no&supplementa7on& PR&are&higher&with&P&supplementa7on&
&&&&&&&&&&(Leeton&et&al.,&1985,&BelaischWAllart&et&al.,&1987,&Yovich&et&al.,&1985)&
• Studies&with&hCG&vs.&no&supplementa7on&& PR&are&higher&with&supplementa7on&
&&&&&&&(Smith&et&al.,&1989,&BelaischWAllart&et&al.,&1990,&Herman&et&al.,&1990)&
• MetaWanalysis:&&&Progesterone&or&hCG&improved&the&pregnancy&rates&in&IVF&cycles&&&&&&&&&&&
Supports&rou7ne&use&of&luteal&phase&support&in&IVF&cycles&(Soliman&et&al.,&1994)&
DAMAS CUS UNI VE RS I T Y
in&IVF/ICSI&cycles:&*&live&birth&rate&was&significantly&higher&with&progesterone&for&luteal&phase&support.&
• Linden et al, Human Reproduction Update, Vol.18, No.5 p. 473, 2012. ** Erdem et al, Fertility and Sterility Vol. 91, No. 6, June 2009.
in&IUI&cycles:&**&live&birth&rate&was&significantly&higher&with&progesterone&for&luteal&phase&&
DAMAS CUS UNI VE RS I T Y
• Con7nued&downWregula7on&by&GnRHa&!&LH&↓&
• Induc7on&of&mul7ple&follicles&per$se$
• Removal&of&large&quan77es&of&granulosa&cells&at&oocyte&retrieval&
• Supraphysiological&E2/P4&in&early&luteal&phase&!&nega7ve&feedback&!&LH&↓&&
• hCG&LH&suppression&
DAMAS CUS UNI VE RS I T Y
LH FSH
Progesterone
Oestrogen
DAMAS CUS UNI VE RS I T Y
22
DAMAS CUS UNI VE RS I T Y
• Effec7ve&• Physiological&
serum&levels&• Painful&(long,&
thick,&needles)&• Occasional&
sterile&abscess&• Occasional&
allergic&reac7on&(oil&vehicle)&
• Needs&to&be&administered&by&nurse&
• Ineffec7ve&
• Low&bioavailability&
• High&rate&of&metabolites&
• Minimal&endometrial&effect&
• High&rate&of&side&effects&(somnolence)&
• Effec7ve&• Convenient&
(selfWadministra7on)&
• First&uterine&pass&effect&/&targeted&delivery&
• Can&be&messy&
• Might&require&mul7ple&dosing&/&day&
DAMAS CUS UNI VE RS I T Y (Cocrane Rev., 2004)
DAMAS CUS UNI VE RS I T Y (Cocrane&Rev.,&2004)&
DAMAS CUS UNI VE RS I T Y
(Textbook of ART, 2nd Ed., 2004; Cocrane Rev., 2004)
DAMAS CUS UNI VE RS I T Y
(Cocrane&Rev.,&2004)&
DAMAS CUS UNI VE RS I T Y
(Cocrane&Rev.,&2004)&
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• Serum&levels&of&progesterone&vs.&local&levels.&
• Recommend& star7ng& vaginal& P& on& oocyte&collec7on&day&or&next&day&(day&before&ET).&
• ‘’first&pass&effect’’&• Low& serum& levels& do& not& equate& to& uterine&concentra7ons.&
• Also& a& beneficial& effect& on& reducing& uterine&contrac7ons.&
DAMAS CUS UNI VE RS I T Y
• There& is& 14x& the& concentra7on& of& progesterone&in& the& uterus& compared& with& the& serum& levels&following& vaginal& administra7on,& whereas& the&ra7o&is&1:1&with&IM&progesterone.&
• Direct&transport&of&progesterone&from&the&vagina&to&the&uterus.&
Cincinelli&E.&et$al.$2000&
DAMAS CUS UNI VE RS I T Y
• There&con7nues&to&be&controversy&about&the&benefit&of&intramuscular&over&
vaginal&use.&
It)is)also)interes:ng)to)note)that)IM)progesterone)is)not)licensed)for)use)in)IVF)/)ART)by)the)FDA)in)
the)United)States!)
DAMAS CUS UNI VE RS I T Y
• More& consistent& uterine& absorp7on& and&u7liza7on&of&progesterone&
• “first&pass&effect”&• Targeted&to&the&uterus&specifically&
• Preferable&to&IM&progesterone&
• Much&more&“pa7ent&friendly”&
DAMAS CUS UNI VE RS I T Y
Conclusion:&The) luteal) phase) support) in) ART) cycles) with) Utrogest)200mg.)Capsules)(three):mes)per)day))or)vaginal)gel)8%)(two) :mes) per) day)) by) the) vaginal) route) resulted) in)similar)outcomes)with) respect) to) implanta:on,)ongoing)pregnancy,) and) abor:on) rates.) The) two) recommended)regimens) of) P) supplementa:on) in) ART) proved) to) be)equivalent&and&safe.)
Kleinstein J Luteal phase study group
Fer:l)Steril.)2005;83(6):1641Z9.)
DAMAS CUS UNI VE RS I T Y
Paul)W.)Zarutskie)and)James)A.)Phillips)
MetaWanalysis&of&progesterone&luteal&support&
&
Conclusion:&
Administra7on&of&vaginal&P&is&comparable&to&administra7on&of&IM&P&for&luteal&phase&support&in&assisted&reproduc7ve&technology.&
Fer:l)Steril)2009;92:163Z9.)
DAMAS CUS UNI VE RS I T Y
• Pa7ent&inconvenience&(painful&injec7ons)&
• Higher&risk&of&OHSS&(Soliman&et&al.,&1994)&
Poten7ally&lifeWthreatening&complica7on&
Risk&of&thrombo&embolism&
Risk&of&myocardial&infarc7on&
Long&hospital&stay&
• No&uterineWrelaxant&proper7es&as&vaginal&P&
“There& no& longer& seems& to& be& place& for& hCG& supplementa7on&during&the&luteal&phase”&
$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$Ludwig$M$et$al,$Eur$J$Obstet$Gynecol$Reprod$Biol$2002;103:48E52$
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Oral&Progesterone&
Reduced&bioavailability&1&
Significantly&lower&rates&of&implanta7on&and&pregnancy&rates&2,3&
Higher&incidence&of&side&effects&3&
Oral&Dydrogesterone&(DG)&
Incomplete&secretory&transforma7on&of&the&endometrium,&suppor7ng&reduced&efficacy&of&this&formula7on&4&
Endometrium&fails&to&present&the&op7mal&condi7ons&for&the&implanta7on&of&human&embryos&4&
Vaginalµnized&progesterone&was&significantly&more&effec7ve&than&oral&DG&in&crea7ng&an&“in&phase”&secretory&endometrium&1&
1- Fatemi HM et al, Hum Reprod Update 2007;13:581–90.
2- Penzias AS et al, Reprod Biomed Online 2003; 6: 287–95.
3- Lan VTN, Reprod Biomed Online 2008; 17: 318–234.
4- Fatemi HM et al, Hum Reprod 2007;22:1260–1263.
“Oral administration is not appropriate for luteal support”
DAMAS CUS UNI VE RS I T Y
• CRINONE&is&a&bioWadhesive&vaginal&gel&which&containsµnized&progesterone&
• CRINONE&preWfilled&vaginal&applicator&• Accurate&delivery&of&90mg&progesterone&in&1.125g&of&gel&
• CRINONE&is&based&on&a&vaginal&moisturising&formula&• White&to&offWwhite&gel&
DAMAS CUS UNI VE RS I T Y
&Progesterone&supplementa7on&or&replacement&as&part&of&an&assisted&reproduc7ve&technology&(ART)&treatment&&
&for&infer7le&women&with&progesterone&deficiency*&
• Once&daily&for&supplementa7on&&&
• Twice&daily&as&replacement&&&&&&&
Preferable&to&applied&in&the&morning&
&
* FDA Approval
DAMAS CUS UNI VE RS I T Y
Polycarbophil&• Bioadhesive&waterW
insoluble&polymer&
• Stays&anached&to&the&vaginal&epithelial&cells&un7l&they&turn&over&
• Not&absorbed&
&Allows&sustained&
&release&of&progesterone&
Emulsion$system&• The&carrier&vehicle&is&an&oilW
inW&water&emulsion&containing&the&polycarbophil&
• The&progesterone&(P)&is&par7ally&soluble&in&both&the&oil&and&water&phases&of&the&vehicle&with&the&majority&of&progesterone&exis7ng&as&a&suspension&&Ensures&controlled&release&of&P&
+!
DAMAS CUS UNI VE RS I T Y
• CRINONE&containsµnized&progesterone&in&an&‘oilWinWwater’&emulsion&
&
• The&majority&of&progesterone&exists&as&a&lipophilic&suspension&• a&lipid&(oil)&reservoir&
• The&aqueous&(water)&por7on&releases&progesterone&
&into&the&cellular&7ssue&and&is&replenished&from&the&&
lipid&reservoir& aqueous
Lipid`
tissue
DAMAS CUS UNI VE RS I T Y
• Direct&delivery&from&vagina&to&uterus&&
• FirstWpass&uterine&effect&
DAMAS CUS UNI VE RS I T Y
1&hour&
3&hours&
2&hours&
4 hours&
Radioactive test substances
Radioactive reference substances
Time
Bulletti C et al, Hum Reprod 1997; 12: 1073–9
Direct&delivery&from&vagina&to&uterus&&FirstWpass&uterine&effect&
Time-dependent diffusion of progesterone from the cervix to the fundus of the uterus
DAMAS CUS UNI VE RS I T Y
Endometrial levels
11.5
1.40
2
4
6
8
10
12
14
Vaginal P IM P
ng P/mg proteinSerum levels
11.9
69.8
0
10
20
30
40
50
60
70
80
Vaginal P IM P
ng/mL
P < 0.05 P < 0.05
Miles RA et al. Fertil Steril 1994;62:485–90
“IM Progesterone in not recommended as a first choice luteal phase support” Fatemi HM et al, Hum Reprod Update 2007;13:581–90
DAMAS CUS UNI VE RS I T Y
• First&uterine&pass&effect&avoiding&firstWpass&hepa7c&metabolism&1&
• Greater&bioavailability&in&the&uterus&2&• Maximum&uterine&effect&and&minimum&systemic&levels&and&
side&effects&3&
“Vaginal progesterone should be the standard choice for luteal phase support”
Ludwig M, Diedrich K et al. Acta Obstet Gynecol Scand 2001;80:452–466.
1- Bulletti C et al: the first uterine pass effect. Hum Reprod 1997; 12: 1073–9. 2- Penzias AS, et al. Reprod Biomed Online 2003; 6: 287–95. 3- Fatemi HM et al,Hum Reprod 2007;22:1260–1263.
DAMAS CUS UNI VE RS I T Y
43
23
46.3
47
39
47.6
0 5 10 15 20 25 30 35 40 45 50
Coutifaris et al.
Williams et al
Yanushopolsky et al
Pregnancy % (P= NS)
IM Progesterone Crinone
Comparable pregnancy rates to IM Progesterone
&Significantly&&lower&rate&of&miscarriage&with&vaginal&progesterone&compared&to&&IM&progesterone&&&Paul&W.&Zarutski&et&al&:Fer7l&Steril.2009;92:163&Yanushpolsky et al : Fertil Steril 2008;89:485-7 ,Williams et al :Fertil Steril.2000;74(suppl 1):S209.Abstract P 363 \,Coutifaris et al : Fertilk Sterli.2000;74(suppl 1)S205.Abstract p 350
DAMAS CUS UNI VE RS I T Y
is not true at all!
is absolutely true!
18.9
30
30.9
28
28.8
39
33.1
31
0 5 10 15 20 25 30 35 40 45 50
Ludwig and Diedrich
Williams et al
Simunic et al
Lan et al
Pregnancy % (P= NS)
Progesterone susppositories Crinone
Comparable&pregnancy&rates&to&&Progesterone&suppositories&
Williams et al :Fertil Steril.2000;74(suppl 1):S209.Abstract P 363
,Ludwig et al : Acta Obstet Gynecol Scand 2001;80:452-466 Lan VTN et al : Reprod Biomed Online 2008;17:318-23
,Simunic V et al :Fertil Steril 2007;87:83-87
DAMAS CUS UNI VE RS I T Y
• The&aim:&evaluate&the&outcome&in&pa7ents&receiving&frozenWthawed&embryo&transfer&arer&doubling&the&vaginal&P&gel&supplementa7on.&
• FrozenWthawed&embryo&transfer&cycles&priming&with&oestradiol&and&vaginal&progesterone&gel&were&included.&
• The& vaginal& progesterone& dose&was& changed& from& 90mg& (Crinone)& once& a&day&to&twice&a&day&
• The& pregnancy& rate& increased& significantly& arer& doubling& of& the&progesterone&dose&(26.7%&(90mg))&versus&38.4%&(180mg);&P=0.021).&
• The&early&pregnancy& loss& rate&decreased& significantly& (67.4%&versus&43.7%&respec7vely;&P=0.014),&which&significantly&increased&the&delivery&rate&(8.7%&versus&20.5%,&respec7vely;&P=0.002).$
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&RBM&online&February&2013&
&
DAMAS CUS UNI VE RS I T Y
Leakage and messiness are complaints commonly
associated with the use of vaginal micronized
progesterone
Lan VTN et al : Reprod Biomed Online 2008;17:318-23
DAMAS CUS UNI VE RS I T Y
Ernest et al :Eur J Obstet Gynecol Reprod Biol 2003;111:50-55
DAMAS CUS UNI VE RS I T Y
Ernest et al :Eur J Obstet Gynecol Reprod Biol 2003;111:50-55
DAMAS CUS UNI VE RS I T Y
Ernest et al :Eur J Obstet Gynecol Reprod Biol 2003;111:50-55
DAMAS CUS UNI VE RS I T Y
Ernest et al :Eur J Obstet Gynecol Reprod Biol 2003;111:50-55
Significantly&more&pa7ents&usingµnized&progesterone&suppositories&versus&Crinone&graded&:&&&W&Inconvenience&of&administra7on&&W&leaking&out&&&W&Interference&with&coitus&&
as Moderate&or&Severe&
DAMAS CUS UNI VE RS I T Y
Levin et al :Fertil Steril 2000;74:836-837
DAMAS CUS UNI VE RS I T Y
Easier& Preferable&94%&of&pa7ents&found&Crinone® easier
to use vs IM progesterone&84%&of&pa7ents&preferred&Crinone®
over IM progesterone&
Some&pa7ents&do&prefer&injec7ons&as&they&believe&they&must&“work&bener”&if&the&are&painful&
DAMAS CUS UNI VE RS I T Y
Simunic V et al :Fertil Steril 2007;87:83-87
DAMAS CUS UNI VE RS I T Y
• Vaginal&progesterone&• Allergy&• ?effec7ve&if&bleeding&• “messy”(?)&
• IM&progesterone&• Allergy&• Abcess&• Pulmonary&
DAMAS CUS UNI VE RS I T Y
DAMAS CUS UNI VE RS I T Y
Pa7ents& receiving& vaginal& progesterone&should& be& counselled& that& early& bleeding&may&occur,&and&that&this&is&a&consequence&of&their¬&being&pregnant&–¬&the&reason&or&cause&for&failure&to&achieve&pregnancy.&
DAMAS CUS UNI VE RS I T Y
ART Procedure Crinone 8% (90mg) – once daily
IVF-ET From day of egg retrieval
Oocyte donation After estrogen priming (around day 15)
Frozen egg cycles As for oocyte donation *
IUI From insemination (36h after hCG) *
OI 12-24 hours after hCG
Luteal phase defect On day following LH surge
DAMAS CUS UNI VE RS I T Y
• Target&Progesterone&Delivery&to&the&Uterus&&&&&&&&High&endometrial&levels,&low&serum&levels&2&
• Effec7ve&Luteal&Phase&Support&3&&&&&&&&&Comparable&PR&to&IM&progesterone&and&suppositories&2W9&
• Significantly&Higher&Pa7ent&Preference&3&Z Less&messy,&no&lying&down&arer&applica7on&4&
Z Less&interference&with&Coitus&2&
Z More&convenient&and&easier&to&use&10&1- Bulletti C et al. Hum Reprod 1997. 2- Ernest HY Ng et al, Eur J Obstet Gynecol Reprod Biol 2003. 3- Penzias AS et al, Reprod Biomed Online 2003. 4- Lan VTN et al, Reprod Biomed Online 2008. 5- Paul W et al, Fertil Steril 2008. 6- Yanushpolsky E et al, Fertil Steril 2008. 7- Williams SC et al, Fertil Steril. 2000 (Data on file). 8- Coutifaris C et al. A preliminary report. Fertil Steril. 2000 (Data on file). 9- Simunic V et al. Fertil Steril 2007. 10- Penzais AS. Fertil Sterl. 2002.
DAMAS CUS UNI VE RS I T Y
The&addi7on&of&E2&to&progesterone&in&the&luteal&phase&&does¬&enhance&the&probability&of&pregnancy.&
DAMAS CUS UNI VE RS I T Y
• Further& research& is& needed& to& assess& the&efficacy& of& adjuvant& luteal& phase& support&treatments& such& as& lowWdose& aspirin,&heparin,& prednisolone,& immuglobulins& and&fat&emulsions.&
• These&interven7ons&are&star7ng&to&be&used&in& clinical& prac7ce& in& the& absence& of& any&RCT& evidence& of& benefit,& and& even& where&there&is&RCT&evidence&of&no&benefit.&
DAMAS CUS UNI VE RS I T Y
• Inadvertent&GnRHa&administra7on&in&the&luteal&phase&does¬&compromise&pregnancy&but&rather&seems&to&improve&implanta7on&
• GnRH&receptor&is&expressed&in&the&human&preimplanta7on&embryos,&endometrium,&and&corpus&luteum,&implica7ng&a&direct&effect&of&GnRHa&on&the&these&targets&
• GnRHa&has&been&shown&to&s7mulate&trophoblast&produc7on&of&hCG.&
DAMAS CUS UNI VE RS I T Y
Oocytes)from)each)donor)were)shared)by)two)recipients,)one)of)whom))received)a&single&dose&of&GnRHa&(0.1&mg&triptorelin)&6&days&arer&ICSI,))and)the)other)received)placebo)at)the)same):me.)Recipient:)pituitary)downZregula:on)by)GnRHa)!)oral)E2)valerate)!))))))))))))))))))oral)E2)valerate)+)vaginal)utrogestan)(±)GnRHa)6)days)ader)ICSI))
GnRH&agonist)administra:on)at&the&7me&of&implanta7on)enhances)embryo)developmental)poten:al,)probably)by)a)direct&effect&on&the&embryo.)
(Hum. Reprod., 2004)
DAMAS CUS UNI VE RS I T Y
1 21 M C
2
FSH + HMG
H C G
GnRHa ICSI Placebo or
GnRHa
ICSI +
6 d
HCG ET
ICSI +
3 d E2 4 mg po + Utrogestan 400 mg Vag. qd
Beneficial&Effect&of&LutealWphase&GnRHa&on&Embryo&Implanta7on&in&GnRHaWtreated&Ovarian&S7mula7on&Cycles&
(Hum. Reprod., 2006)
LutealWphase&GnRHa&&(Triptorelin&0.1&mg&6&d&arer&ICSI)&enhances&embryo&implanta7on&&and&live&birth&rates&
DAMAS CUS UNI VE RS I T Y
Beneficial&Effect&of&LutealWphase&GnRHa&on&Embryo&Implanta7on&in&GnRHantWtreated&Ovarian&S7mula7on&Cycles&
1 21 M C
2
FSH + HMG
H C G
GnRH ant ICSI
Placebo or GnRHa
ICSI +
6 d
HCG ET
ICSI +
3 d E2 4 mg po + Utrogestan 400 mg Vag. qd
6
Oral pill
LutealWphase&GnRHa&&(Triptorelin&0.1&mg&6&d&arer&ICSI)&enhances&embryo&implanta7on&&and&live&birth&rates&
(Hum. Reprod., 2006)
DAMAS CUS UNI VE RS I T Y
• Evidence&from&the&literature&supports&progesterone&supplementa7on&in&the&luteal&phase&of&IVF&cycles&
" Un7l&the&pregnancy&test&" Not&indicated&beyond&posi7ve&pregnancy&test&
• Although& serum& progesterone& levels& are& higher&arer&the&IM&route&vs.&vaginal&route,&the&pregnancy&rates&are&comparable&
)))))))))))))))))))))))))))))))))))))))))))))))))))))))(Penzias)A.)Fer:l)Steril)2002))
DAMAS CUS UNI VE RS I T Y
Mochtar&el&al.,&(2006)&
385&pa7ents&randomized&into&three&groups:&
1. LPS&start&on&HCG&day&2. LPS&start&on&day&of&OR&3. LPS&start&on&ET&day&
DAMAS CUS UNI VE RS I T Y
• The&administra7on&of&progesterone&before&oocyte&retrieval&is&associated&with&a&lower&pregnancy&rate&than&the&administra7on&of&progesterone&arer&oocyte&retrieval&(Sohn&et&al.,&1999)&
• Decrease&of&24%&was&seen&when&luteal&phase&support&was&delayed&un7l&6&days&arer&OR&compared&to&3&days&arer&OR&(Williams&et&al.,&2001)&
• No&difference&was&found&when&luteal&phase&support&was&started&at&OR&compared&to&star7ng&at&ET&(Baruffi&et&al.,&2003)&
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Nyboe&et&al.&(2002)&385&pa7ents&randomized&into&three&groups:&
1. LPS&con7nued&un7l&posi7ve&pregnancy&test.&
2. LPS&con7nued&for&three&weeks&into&pregnancy&
Pregnancy&rates&(1) (n=153)&=&78.7%&delivered&
(2) (n=150)&=&82.4%&delivered&(NS)&
Conclusion:&&prolonga7on&of&LPS&beyond&a&posi7ve&pregnancy&test&is¬&beneficial&
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• Progesterone&only&for&LP&support.&• Vaginal&P&equivalent&to&IM&P.&
• Do¬&rou7nely&use&HCG.&• The&evidence&does¬&support&con7nuing&LPS&beyond&8&weeks&gesta7on.&
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&…&IVF&using&GnRha&for&pituitary&downWregula7on&should& be& informed& that& luteal& support& using&human&chorionic&gonadotrophin&or&progesterone&improves&pregnancy&rates&
&&…rou7ne&use&of&human&chorionic&gonadotrophin&for& luteal& support& is& not& recommended& because&of& the& increased& l ikelihood& of& ovarian&hypers7mula7on&syndrome.&&
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Criteria 25,000 cycles 50,000 cycles
Vaginal cream/gel 34% 34%
Vaginal capsule 28% 30%
IM progesterone 10% 13%
hCG 7% 4%
Oral progesterone 1% 2%
Vaginal P + IM P 19% 15%
Vaginal + Oral P 1% 1%
hCG + any progesterone 0% 1%
The&result&represent&25,500&and&50,000&IVF&cycles&from&35&countries.&www.ivf-worldwide.com
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http://www.ivf-worldwide.com
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http://www.ivf-worldwide.com
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http://www.ivf-worldwide.com
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• 84& IVF& treatment& centers& from& 35& countries;& total& of& 51,155&IVF&cycles&per&year,&completed&the&survey.&
• There& is& a& major& change& in& clinical& use& of& agents& or& luteal&support:&" hCG&is&now&out&of&use.&" The&use&of&IM&progesterone&has&declined&significantly.&" There&is&an&increase&in&the&use&of&vaginal&progesterone&" If& the& pa7ents& conceive,& the& use& of& progesterone& is& now&being&shortened.&
• The& shir& in& the& clinical& prac7ce& of& progesterone& is&approaching&the&E.B.M.&published&in&the&field.&&
www.ivf-worldwide.com
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&&
&Current&UK&prac7ce&in&ART&luteal&phase&support&
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64.5
30.6
3.2 1.6
0
10
20
30
40
50
60
70
%
Very ImportantImportantOthers+DKNot Important
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48.3
25.8
19.3
4.8
05
101520253035404550
%
Day ECDay ETDay EC+1Others
DAMAS CUS UNI VE RS I T Y
48.4
11.2
4.8
24.2
11.2
05
101520253035404550
%
12 weeks8 weeksFetal HeartPregnancy Testother
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Summary&of&findings:&• 69&studies&included;&16,327&women.&
• Significant&effect&in&favor&of&P&for&LPS.&• Addi7on&of&E2&or&hCG&to&LPS&of&no&benefit.&• Route&and&dura7on&of&administra7on&of&P&were&equivalent.&
• Adding&hCG&to&P&for&LPS&associated&with&higher&risk&of&OHSS.&Use&of&hCG&should&be&avoided.&
• Significant&benefit&to&addi7on&of&GnRH&agonist&to&P&for&LPS.&
Van&der&Linden&et&al.&
Van&de&Linden&M&et&al.&Hum.&Reprod.&Update&2012;18:473W473&&&Cochrane&Review&2011.&
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Final&conclusions:&• Evidence&for&a&significant&effect&in&favor&of&progesterone&for&
luteal&phase&support.&Best&result&with&synthe7c&progesterone.&• Evidence&that&the&addi7on&of&othe&substances&such&as&
estrogen&or&hCG&doe¬&improve&outcomes.&• Evidence&for&equivalence&of&IM&and&vaginal&routes&of&
administra7on.&Vaginal&route&is&best&tolerated&by&pa7ents.&• hCG,&or&hCG&plus&progesterone,&was&associated&with&a&higher&
risk&of&OHSS.&The&use&of&hCG&should&therefore&be&avoided.&• Evidence&showing&a&benefit&from&the&addi7on&of&GnRH&agonist&
to&progesterone&in&luteal&phase&support.&
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1.&Wash&your&hands&with&soap&and&water.&&2.&Remove&the&applicator&from&wrapper.&&3.&Hold&the&applicator&at&the&flat&end.&&Shake&down&several&7mes&like&a&thermometer&to&ensure&the&contents&are&at&the&thin&end.&
4.&Hold&the&applicator&by&the&flat&sec7on&of&the&thick&end.&Twist&off&the&tab&at&the&thin&end&and&discard&the&tab.&Do¬&squeeze&the&bubble&while&twis7ng&off&the&tab.&
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5.&&Carefully&insert&the&thin&end&of&the&applicator&well&into&the&vagina&while&you&are&in&a&siwng&posi7on,&or&when&lying&on&your&back&with&your&knees&bent.&
6.&Squeeze&the&bubble&of&the&applicator&firmly&to&release&the&gel&into&the&vagina.&Remove&and&discard&the&applicator.&&Some&gel&may&be&ler&in&the&applicator.&Do¬&worry,&the&correct&dose&will&have&been&delivered.&
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