rationale and regimens of progesterone andrationale and ... · rationale and regimens of...

Rationale and regimens of progesterone andRationale and regimens of progesterone and estrogen supplementation for luteal phase

tsupport.

Cicinelli E.

IV Dept. Ob/Gyn, University of Bari, Italy [email protected]

Luteal phase defect (LPD)

■ The prevalence of LPD in natural cycles in normo■ The prevalence of LPD in natural cycles in normo-ovulatory patients with primary or secondary infertility is about 8 1% (Rosenberg et al 1980)infertility is about 8.1% (Rosenberg et al.,1980).

■ In IVF cycles LPD in about 100% of cases (Ubaldi et al., 1997; Macklon and Fauser, 2000; Kolibianakis et al., 2003).

LPD

Etiology of LPD in IVF cycles1. Removal of large quantities of granulosa cells during the oocyte

retrieval (OR).1. However, the aspiration of a preovulatory oocyte in a natural cycle neither diminished

the luteal phase steroid secretion nor shortened the luteal phase (Kerin et al., 1981).

2. Prolonged pituitary recovery following the GnRH-a co-treatment may result in lack of support of the CL (Smitz et al., 1992). y pp ( , )

3. hCG for the final oocyte maturation in stimulated IVF cycles could y ypotentially suppress the LH production via a short-loop feedback mechanism (Miyake et al., 1979). 1. However, the administration of hCG did not down-regulate the LH secretion in the

luteal phase of normal, unstimulated cycles in normo-ovulatory women (Tavaniotou and Devroey, 2003).

LPD

Etiology of LPD in IVF cycles

4. Supraphysiological levels of steroids secreted by a high number of corpora lutea during the early luteal phase directly inhibit the LH release via negative feedback actions at the hypothalamic-pituary axis level (Fauser and Devroey, 2003). 1. Studies in human and primates have demonstrated that the CL requires a

consistent LH stimulus in order to perform its physiological function (Jones, 1991). ( , )

2. LH support during the luteal phase is entirely responsible for the maintenance and the normal steroidogenic activity of the CL (Casper and Yen 1979)Yen, 1979).

3. However, withdrawal of LH, unnecessary causes premature luteolysis (Duffy et al., 1999).

GnRH antagonists:LPD

GnRH antagonists:■ Preliminary studies (IUI cycles) no deleterious effects on luteal P

levels and LP duration (Ragni et al 2001)levels and LP duration (Ragni et al., 2001)

■ Subsequent studies in IVF:■ Subsequent studies in IVF:● Premature luteolysis (Albano et al., 1998; Beckers et al., 2003).● Reduced chances for pregnancy:● Reduced chances for pregnancy:

in non-supplemented LP of patients stimulated with rFSH + GnRH antagonist (antide; 1 mg/day) the overall pregnancyGnRH antagonist (antide; 1 mg/day) the overall pregnancy rates (PR) was very poor (7.5%) and the study stopped (Beckers et al., 2003).

■ Despite the rapid recovery of the pituitary function in GnRH-ant. p p y p yprotocols (Dal Prato and Borini, 2005), LPS remains mandatory (Tarlatzis et al., 2006).

Luteal phase support in infertility treatmentsLuteal phase support in infertility treatments

Gonadotropins hCG

COHhCG

COH

P4 P4P4In COH with GnRH-a or GnRH-antagonist luteal support isIn COH with GnRH a or GnRH antagonist, luteal support is necessary because the pituitary drive to the CL is deficient.

PLuteal phase

Triggering ovulation with hCG alters LH production in the luteal phase

Pregnancy test

Luteal phase support in infertility treatmentsLuteal phase support in infertility treatments

Gonadotropins hCG

COHhCG

COH

P4 P4P4E2 E2By extension: E2 E2y

Donor egg IVF1

PLuteal phaseFrozen embryo transfer (FET)2

Pregnancy test

Rationale and regimens of progesterone and estrogen supplementation for luteal phase support.

Rationale for LPS ith progesterone■ Rationale for LPS with progesterone■ Regimens for progesterone supplementationg p g pp■ Rationale for LPS with estrogens

R i f t i l t ti■ Regimens for estrogenic supplementation■ When to start with LPS■ When to stop LPS

Rationale for LPS with progesterone

■ Progesterone induces:● a secretory transformation of the endometrium in the luteal phase

(Bourgain et al., 1990). ● after adequate estrogen priming, progesterone improves● after adequate estrogen priming, progesterone improves

endometrial receptivity (Kolibianakis and Devroey, 2002).

● local vasodilatation.● uterine musculature quiescence

Pinopodes expression correlates with P levels

LD 2 LD 5Temporal and morphologic characteristics of pinopod expression across the secretory phase of the endometrial p y pcycle in normally cycling women with proven fertilityUsadi RS et al., Fertil Steril 2003

LD 8 LD 10

LD 11 LD 14LD 11 LD 14

Ayoubi J-M et al. Ferti Steril 2001;76:736-40.

Uterine contractility and IVFUC in menstrual cycle and IVF

5

7

/min

4.5

5

5.5

tion

(min

)

3D derived method

Fast play

Effects of P

*1

3

5

UC

2 5

3

3.5

4

Ute

rine

cont

ract

LH/hCG LH+2/Retrieval LH+4/ET LH+6/ET+2

Ayoubi et al. Fertil Steril Oct 2001

12

2.5

15 16 17 18 19 20

Cycle dayAyoubi et al. Fertil Steril 2003

In IVF, starting of Crinone 8% h d f i l8% on the day of retrieval decreases UC frequency on

<3 3-4 4-5 >5

q ythe day of ET (Fanchin et al 2001)al., 2001)

MorphologyUl

Rationale for LPS with progesteronep gy

Ultrastructure UTZ

U i i iUterine receptivityE d t i + M t i

P+Endometrium + Myometrium

Doppler Contractility

Rationale for LPS with progesterone

Meta-analyses

S Daya and J GunbyThe Cochrane Database of Systematic Reviews 2004 Issue 4C i h © 2004 Th C h C ll b i P bli h d b J h Wil & S L dCopyright © 2004 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.DOI: 10.1002/14651858.CD004830 This version first published online: 19 July 2004 in Issue 3, 2004

Nosarka S et al.Nosarka S et al. Luteal phase support in in vitro fertilization: meta-analysis of randomized trials.Gynecol Obstet Invest. 2005;60:67-74. Department of Obstetrics and Gynaecology, Stellenbosch Univ., Tygerberg, SA.

Reviewers' conclusions• Luteal phase support with hCG or progesterone after assisted p pp p greproduction results in an increased pregnancy rate. • hCG does not provide better results than progesterone and is associated with greater risks of OHSS when used with GnRHa.

h i l f d i i i h bg

• The optimal route of progesterone administration has not been established yet.

Regimens for progesterone supplementation

How to administer P4?

Alternative to IM P4 in oil

The optionsThe optionsCurrently available formulations of

i l d l i lprogesterone include oral, vaginal, rectal and intramuscular (IM) (Chakmakjian, 1987; Fatemi et al.(Chakmakjian, 1987; Fatemi et al. Penzias, 2002).

IM progesterone■ Doses for LPS in IVF cycles: 25 100 mg/day without■ Doses for LPS in IVF cycles: 25 - 100 mg/day without

any significant difference concerning the outcome (Pritts & Atwood 2002)(Pritts & Atwood, 2002).

■ Side effects: ● painful injections and a rash (Lightman et al., 1999)● inflammatory reactions and abscesses (Propst et al., 2001)● acute eosinophilic pneumonia (Boukaert et al., 2004; Veysman

et al., 2006). ● possible severe morbidity in otherwise healthy young patients

(Boukaert et al., 2004).

■ Lack of enthusiasm for this treatment modality (Costabile et al., 2001).

Oral progesterone

■ Oral micronized progesterone: ● not effective for inducing secretory transformation in patients

with POF (Devroey et al., 1989; Bourgain et al. 1990). ■ Dydrogesterone (DG)

● Good oral bioavailability and capacity to achieve secretory transformation (Whitehead, 1980; Chakravarty et al., 2005).

● LPS: uncertain efficacyLPS after IVF: PRT (n = 430), DG and vaginal P had similar

t f f l i (24 1 22 8%rates of successful pregnancies (24.1 versus 22.8%, respectively; P = NS) (Chakravarty et al. 2005). In POF: PRT vaginal micronized P more effective than oralIn POF: PRT, vaginal micronized P more effective than oral DG in creating an ‘in phase’ secretory endometrium (Day 21) (P = 0.021) (Fatemi et al., 2007). In 1989 Pellicer et al. found(P 0.021) (Fatemi et al., 2007). In 1989 Pellicer et al. found similar results.

Side-Effects of oral Progesterone

P t d l t CNS GABA■ Progesterone can modulate CNS GABAAreceptor activity through its reduced metabolite, allopregnanolone● Sleepiness, moodiness, depression

CH3

O CH3

CH3

O CH3

HCH3 HCH3

O

HH

HO

HH

Progesterone Allopregnanolone

Nahoul K. et al. Maturitas 1993:16;185-202

Endometrial Morphology for Women Who Received Crinone® 8% (progesterone gel)Received Crinone 8% (progesterone gel)

or IM Progesterone

100 96

80

100a

(%)

60

80

ndom

etria

20

40

Pha

se E

n

0In-P

Crinone® 8% IM Progesterone(progesterone gel)(n=55)

IM Progesterone(n=24)

From: Gibbons WE et al Fertil Steril 1998;69:96 101From: Gibbons WE et al. Fertil Steril. 1998;69:96-101.

Vaginal Progesterone:g gPrivileged transport to the uterus

Uterine effects exceed

expectationsexpectations drawn from

i l icirculating levelslevels

The first uterine fpass effect

Crinone® 8% (progesterone gel)Crinone® 8% (progesterone gel)Serum and uterine tissue concentration

S P4 E d t i l ti P4

Serum and uterine tissue concentration

30 1,2

Serum P4 Endometrial tissue P4 P4 levels (ng/mL)

15

20

25

0,6

0,8

1

0

5

10

0

0,2

0,4

From: Cicinelli E et al. Obstet Gynecol. 2000;95:403-406. Crinone 8%IM progesterone

Endometrial samples obtained from hysterectomies

Vaginal vs IM progesterone in estrogenized postmenopausal women

E d i / l l 100Endometrium/serum progesterone levels x 100

*15

IM P Vaginal P

5

10 Median 1,15 14,08M in 0,51 8,46M 13 07 59 43

0

5

l

Max 13,07 59,43

IM P Vaginal P

(Cicinelli et al., Obstet Gynecol, 2000)~ 1 : 14

First Uterine Pass EffectFunctional portal system through counter-current exchanges

From: Cicinelli and de Ziegler Human Reprod Update 2000

Continental divideOvarian artery – Uterine arteryE2/P E2/P

Ov. art. Ov. art.

Ut. art.

Ut. art.

Follicular phase Luteal phaseFollicular phase Luteal phase

(Cicinelli et al., Hum Reprod 2004)

1st uterine pass effect

Discovered for P4 but physiological role for

GPGsFrom: Cicinelli and de Ziegler Human Reprod 2000

PP

P P

First uterine pass effectFirst uterine pass effect

1st uterine pass effect

Discovered for P4 but physiological role for

GPGsFrom: Cicinelli and de Ziegler Human Reprod 2000

PGsPGsPP

PGs PGsP P

First uterine pass effectFirst uterine pass effectFirst uterine pass effectFirst uterine pass effect

Variation in blood flow in the uterine artery and in the arteries of urethra-vaginal septum depending on the level of vaginal administration

300 *

200300

O l t l t i

**

0100%

Omolateral uterinearteryC t l t l

-1000 Contralateral

uterine arteryV l f thUpper 1/3 Lower 1/3

Sit f i l

Vessels of urethro-vaginal septum

Site of vaginal administration

(Cicinelli et al., Am J Obstet Gynecol 2003)

Importance of the level of vaginal administration

Local (preferential) transfer of vaginal

Uterustransfer of vaginal steroids is influenced by theinfluenced by the level of vaginal administration:

Badministration:

Upper third: to the uterus

U Steroidthe uterus

Lower third: to the urethrathe urethra

(Cicinelli et al., Am J Obstet Gynecol 2003)

Regimens for progesterone supplementation

.Luteal phase support in infertility treatment: a meta-analysis of the randomized trialsrandomized trials.E.A. Pritts and A.K. Atwood. Human Reprod 2002;17:2287-99.

P4Questions Outcome

measureAuthor No. of

studiesNo. of

patientsRR 95% CI Meta-

analysisPower #2 Power #1

P4 vs. no treatment

P4 (vaginal) vs. no TT CPR Artini et al ., 1995; Abate et al ., 1999b

2 192 2.1 0.95–4.67 yes 0.88 0.35

P4 (vaginal) vs. no TT DR Abate et al ., 1999b 1 104 2 0.33–15.52 no 0.61 0.24P4 (vaginal) vs no OPR Artini et al 1995; Abate 2 192 1 7 0 77–6 02 yes 0 88 0 35P4 (vaginal) vs. no treatment

OPR Artini et al ., 1995; Abate et al ., 1999b

2 192 1.7 0.77 6.02 yes 0.88 0.35

P4 (vaginal) vs. no TT SAB Artini et al ., 1995 1 11 1.1 0.10–31.09 no 0.1 0.07hCG vs. no TT CPR Smith et al ., 1989;

Herman et al ., 1990; A ti i t l 1995

4 262 2.7 1.56–4.90* yes 0.96 0.46

Artini et al ., 1995; Beckers et al ., 2000

hCG vs. no TT OPR Herman et al ., 1990; Artini et al ., 1995; Beckers et al ., 2000

3 147 2.4 0.93–6.7 yes 0.77 0.28

hCG vs. no TT SAB Herman et al ., 1990; Artini et al ., 1995

2 22 1.4 0.15–34.57 yes 0.17 0.08

P4 (i.m.) versus placebo/no TT

CPR Artini et al ., 1995; Abate et al ., 1999a,b

3 278 2.4 1.36–4.27* yes 0.97 0.48

P4 (i m ) versus placebo/no OPR Artini et al 1995; Abate 2 192 3 8 1 42 11 38* yes 0 88 0 35P4 (i.m.) versus placebo/no TT


2 192 3.8 1.42–11.38 yes 0.88 0.35

P4 (i.m.) vs. placebo/no TT DR Abate et al ., 1999b 1 104 5.5 1.25–35.53* no 0.61 0.21P4 (i.m.) vs. placebo/no TT SAB Artini et al ., 1995 1 10 1.3 0.12–36.19 no 0.1 0.07


P4Questions Outcome


studiesNo. of



P4 vs. no treatment >1 Consensus

P4 (vaginal) vs. no TT CPR Artini et al ., 1995; Abate et al ., 1999b

2 192 2.1 0.95–4.67 yes 0.88 0.35

P4 (vaginal) vs. no TT DR Abate et al ., 1999b 1 104 2 0.33–15.52 no 0.61 0.24P4 (vaginal) vs no OPR Artini et al 1995; Abate 2 192 1 7 0 77–6 02 yes 0 88 0 35P4 (vaginal) vs. no treatment


2 192 1.7 0.77 6.02 yes 0.88 0.35

P4 (vaginal) vs. no TT SAB Artini et al ., 1995 1 11 1.1 0.10–31.09 no 0.1 0.07hCG vs. no TT CPR Smith et al ., 1989;

Herman et al ., 1990; A ti i t l 1995

4 262 2.7 1.56–4.90* yes 0.96 0.46

Artini et al ., 1995; Beckers et al ., 2000

hCG vs. no TT OPR Herman et al ., 1990; Artini et al ., 1995; Beckers et al ., 2000

3 147 2.4 0.93–6.7 yes 0.77 0.28

hCG vs. no TT SAB Herman et al ., 1990; Artini et al ., 1995

2 22 1.4 0.15–34.57 yes 0.17 0.08

P4 (i.m.) versus placebo/no TT

CPR Artini et al ., 1995; Abate et al ., 1999a,b

3 278 2.4 1.36–4.27* yes 0.97 0.48

P4 (i m ) versus placebo/no OPR Artini et al 1995; Abate 2 192 3 8 1 42 11 38* yes 0 88 0 35P4 (i.m.) versus placebo/no TT


2 192 3.8 1.42–11.38 yes 0.88 0.35

P4 (i.m.) vs. placebo/no TT DR Abate et al ., 1999b 1 104 5.5 1.25–35.53* no 0.61 0.21P4 (i.m.) vs. placebo/no TT SAB Artini et al ., 1995 1 10 1.3 0.12–36.19 no 0.1 0.07


V i l l P4Questions Outcome

measureAuthor(S) No. of

studiesNo. of



Vaginal vs. oral P4 >1 Consensus

P4 (vaginal) vs. P4 (oral)

IR Pouly et al ., 1996; Friedler et al ., 1999

2 467 1.5 1.10–2.05*

yes 0.99 0.72


CPR Pouly et al ., 1996; Friedler et al 1999

2 347 1.22 0.87–1.74 yes 0.99 0.58(oral) Friedler et al ., 1999P4 (vaginal) vs. P4 (oral)

DR Pouly et al ., 1996 1 283 1.04 0.65–1.64 no 0.97 0.49


SAB Pouly et al ., 1996; Friedler et al ., 1999

2 102 0.81 00.15–4.47

yes 0.6 0.21

P4 (i ) P4 ( l) CPR Li i di t l 1999 1 45 1 26 0 64 2 37 0 3 0 12P4 (i.m.) vs. P4 (oral) CPR Licciardi et al ., 1999 1 45 1.26 0.64–2.37 no 0.3 0.12hCG vs. P4 (oral) (short protocol)

IR Buvat et al ., 1990 1 81 12.1 1.85–246.45*

no 0.5 0.17

hCG vs. P4 (oral) (long protocol)

IR Buvat et al ., 1990 1 156 1.14 0.49–2.73 no 0.8 0.29

hCG vs. P4 (oral) (short protocol)

CPR Buvat et al ., 1990 1 27 8.36 1.44–173.74*

no 0.2 0.09


CPR Buvat et al ., 1990 1 52 1.15 0.50–2.91 no 0.34 0.13

hCG vs. P4 (oral) OPR Buvat et al ., 1990 1 27 7.43 1.22–156. no 0.2 0.09hCG vs. P4 (oral) (short protocol)

OPR Buvat et al ., 1990 1 27 7.43 1.22 156.64*

no 0.2 0.09


OPR Buvat et al ., 1990 1 52 1.61 0.61–4.88 no 0.34 0.13


Q i O A h ( ) N f N f RR 9 % CI M P #2 P #1

i.m. vs. vaginal P4 Equivalent

Questions Outcome measure

Author(s) No. of studies

No. of patients

RR 95% CI Meta-analysis

Power #2 Power #1

P4 (i ) CPR Ab t t l 1999b 5 891 1 3 1 02 1 75* 0 99 0 95

NS NSP4 (i.m.) vs. P4 (vaginal)

CPR Abate et al ., 1999b; Anserini et al ., 2001

5 891 1.3 1.02–1.75* yes 0.99 0.95

Artini et al . 1995; Guesa et al 2001;Guesa et al ., 2001; Perino et al ., 1997

P4 (i.m.) vs. P4 (vaginal)

OPR Artini et al ., 1995; Abate et al 1999b

2 194 1.6 0.50–4.93 yes 0.88 0.35P4 (vaginal) Abate et al ., 1999bP4 (i.m.) vs. P4 (vaginal)

DR Perino et al ., 1997; Abate et al ., 1999b

2 404 2.1 1.48–2.88* yes 0.99 0.65

P4 (i m ) vs SAB Artini et al 1995; 2 202 0 7 0 09–2 36 yes 0 69 0 24P4 (i.m.) vs. P4 (vaginal)

SAB Artini et al ., 1995; Perino et al ., 1997

2 202 0.7 0.09 2.36 yes 0.69 0.24


P4 dQuestions Outcome


studiesNo. of



P4 dosemeasure studies patients analysis

P4 dose (vaginal) 400 mg vs. 600 mg each day)

CPR Chanson et al ., 1996 1 40 1 0.23–4.36 no 0.27 0.11

P4 dose (i.m.) (25 mg vs. CPR Check et al ., 1991 1 127 2.3 0.86–6.63 no 0.71 0.25P4 dose (i.m.) (25 mg vs. 100 mg each day)

CPR Check et al ., 1991 1 127 2.3 0.86 6.63 no 0.71 0.25

P4 dose (i.m.) (25 mg vs. 100 mg each day)

OPR Check et al ., 1991 1 127 2.3 0.66–8.87 no 0.71 0.25

P4 dose (i.m.) (25 mg vs. SAB Check et al ., 1991 1 18 1 0.22–7.26 no 0.15 0.08dose ( ) ( 5 g s100 mg each day)

S C ec e a , 99 8 0 6 o 0 5 0 08

P4 dose (vaginal) (90 mg vs. 600 mg each day)

CPR Strehler et al ., 1999 1 99 0.9 0.53–1.68 no 0.59 0.2

P4 dose (vaginal) (90 mg vs. SAB Strehler et al ., 1999 1 36 1.5 0.22–12.3 no 0.25 0.1( g ) ( g600 mg each day)

,9

P4 dose (i.m.) (341 mg t.i.d. vs. 50 mg each day)

CPR Costabile et al ., 2001 1 300 1 0.79–1.35 no 0.98 0.52

P4 dose (i.m.) (341 mg t.i.d. OPR Costabile et al ., 2001 1 300 1.1 0.78–1.39 no 0.98 0.52( ) ( gvs. 50 mg each day)

,


SAB Costabile et al ., 2001 1 132 0.9 0.20–3.53 no 0.72 0.25


P4 dQuestions Outcome


studiesNo. of



P4 doseVag: 400 vs. 600mg/day NSmeasure studies patients analysis

P4 dose (vaginal) 400 mg vs. 600 mg each day)

CPR Chanson et al ., 1996 1 40 1 0.23–4.36 no 0.27 0.11

P4 dose (i.m.) (25 mg vs. CPR Check et al ., 1991 1 127 2.3 0.86–6.63 no 0.71 0.25

g g y


CPR Check et al ., 1991 1 127 2.3 0.86 6.63 no 0.71 0.25


OPR Check et al ., 1991 1 127 2.3 0.66–8.87 no 0.71 0.25

P4 dose (i.m.) (25 mg vs. SAB Check et al ., 1991 1 18 1 0.22–7.26 no 0.15 0.08Vag: 90 vs. 600mg/day NSdose ( ) ( 5 g s100 mg each day)

S C ec e a , 99 8 0 6 o 0 5 0 08

P4 dose (vaginal) (90 mg vs. 600 mg each day)

CPR Strehler et al ., 1999 1 99 0.9 0.53–1.68 no 0.59 0.2

P4 dose (vaginal) (90 mg vs. SAB Strehler et al ., 1999 1 36 1.5 0.22–12.3 no 0.25 0.1

g g y

( g ) ( g600 mg each day)

,9


CPR Costabile et al ., 2001 1 300 1 0.79–1.35 no 0.98 0.52

P4 dose (i.m.) (341 mg t.i.d. OPR Costabile et al ., 2001 1 300 1.1 0.78–1.39 no 0.98 0.52( ) ( gvs. 50 mg each day)

,


SAB Costabile et al ., 2001 1 132 0.9 0.20–3.53 no 0.72 0.25

IR Vag P

Crinone 8%IM P

IR

Alan Penzias, Boston IVF

1’675 IVF cases, in relation to the type of P4 preparation used for

Crinone 8%

NON Crinonetype of P4 preparation used for luteal support

PRPRPenzias AS.

Luteal phase support. Fertil Steril. 2002;77:318-23.

Penzias AS, Alper MM.Luteal support with vaginal micronized

progesterone gel in assisted reproduction. Reprod Biomed Online. 2003;6:287-95.

S Daya and J GunbyThe Cochrane Database of Systematic Reviews 2004 Issue 4Copyright © 2004 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.DOI: 10 1002/14651858 CD004830 This version first published online: 19 July 2004 in Issue 3 2004

Progesterone vaginal vs. IM administrationClinical pregnancy per embryo (gamete) transfer – with GnRHa

DOI: 10.1002/14651858.CD004830 This version first published online: 19 July 2004 in Issue 3, 2004

p g y p y (g )

NSNS

Vaginal natural micronized progesterone

■ Wide application as a first choice LPS regimen, mainly due to patient comfort and effectiveness (Levin et al., 2001).p ( , )

■ At least as effective as IM progesterone at providing LPS in induced cycles (Simunic et al., 2007).

■ In Europe, two different forms:● Capsules 100-200 mg (Utrogestan, Prometrium, Progeffiik) ● Crinone 8%, controlled sustained-release vaginal gel, 90 mg.● Ring in U.S.

D■ Dosage: ● Capsules: 200 mg 2-3 times a day (400-600 mg/day)● Crinone 8% once a day (Ludwig et al 2002; Simunic et al 2007)● Crinone 8% once a day (Ludwig et al., 2002; Simunic et al., 2007)

■ At the moment no dose finding studies performed ■ Further PRT essential to define the necessary dose for LPS in■ Further PRT essential to define the necessary dose for LPS in

IVF.

Crinone vs Vaginal capsules

■ RCT (n = 126) (Ludwig et al 2002):■ RCT (n = 126) (Ludwig et al., 2002): Clinical PR 28.8 vs 18.9% NSClinical abortion rates 14.3 vs 10.0% NSClinical abortion rates 14.3 vs 10.0% NSOngoing PR 24.7 vs 17.0% NS

■ Side-effects:Crinone 8% gel 38/125 Utrogestan vaginal capsules 68/132

Compliance with capsules better than with gel (P < 0.05) (Simunic et al., 2007; Ludwig et al., 2002).

Supplementing Luteal E2

pp gluteal E2?Luteal E2

Not supported by donor-egg IVF data (mock cycles).de Ziegler D. J Clin Endocrinol Metab, 1992:74:322-31.Younis J S Fertil Steril 1994;62:103 7

Not supported by early IVF data Smitz J. Human Reprod 1988;3:585-90Smitz J Human Reprod 1992;7:168 75

Younis J.S. Fertil Steril 1994;62:103-7.Lewin A. Fertil Steril 1994;62:121-125.

Smitz J. Human Reprod 1992;7:168-75

Motivated by fear of mid-luteal drop in E2 levels

Smitz J. Human Reprod 1993;8:40-5

Motivated by fear of mid luteal drop in E2 levelsHung E. Human Reprod 2000;15:1903-8Sahara F.I. Human Reprod 1999;14:2777-82

Are IVF results better when hCG is used for luteal support?: Hutchinson-W KA Fertil Steril 1990;53:495-5001Yes ;

: Martinez F. Gynecol Endocrinol 2000;14:316-20No

Effect of the additon of E2 to P on LPS in different stimulation schemes

COH GnRH agonist GnRHCOH GnRH agonist GnRH antagonist

Smitz et al. (1993)

Fahri et al.(2000)

Lukaszuk et al (2005)

Lewin et al (1994)

Fatemi et al.. (2006)(1993) (2000) al. (2005) (1994) (2006)

Patients 378 271 231 100 201

E2 (mg) 6 2 6,2 and 0 2 4

IR (%) (P+E 32.8 vs. 35.5 15.2* vs 10.2 29.9* vs. 17.8 - 42.4 vs. 37.8vs. P alone) and 9.8

Clinical PR/ET (P+E

29.2 vs. 29.5 39.5* vs. 25.6 51.3* vs. 32.8 and 23.1

28 vs. 26.5 32.6 vs. 28.9PR/ET (P E vs. P alone)

and 23.1

From Fatemi et al., Hum Reprod 2007* P < 0.05

Supplementing luteal E2 ?Supplementing luteal E2 ?Lukaszuk K et al. Fertil Steril 2005;83:1372-6.

n=80 n=73 n=78

Ctr 2mg 6mgCtr 2mg 6mg

Supplementing luteal E2 ?Supplementing luteal E2 ?Lukaszuk K et al. Fertil Steril 2005;83:1372-6.

PR and IR / E2 supplement

60 E2 2mg/d E2 6mg/dplacebo

40

0

20

PR/IR PR/IR PR/IR

E2E22mg BID orally or

vaginallyvaginally

Vag E2 Vag E2

Tourgman DE et al. Fertil Steril 2001;75:1156-8.

Supplementing luteal E2 ?Critical points:

pp g

■ Starting time: at least 3 days after ET■ Dosage■ GnRHa vs. GnRH antagonist: The difference in results with

the GnRH ant cannot be explained by the different forms ofthe GnRH ant. cannot be explained by the different forms of stimulation protocols used, since the luteal phase characteristics and dynamics of IVF cycles using GnRH agonist or antagonists have been shown to be similar (Friedler et al., 2006)

■ Vaginal route■ Vaginal route

■ Need of further RCTs■ Need of further RCTs

When to start LPSStarting time debated■ Starting time debated

■ No difference on ongoing PR when LPS started on:● the day of hCG administrationthe day of hCG administration● the day of OR ● the day of embryo transfer (occurring on day 3) (Baruffi et al., 2003)

and administered until 18 days following OR (20.8%, 22.7 and 23.6%) (Mochtar et al., 2006)

■ Delaying LPS until 6 days after OR decreases PR of 24% vs 3 days after OR■ Delaying LPS until 6 days after OR decreases PR of 24% vs. 3 days after OR (Williams et al., 2001).

Fanchin R et al. Uterine contractility decreases at the time of blastocyst transfers. Hum Reprod. 2001;16:1115 92001;16:1115-9.

Fanchin R, Righini C, de Ziegler D et al. Effects of vaginal progesterone administration on uterine contractility at the time of embryo transfer. Fertil Steril. 2001;75:1136-40. .

UC frequency decreases at the time of blastocyst transfers (day 5).

contractility at the time of embryo transfer. Fertil Steril. 2001;75:1136 40. .Early P4 supplementation decreases UC frequency at the time of ET.

Mochtar MH, Van Wely M, Van der Veen F. Timing luteal phase support in GnRH agonist down-regulated IVF/embryo transfer cycles. Hum Reprod. 2006;21:905-8.g y y p

No apparent differences between day hCG, retrieval and ET.

When to stop LPSLuteal phase support in infertility treatments

Gonadotropins hCGhCG

COHCOH

P4 P4E2 E2

P4 E2E2 E2

BP

BEarly pregnancy

Pregnancy test

Progesterone supplementation during early gestation after in vitro fertilization has no effect on the delivery ratefertilization has no effect on the delivery rate.Schmidt KL et al. Fertil Steril 2001;75:337-41

Obj ti T th d li t ith IVF ICSI i h didObjective: To compare the delivery rate with IVF or ICSI in women who did and did not receive progesterone supplementation in the first 3 weeks after a positive hCG test result. Design: Retrospective study.Method: Patient(s): 200 pregnant women who did not receive progesterone (i t ti ) d 200 t h i d t f 3(intervention group) and 200 pregnant women who received progesterone for 3 weeks after a positive hCG result.

P4Vaginal P4600 mg/day

Vaginal P4600 mg/day

200

P 3 kControls

n=200

n=200Pregnancy

test3 weeks


R lt( ) Th b f d li i 126 i th t d d 128 i thResult(s): The number of deliveries was 126 in the study group and 128 in the control group.

Conclusion(s): The delivery rate was the same in pregnant women whoConclusion(s): The delivery rate was the same in pregnant women who received and those who did not receive P4 for 3 weeks after a positive hCG result. P4 supplementation for more than 2 weeks after embryo transfer may th f i ld b fit i t ftherefore yield no benefit in terms of pregnancy.



126/200

200

P4

P 3 kControls 128/200n=200

n=200Pregnancy

test3 weeks No difference


R lt( ) Th b f d li i 126 i th t d d 128 i thResult(s): The number of deliveries was 126 in the study group and 128 in the control group.

Conclusion(s): The delivery rate was the same in pregnant women whoConclusion(s): The delivery rate was the same in pregnant women who received and those who did not receive P4 for 3 weeks after a positive hCG result. P4 supplementation for more than 2 weeks after embryo transfer may th f i ld b fit i t ftherefore yield no benefit in terms of pregnancy.



126/200

200

P4

P 3 kControls 128/200n=200

n=200

No rationale for continuing luteal support beyond the pregnancy testBut like us most do!Pregnancy

test3 weeks No differenceBut like us, most do!

The duration of LPS

Fi t t i t t■First trimester progesterone supplementation in IVF may support

l th h 7 k bearly pregnancy through 7 weeks by delaying a miscarriage but it does not

(improve live birth rates (Proctor et al., 2006).)

Conclusions ■ LPS with HCG or P after assisted reproduction increases PR.■ HCG increases risk of OHSS. LPS with hCG should be avoided

if E2 2700 / l d if f lli l 10if E2 > 2700 pg/ml and if follicles > 10.■ Natural micronized progesterone is not efficient if taken orally.

V i l d IM h bl i l i d■ Vaginal and IM progesterone have comparable implantation and clinical PR and delivery rates.V i l P h ld b d li d i th thi d f th i■ Vaginal P should be delivered in the upper third of the vagina.

■ The addition of E2 to the progestin support in long GnRH-a protocol regimen may have a beneficial effect on PR and IRprotocol regimen may have a beneficial effect on PR and IR. However, no positive effects in short GnRH agonist and GnRH-ant protocols.p

■ LPS should begin no later than 5 days after HCG to trigger ovulation.

■ The length of LPS not > 14 days: from ET (day 3 post OR) until the day of a positive HCG test.

rationale and regimens of progesterone andrationale and ... · rationale and regimens of...

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