luteal phase support (lps): dose ranging issues … ziegler-2.pdf · dose ranging issues and new...

Luteal phase support (LPS): dose ranging issues and new perspectives

Charlers Chapron Bruno Borghese

Hervé Foulot

Amin Bititi

Paul Mazurk

Guillaume Pierre

Marie Christine Lafay

Fouzia Decupere

François X. Aubriot

Dominique de Ziegler Vanessa Gayet

Pietro Santulli

Rebecca Monffat

Paul Pitrea

Corine Menez

Bander Kuttbi

Ann Marszalek

Alessandra Fubini

Université

Paris-Descartes,

Hôpital

Cochin Paris,

France

Université

Paris-Descartes,

Hôpital

Cochin Paris,

France

The options existing and doses used

The needs for LPS

A sub-cutaneous P4 preparation

Non-pelvic effects of P4?



The needs for LPS




Université

Paris-Descartes,

Hôpital

Cochin Paris,

France

Defective luteal support in ART due to high hormone levels, GnRH analogues and hCG.


Université

Paris-Descartes,

Hôpital

Cochin Paris,

France

On retrieval day or the day after, for minimizing UC at time of transfer. Earlier onset may advance closure of window of receptivity


Université

Paris-Descartes,

Hôpital

Cochin Paris,

France

At time of luteo-placental shift or as early as the time of the positive pregnancy test.

On retrieval day or the day after, for minimizing UC at time of transfer. Earlier onset may advance closure of window of receptivity


Université

Paris-Descartes,

Hôpital

Cochin Paris,

France


The needs for LPS




Université

Paris-Descartes,

Hôpital

Cochin Paris,

France

Parenteral Oral Vaginal Transdermic

Poor bioavailability

Poor permeability

First described


http://www.acclaimimages.com/usepolicy.html

P4 Oral P4: Not efficacious due to hepatic metabolism

Trans dermal P4: Not possible due to quantities (25mg/day) and skin metabolism

IM SC



P4

IM SC

P4

first uterine pass effect

vaginal

Oral P4: Not efficacious due to hepatic metabolism


Vaginal P4: The only practical alternative to IM P4



P4

P4


IM SC vaginal

0

5

10

15

20

25

30

0

0.2

0.4

0.6

0.8

1

1.2

Uterine tissue Serum levels

IM

IM vag

vag IM vs. vaginal No differences: why?

Oral P4: Not efficacious due to hepatic metabolism


Vaginal P4: The only practical alternative to IM P4



P4 IM SC vaginal

IM vs. vaginal No differences: why?

P4

0

5

10

15

20

25

30

0

0.2

0.4

0.6

0.8

1

1.2

Uterine tissue Serum levels

IM

IM vag

vag




Parenteral

First described

5/5/13



Vaginal


Doses


Université

Paris-Descartes,

Hôpital

Cochin Paris,

France

Doses

Hormone: P4


Université

Paris-Descartes,

Hôpital

Cochin Paris,

France


The needs for LPS




Université

Paris-Descartes,

Hôpital

Cochin Paris,

France

Parenteral Oral Vaginal Transdermic

Poor bioavailability

Poor permeability

First described



Vaginal Transdermic

cyclodextrin

New self-injectable P4 (25mg/d)


cyclodextrin



Université

Paris-Descartes,

Hôpital

Cochin Paris,

France

cyclodextrin

25 & 50mg: 100% decidua-lized endomrium No difference between the 2 doses tested

25 50

de Ziegler et al. Fertil Steril 2013


Université

Paris-Descartes,

Hôpital

Cochin Paris,

France


cyclodextrin

25 50

0

20

40

60

80

100

120

0 5 10 15 20

hours (day 11)

Pro

geste

ro

ne n

g/m

l


Sator et al. Gyn End 2013;29:205-8.


Université

Paris-Descartes,

Hôpital

Cochin Paris,

France


cyclodextrin

25 50


Sator et al. Gyn End 2013;29:205-8.

AEs related to study drug: Nb of AEs recorded durigng the 14 days of treatment /tot Nb of injections per group (%)

0,00

10,00

20,00

30,00

40,00

50,00

60,00

70,00

Injection site

bruising

Injection site

erythema

Injection site

redness

Injection site

swelling

Other Total

AE

s/N

b o

f in

jecti

on

s (%

)

Prog IBSA 50 mg IM

Oily Prog 50 mg IM

tolerability


Université

Paris-Descartes,

Hôpital

Cochin Paris,

France


Physiology: production of progesterone = 25 mg/day


Université

Paris-Descartes,

Hôpital

Cochin Paris,

France

LH

P4

P4: pulsatile production under the control of LH:

5ng/mL

Day LH +10



Université

Paris-Descartes,

Hôpital

Cochin Paris,

France


Université

Paris-Descartes,

Hôpital

Cochin Paris,

France

0

10

20

30

40

Crinone Prolutex

Université

Paris-Descartes,

Hôpital

Cochin Paris,

France


The needs for LPS




Université

Paris-Descartes,

Hôpital

Cochin Paris,

France


Université

Paris-Descartes,

Hôpital

Cochin Paris,

France

01020304050

P <0.0001

Crinone IM P4


There appears to be a superiority of IM over vaginal progesterone for frozen embryo transfers (FET)

The difference may result from non-pelvic effects of progesterone (immuno-suppression and/or Vasopressin/oxytocin)


Université

Paris-Descartes,

Hôpital

Cochin Paris,

France


Université

Paris-Descartes,

Hôpital

Cochin Paris,

France

LPS is necessary in ART because CL support by LH is deficient

Progesterone production during the luteal phase is of ~25ng/mL

A new sub cutaneous progesterone preparation is available: Prolutex (25mg/day)

Endometrial effects of vag and injectable progesterone are equivalent.

In FET, injectable progesterone results in higehr PR possibly, through non-pelvic effects.

Charlers Chapron Bruno Borghese

Hervé Foulot

Amin Bititi

Paul Mazurk

Guillaume Pierre

Marie Christine Lafay

Fouzia Decupere

François X. Aubriot

Dominique de Ziegler Vanessa Gayet

Pietro Santulli

Rebecca Monffat

Paul Pitrea

Corine Menez

Bander Kuttbi

Ann Marszalek

Alessandra Fubini


Université

Paris-Descartes,

Hôpital

Cochin Paris,

France

P4: pulsatile production under the control of LH:

Day LH +8 LH

P4



Université

Paris-Descartes,

Hôpital

Cochin Paris,

France

Université

Paris-Descartes,

Hôpital

Cochin Paris,

France


luteal phase support (lps): dose ranging issues … ziegler-2.pdf · dose ranging issues and new...

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