Luteal phase support in ART

Luteal phase support in
ART
Aboubakr Elnashar
Benha university Hospital, Egypt
Aboubakr Elnashar

CONTENTS
1. WHY?
2. INDICATIONS
3. WHEN TO START?
4. WHEN TO STOP?
5. WHAT TO USE?
6. CO TREATMENT
CONCLUSION
Aboubakr Elnashar

1. WHY?
Abnormal luteal function after COS for IVF
 Suppression of LH
 Continued down-regulation by GnRHa
 Removal of of granulosa cells at OR
 Supra physiological E2/P4 in early luteal phase
 hCG injection before OR
Aboubakr Elnashar

2. INDICATIONS
1.Agonist and antagonist protocols
A. PR are significantly reduced in GnRHa ovarian
stimulation without LPS
(Daya & Gunby,2004)
B. Both GnRHa and antagonist IVF cycles: abnormal LPD
in all stimulated IVF cycles
C. Luteolysis is also initiated prematurely in antagonist co-
treated IVF cycles}
(Albano et al., 1998; Beckers et al., 2002)
Aboubakr Elnashar

2. Frozen natural cycles?
Controversial
 LPS increases LBR after frozen ET
(Bjuresten et al. 2010)
 LPS has no effect on ongoing PR in hCG-induced
natural frozen-thawed ET cycles
(Kyrou et al. 2010)
 Endometrial preparation for women undergoing ET
with frozen embryos or embryos derived from
donor oocytes (Glujovsky et al.,2010)Aboubakr Elnashar

3. WHEN TO START
From day of OR or ET
Not be later than day 3 after OR
Aboubakr Elnashar

4. WHEN TO STOP
Minimum’ 14 days from the day of ET until the day
of a positive HCG test.
(Andersen et al., 2002)
‘Minimum’ 18 days following OR
(Mochtar et al., 2006)
1st T progesterone supplementation in IVF support
early pregnancy through 7 w by delaying a
miscarriage but not improve LBR
(Andersen et al, 2002, Aboulghar et al, 2008)
 8-10 w of gestation.
Aboubakr Elnashar

5. WHAT TO USE FOR LPS?
 hCG
 Progesterone
Aboubakr Elnashar

HCG:
 Rescue corpus luteum
(Hutchins Williams et al. 1990)
 improves the implantation by increasing relaxin,
integrin & placntal ptn
(Mochtar, 1998)
 increase the risk of OHSS
(van der Linden et al., 2012)
Aboubakr Elnashar

CompanyPrice
(LE)
FormMgGeneric
name
FormTrade name
Ibsa7230 vag pessaries200ProgesteronVag or
rectal
Prontogest
Ibsa10230 vag pessaries400
Ibsa82.510 amp100ProgesteronIM
Actavis9015 vag pessaries200ProgesteronVag or
rectal
Cyclogest
Actavis12515 vag pessaries400
Ferring20021 vag tab100ProgesteronvagEndometrin
Serono236jell15 tube8 %ProgesteronevagCrinon
Octoper2430 caps100ProgesteroneVag or oralUterocare
Pharco1824100ProgesteroneVag or oralProgest
Aboubakr Elnashar

Progestagen: Definite benefit
 Improves endometrial receptivity
(Kolibianakis & Devroy, 2002)
 Promotes local VD and uterine musculature
quiescence by inducing nitric oxide synthesis in
decidua
(Bulletti & de Ziegler, 2005)
 act as immunologic suppressant blocking Th1 and
inducing release of Th2 cytokines
 (Ng et al. 2002)
 No value as regards miscarriage
Aboubakr Elnashar

hCG Vs progesterone
 hCG is better
(Soliman, 1994)
 No differences but OHSS is twice more common in
hCG group
(Pritts & Atwood, 2002)
 hCG is equal to I.M. progesterone
(Daya & Grundy, 2004; van der Linden et al., 2012)
Aboubakr Elnashar

hCG +progesterone Vs progesterone alone
Both are equally effective
Aboubakr Elnashar

1. Oral progesterone
 Only 10% of oral dose circulates as active P4 {first
pass effect}
 No secretory transformation of the endometrium
in patients with POF who had been treated with
oral micronized progesterone
(Devroey et al.1989; Bourgain et al. 1990)
Aboubakr Elnashar

2. IM progesterone
 Serum P4 levels well above the physiological
range with adequate endometrial secretory
changes
 Dose:
natural progesterone in oil, 25 and 100 mg/d: No
significant difference in outcome
(Costabile et al., 2001, Pritts & Atwood, 2002)
Aboubakr Elnashar

 Side effects:
 painful injections
 inflammatory reactions
 rash
 needs to be administered by nurse
(Lightman et al., 1999)
Aboubakr Elnashar

3. Vaginal progesterone
 “Targeted drug delivery” from vagina to uterus:
better endometrial histology
 High uterine progesterone concentrations
{anatomically close blood vessels: uterine first
pass effect}
(Cicinelli et al., 2000, de Ziegler et al., 1995)
Aboubakr Elnashar

Micronized progesterone:
no dose finding studies.
Most frequently: 300–600 mg daily, spread over 2-
3 dosages
(Tavaniotou et al., 2000)
Vaginal progesterone pessaries:
no dose finding studies
frequently used: 400-800 mg daily, spread over 3-4
doses
(NG et al, 2002, Tay et al, 2005)
Aboubakr Elnashar

 Vaginal gel
 8% gel in a dose of 90 mg once daily
no differences when administered twice daily
(Tavaniotou et al, 2000)
 Low dose or high dose vaginal progesterone gel
Both are equally effective
Aboubakr Elnashar

Which vaginal preparation?
Gel or capsules ?
Both are equally effective
(Daya & Grundy, 2004)
Capsule:
solid evidence of effectiveness and convenience
(Elenany et al, 2011)
more cost effective than gel: Gel is at least 4 times
more expensive than Capsules
No difference exists regarding CPR between
vaginal P gel and all other vaginal preparations for
LPS
(MA: Polyzoz et al, 2010)
Aboubakr Elnashar

4. Rectal application
 resulted in serum concentration during the first 8h
twice as high as other forms.
 no prospective RCT to compare the rectal
administration of progesterone with other
administration routes for IVF
(Chakmakijan & Zachariah, 1987)
Aboubakr Elnashar

5. SC
A new water-soluble progesterone
Implantation rate, PR, LBR and early miscarriage
rate for Prolutex were similar to those for Crinone.
The adverse event profiles were similar and
Prolutex was safe and well tolerated.
Aboubakr Elnashar

Oral or I.M. progesterone ?
Definitely I.M. progesterone
Oral or vaginal progesterone ?
Definitely vaginal progesterone
I.M. or vaginal progesterone ?
Both are equally effective
No difference in CPR
(Daya & Grundy, 2004; MA: Zarutiski & Philips, 2009)
Aboubakr Elnashar

Vaginal progesterone increases endometrial tissue
levels (Fert.Steril, 2012)
Aboubakr Elnashar

IM progesterone is associated with the highest
serum levels (Fert.Steril, 2012)
Aboubakr Elnashar

For IDEAL LPS:
IM P for the Highest Serum levels and Vaginal P for
increasing the Endometrial levels, Until Placental
progesterone production adequate, around week
8-10 w of gestation.
(Fert.Steril, 2012)
Aboubakr Elnashar

6. CO-TREATMENTS TO
PROGESTERONE
1.Addition of E2 to progesterone
No effect of oral estrogens
Transdermal estrogen is beneficial
No effect in antagonist protocol
Aboubakr Elnashar

2. Low dose aspirin
 VD and decreased platelet aggregation increased
ovarian and endometrial blood flow  ovarian
responsiveness,  endometrial thickness,  IR
 Decrease uterine contraction at the time of ET
 Low-dose aspirin (100 mg/d) doesn’t improve
ovarian responsiveness, blood flow, and PR
(Dirckx et al., 2009; Lambers et al., 2009)
Aboubakr Elnashar

3. Piroxicam
An oral dose 10 mg 1-2 h before ET
significantly improves PR
(Moon., 2004)
Doesn’t improve PR
(Dal and Borini, 2009)
Aboubakr Elnashar

100 mg q12h rectally for 3 doses from the night
before ET does not improve PR in oocyte
recipients
(Bernabue, 2006)
4. Indomethacin
Aboubakr Elnashar

4. low dose heparin
5000 IU bid and aspirin 100 mg/day from
the day of ET did not improve PR or IR
(Stern et al., 2003)
Aboubakr Elnashar

5. Prednisolone
10 mg/d before or after ET does not increase PR
(Ubaldi et al., 2002)
Aboubakr Elnashar

6. Viagra
25 mg qid vaginally from stimulation D1 to hCG day
(Sher, 2002; Paulus,2002)
Aboubakr Elnashar

7. Ascorbic acid
 Luteal regression is associated with ascorbate
depletion and the generation of reactive oxygen
species, which inhibit the action of LH and block
steroidogenesis
 No value
(Griesinger et al.,2002)
Aboubakr Elnashar

8. GnRHa in midluteal phase
 GnRH receptor is expressed in the human
preimplantation embryos, endometrium, corpus
luteum
 GnRHa has been shown to stimulate trophoblast
production of hCG
 Increased LBR
(MA: Kyrou et al., 2008)
Aboubakr Elnashar

GnRHa Vs no tt
GnRHa is beneficial
(Glujovsky et al., 2010)
Effective
Which GnRHa is more beneficial?
No differences
(Glujovsky et al., 2010)
Aboubakr Elnashar

CONCLUSION
 LPS is necessary to optimize the outcome of ART
 LPS with hCG is not superior to P.
 Supplementary hCG brings no advantage to P with
hCG increases risk of OHSS as compared with P
Aboubakr Elnashar

 The use of oral P is clearly inferior to IM or vaginal
administration and is associated with an increased
rate of side effects due to its metabolites
 IM and vaginal P therapy seem to be equally
effective
Aboubakr Elnashar

 The administration of estrogen to supplement the
luteal phase in standard stimulated IVF cycles needs
further clarification and evidence
 No evidence to support co-tt to progesterone
including aspirin, heparin, viagra….apart from
midluteal phase GnRHa which is promising
and needs further evaluation
Aboubakr Elnashar

Luteal phase support in ART

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