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

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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

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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)

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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

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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.

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5. WHAT TO USE FOR LPS?

hCG

Progesterone

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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)

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Company Price

(LE)

Form Mg Generic

name

Form Trade name

Ibsa 72 30 vag pessaries 200 Progesteron Vag or

rectal Prontogest

Ibsa 102 30 vag pessaries 400

Ibsa 82.5 10 amp 100 Progesteron IM

Actavis 90 15 vag pessaries 200 Progesteron Vag or

rectal Cyclogest

Actavis 125 15 vag pessaries 400

Ferring 200 21 vag tab 100 Progesteron vag Endometrin

Serono 236 jell15 tube 8 % Progesterone vag Crinon

Octoper 24 30 caps 100 Progesterone Vag or oral Uterocare

Pharco 18 24 100 Progesterone Vag or oral Progest

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Progestagen: Definite benefit (van der Linden et al., 2012)

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 (van der Linden et al., 2012)

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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)

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hCG +progesterone Vs progesterone alone

Both are equally effective

(van der Linden et al., 2012)

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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)

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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)

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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)

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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)

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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

(van der Linden et al., 2012)

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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)

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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)

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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.

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Oral or I.M. progesterone ?

Definitely I.M. progesterone

(Daya & Grundy, 2004)

Oral or vaginal progesterone ?

Definitely vaginal progesterone

(Daya & Grundy, 2004)

I.M. or vaginal progesterone ?

Both are equally effective

No difference in CPR

(Daya & Grundy, 2004; MA: Zarutiski & Philips, 2009)

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Vaginal progesterone increases endometrial tissue

levels (Fert.Steril, 2012)

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IM progesterone is associated with the highest

serum levels (Fert.Steril, 2012)

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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)

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6. CO-TREATMENTS TO

PROGESTERONE

1. Addition of E2 to progesterone

No effect of oral estrogens

(van der Linden et al., 2012)

Transdermal estrogen is beneficial

(van der Linden et al., 2012)

No effect in antagonist protocol

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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)

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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)

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100 mg q12h rectally for 3 doses from the night

before ET does not improve PR in oocyte

recipients

(Bernabue, 2006)

4. Indomethacin

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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)

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5. Prednisolone

10 mg/d before or after ET does not increase PR

(Ubaldi et al., 2002)

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6. Viagra

25 mg qid vaginally from stimulation D1 to hCG day

(Sher, 2002; Paulus,2002)

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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)

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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)

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GnRHa Vs no tt

GnRHa is beneficial

(Glujovsky et al., 2010)

Effective

(van der Linden et al., 2012)

Which GnRHa is more beneficial?

No differences

(Glujovsky et al., 2010)

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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

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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

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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

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Thank you Aboubakr Elnashar