You can get: This lecture from: My scientific page on Face book: Aboubakr Elnashar Lectures. https://www.facebook.com/groups/227744884091351/ Slide share web site elnashar53@hotmail.com All lectures from: My clinic, 3 Althawra St. Almansura

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

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

3. WHEN TO START? From day of OR Not be later than day 3 after OR

4. WHEN TO STOP? Minimum: 14 days from the day of ET until the day of a positive HCG test. (Andersen et al., 2002) 18 days following OR (Mochtar et al., 2006) 8-10 w of gestation 1st T: delaying miscarriage but not improve LBR (Andersen et al, 2002, Aboulghar et al, 2008)

5. WHAT TO USE FOR LPS? hCG Progesterone

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)

Progestagen in Egyptian market Company Price (LE) Form Mg Generic name Trade name Abbott 36 20 tab 10 Dydrogesterone Oral Duphaston Ibsa 105 10 amp 100 Progesteron IM Prontogest 72 30 vag pessaries 200 Vag or rectal 102 400 Actavis 90 15 vag pessaries Cyclogest 125 Ferring 21 vag tab Vag Endometrin Serono 236 jell15 tube 8 % Progesterone Crinon Octoper 29 30 caps Vag or oral Uterocare Pharco 21 24 caps Progest adwia progesterone Oral only cyclotron Globe 22 15 caps Hysterogest

Only 10% of oral dose circulates as active P4 {first pass effect} 1. Oral progesterone Micronized: 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)

Retro steroid progesterone (dydrogesterone) Better oral bioavailability Rapidly absorbed: maximal levels: 30 min- 2.5 h Mean terminal half life: 5-7 h Fast and stable effect Its metabolites have progestogenic activity. Requires a 10–20 times lower oral dose than micronized progesterone

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)

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

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)

Comparing routes of progesterone administration IM progesterone to have more effect on CPR than oral and vaginal or rectal progesterone, but none of these results were significant. (Cochrane SR, 2011)

Micronized progesterone Vs synthetic progesterone Oral: Micronized progesterone Vs synthetic progesterone significant benefit from synthetic progesterone (Peto OR 0.79, 95% CI 0.65 to 0.96). Significant effect in favour of synthetic progesterone compared to micronized progesterone. The only synthetic progesterone used was oral dydrogesterone (Cochrane SR, 2011)

Both are equally effective Vaginal Gel or capsules ? Both are equally effective (Daya & Grundy, 2004) Capsule more cost effective than gel: Gel is 4 times more expensive than Capsules (Elenany et al, 2011) No difference in CPR between gel and all other vaginal preparations (MA: Polyzoz et al, 2010)

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

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.

IM P for the Highest Serum levels and 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)

6. CO-TREATMENTS TO PROGESTERONE 1 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 (Cochrane SR, van der Linden et al., 2012) No effect in antagonist protocol

doesn’t improve ovarian responsiveness, blood flow, and PR 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 doesn’t improve ovarian responsiveness, blood flow, and PR (Dirckx et al., 2009; Lambers et al., 2009)

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

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

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

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

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

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)

8. GnRHa in midluteal phase Rationale: GnRH receptor is expressed in preimplantation embryos Endometrium corpus luteum GnRHa stimulate trophoblast production of hCG

Triptorelin 0.1 SC (or 0.5 mg Leuprolide acetate) 6 days after ICSI Dose: Single dose: Triptorelin 0.1 SC (or 0.5 mg Leuprolide acetate) 6 days after ICSI (Tesarik et al., 2006; Ata et al., 2008; Isik et al., 2009; Razieh et al., 2009) Multiple doses: Triptorelin: daily 0.1 mg SC until day of beta-HCG or 14 days after OR (Fujii et al., 2001; Isikoglu et al., 2007, Abouelghar et al, 2015) Which GnRHa is more beneficial? No differences (van der Linden et al., 2012)

You can get: This lecture from: My scientific page on Face book: Aboubakr Elnashar Lectures. https://www.facebook.com/groups/227744884091351/ Slide share web site elnashar53@hotmail.com All lectures from: My clinic, 3 Althawra St. Almansura