Novel treatments to trigger final follicular maturation and luteal phase support
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Novel treatments to trigger final follicular maturation and luteal phase support
- 1. Novel treatments for triggering final follicular matura3on and suppor3ng luteal phase Sandro Esteves Medical & Scien3fic Director ANDROFERT -‐ Brazil
- 2. Learning objec3ves At the comple3on of this presenta3on, par3cipants should be able to: • Appraise novel strategies to triggering the final follicle matura5on and suppor5ng the luteal phase as per a quality management perspec5ve • Individualize trigger and luteal phase support according to different pa5ent segments ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2015 ANDROFERT
- 3. “Process”: the only objec3ve and measurable aspect of quality Process = Any activity or set of activities that uses resources to transform raw material, supplies and labor (inputs) into products or services (outputs) ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2015 ANDROFERT
- 4. Quality of trigger and LPS methods can be measured, but how? Using indicators for the most important quality dimensions in infer3lity care… Safety Pa3ent-‐ centeredness Effec3veness ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2015 ANDROFERT
- 5. What are the most effec3ve, safest and pa3ent-‐centered strategies? • Effec3veness: technical aspects to deliver the best possible outcome (e.g. pregnancy, live birth, cumula5ve LBR) • Safety: complica5ons (OHSS), adverse effects, risks (pa5ent & offspring), errors/ mistakes • Pa3ent-‐centeredness: convenience, physical burden, invasiveness of techniques ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2015 ANDROFERT
- 6. How to offer the most effec3ve, safest and pa3ent-‐ centered trigger and LPS methods? Clinical Needs Standard Opera3ng Procedures Results • Agents • Route of administration • Dose • Timing ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2015 ANDROFERT
- 7. 14h 14h 20h 48h 0 20 h Natural LH surge hCG Adapted from Chan et al. Hum Reprod. 2003;18:2294-‐7 Day 6 hCG and GnRHa elicit final follicular matura3on as surrogates for the mid-‐cycle LH surge GnRHa 36-48 h ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2015 ANDROFERT Day 8
- 8. Trigger Prac3ces at Androfert ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2015 ANDROFERT High responders at risk of OHSS Fresh ET + modified LPS FRALL + blastocyst ET ar3ficial cycle GnRH-‐a trigger (0.2 mg triptorelin) High*, normal and poor responders FRALL Fresh D3/D5 ET + standard LPS Rec-‐hCG trigger (250 mcg) *Low OHSS risk
- 9. Propor3on of total immunoreac3vity (%) Pregnyl® Choragon® Profasi® Ovitrelle® Intact bioac3ve hCG 50 30 96 >99 Hyperglycosylated hCG 0.6 4 0.5 <0.1 Free β subunit 6.2 8 2.4 <0.1 β-‐core fragment1 43 58 1.2 -‐-‐ Epidermal growth factor2 181-‐204 154 4-‐10 -‐-‐ Gervais et al. Glycobiology 2003;13:179-89; Yarram et al. Fertil Steril 2004;82:232-3 1degradation product of hCG; 2EGF is a contaminant (ng/5000IU) Func3onally intact hCG and contamina3on in hCG formula3ons ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2015 ANDROFERT
- 10. Farrag et al. JARG 2008; 25:461-6 8.4 7.3 7.1 4.7 0 2 4 6 8 10 No. Retrieved oocytes No. MII with mature cytoplasm rec-hCG (250 mcg; n=42) u-hCG (10,000 IU; n=47) *p<0.01 * ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2015 ANDROFERT
- 11. Effec3veness of hCG trigger RCT comparing trigger with rec-‐hCG (250 mcg) vs u-‐hCG (10,000 IU) on delivery rates in eSET antagonist cycles 26.7% 44.1% Delivery rate (%) u-hCG rec-hCG N=119 aged<32 OR: 2.16 (95% CI: 1.01-‐4.67; p=0.04) Papanikolaou EG et al. Fer&l Steril 2010; 94:2902-‐4 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2015 ANDROFERT
- 12. RCT N Odds-‐ra3o Local site reac3ons* rec-‐hCG vs. u-‐hCG 3 374 0.39 95% CI: 0.25 to 0.61 Driscoll et al. 2000: 27% vs 42% ERHCG group 2000: 23% vs 45% Abdelmassih et al. 2005: 23% vs 45% Youssef et al. Cochrane Database Syst Rev. 2011; 13(4):CD003719 * Pain and/or inflammation ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2015 ANDROFERT
- 13. hCG preferences in treatment-‐ experienced pa3ents at Androfert Total (n=76) 60% 29% 3% 8% prefer new pen prefer pre-filled syringe prefer lyophilized powder to reconstitute Not matter ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2015 ANDROFERT
- 14. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2015 ANDROFERT RCT comparing rec-‐hCG (ovitrelle; 250 mcg) vs GnRH agonist (0.2 mg triptorelin) trigger in oocyte dona3on cycles 12 11.4 8 7.5 67.8 71.1 rec-‐hCG GnRHa N oocytes N mature oocytes %2PN Galindo et al. Gynecol Endocrinol. 2009;25(1):60-‐6 N=257; p=NS
- 15. Reasons for trigger failure with hCG and GnRHa Empty follicle: Ø hCG: 0.1%-‐2.0%1,2 Ø GnRHa: 0.6%-‐3.5%3,4 Root causes: • Human errors • High BMI • Low baseline LH levels* • Less bioac5ve LH* 1Quintans et al. 1998; 2Zegers Hochschild et al. 1995; 3Castillo et al. 2012; 4Kummer et al. 2013. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2015 ANDROFERT *GnRHa
- 16. <34h 34-‐35h 35.5h >35.5-‐36h >36-‐38h 63% 73% 76% 79% 82% ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2015 ANDROFERT Oocyte maturity by interval between trigger (rec-‐hCG 250 mcg) and oocyte retrieval in antagonist cycles Androfert; N=2,230 cycles
- 17. GnRH-‐agonist vs hCG trigger Fresh autologous cycles Moderate/ severe OHSS OR 0.10 0.01-‐0.82 Live birth OR 0.44 0.29-‐0.68 Youssef et al. Cochrane Database Syst Rev. 2011 High responders Fresh ET Freeze all GnRH-a trigger GnRH-‐a trigger in IVF cycles ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2015 ANDROFERT
- 18. Agents Effec3veness Safety Pa3ent-‐ centeredness Rec-‐hCG ✔✔✔ ✔✔ ✔✔✔ u-‐hCG ✔✔ ✔ ✔✔ GnRH-‐a ✔✔ ✔✔✔ ✔ ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2015 ANDROFERT How to offer the most effec3ve, safest and pa3ent-‐centered trigger method?
- 19. Abnormal luteal phase in s3mulated cycles • Supraphysiologic steroid levels (by mul3follicular development) inhibits LH secre3on • Low LH levels causes luteolysis, shortened luteal phase, and may result in implanta3on failure Jones 1996; Albano et al 1998;Tavaniotou et al 2000; Fauser & Devroey 2003; Trinchard-‐Lugan et al 2002; Sherbahn 2013 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2015 ANDROFERT
- 20. Corpus luteum func3on depend on pulsa3le LH release from pituitary Mid-‐cycle LH levels Natural cycle 6.0 IU/l hCG trigger 0.2 IU/l GnRHa trigger 1.5 IU/l Tavaniotou & Devroey, 2003; Humaidan et al. 2005 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2015 ANDROFERT
- 21. Damewood et al., 1989; Gonen et al., 1990; Itskovitz et al., 1991; Weissman et al., 1986 ; Bonduelle et al., 1988 In s3mulated cycles, there is a period of deficient LH ac3vity ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2015 ANDROFERT Day 6 Trigger Luteal phase length (days) hCG Day 8 LH activity deficient period Day 14 28-32h GnRHa LH activity deficient period
- 22. Clinical Needs Standard Opera3ng Procedures Pa3ent subgroups How to offer the most effec3ve, safest and pa3ent-‐ centered LPS? • Agents • Routes of administra3on • Dose • When to start • When to stop ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2015 ANDROFERT
- 23. GnRHa trigger § Vaginal P gel 90 mg 2x/d § Onset day OPU § Cessa3on ~9th week if pregnancy hCG trigger § Vaginal P gel 90 mg 1x/d § Onset day OPU § Cessa3on ~9th week if pregnancy 2 hCG bolus 1,500 IU (rec-‐ hCG; 6 clicks pen of 250 mcg OPU) § Vaginal P gel 90 mg 1x/d § ET 5 days ater P § Cessa3on ~9th week if pregnancy FET Ar3ficial cycle: Transdermal estradiol step-‐up regimen (100mcg/d up to 300 mcg/d) 3 1 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2015 ANDROFERT LPS SOP at Androfert standardized steps, which are used every time the task is done, to ensure the process is done the same way each time
- 24. In FET cycles, all of the current methods of endometrial prepara3on appear to be equally effec3ve in terms of ongoing pregnancy rate* • Meta-‐analysis of 20 compara3ve studies • ~13,000 cycles • Natural and ar3ficial cycles with and w/o GnRHa • Safety and pa3ent-‐centeredness not addressed Groenewoud ER et al. Hum Reprod Update. 2013;19:458-70 *in eumenorrhoic patients ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 24 2015 ANDROFERT 3
- 25. Gelbaya et al Fertil Steril. 2008; Kolibianakis et al Hum Reprod. 2008; Jee et al Fertil Steril. 2010; van der Linden et al Cochrane Database 2011 High-‐quality evidence on effec3veness of LPS methods ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2015 ANDROFERT 2
- 26. P routes & types Evidence Effect Conclusion Vaginal as effective as IM/oral 13 RCT; 2 MA; >2,000 cycles Similar CPR, LBR & miscarriage True Vaginal safer and more patient- friendly than IM/oral 3 RCT; 1 MA; >2,000 cycles Lower side effects; Increased patient satisfaction True Schoolcraft et al 2000; Yanushpolsky et al-2008; Zarutskie & Phillips 2009; Polyzos et al 2010; van der Linden et al Cochrane 2011 High-‐quality evidence on safety & pa3ent-‐ centeredness of progesterone usage ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2015 ANDROFERT 2
- 27. 0 5 10 15 20 25 30 35 40 IM P Vaginal P ng/mL Endometrial Levels 0 0.5 1 1.5 2 2.5 3 3.5 IM P Vaginal PngP/mgprotein Serum Levels P<0.0001 P<0.0001 Ficicioglu et al. Gynecol Endocrinol 2004; 18: 240-3 P in oil (50mg) vs. P gel (vaginal; Crinone 8%) ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2015 ANDROFERT
- 28. • Vaginal pessaries/tablets/suppositories – can be required t.i.d. – lay flat for 30 minutes following inser5on – messy, vaginal discharge • vaginal itching and perineal irrita5on • CRINONE gel – 90mg once daily dosage • some women may need 90mg twice daily – no need to lay flat afer administra5on Vaginal delivery op3ons Lan VTN. Repro BioMed Online. 2008; Simunic V et al. Fer9l Steril. 2007 Ludwig M & Diedrich K. Acta Obs Gyn Scand. 2001; Penzias AS. Fert Steril. 2002. ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2015 ANDROFERT
- 29. High vs low dosage vaginal delivery with applicator Khan et al. Fer5l Steril 2009; 91:2245-‐50 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2015 ANDROFERT
- 30. 1 hour 3 hours 2 hours 4 hours Time Vaginal bioadhesion essen3al because it takes ~4h to reach steady state in the uterus (first-‐pass effect) Bullek C et al. Hum Reprod 1997 aqueous lipid 3ssue micronized progesterone in an ‘oil-‐in-‐water’ emulsion (Crinone® 8%) ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2015 ANDROFERT
- 31. Vaginal P started at the 3me of OPU reduces uterine contrac3ons at the 3me of ET 4.6 2.8 4.5 4.2 UC on day of hCG UC on day of ET Crinone started on the day of OPU (n=43) Crinone started on the evening of ET (n=41) P<0.001 Fanchin et al. Fer3l Steril 1999; Fanchin et al Hum Reprod 1998 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2015 ANDROFERT High uterine contrac3ons (UC) at the 3me of ET decrease IR
- 32. Similar outcome early vs. late cessa3on pregnancy test or clinical pregnancy vs. 6-‐7 week gesta5on Outcome Evidence Conclusion OPR 2 RCT; 1 MA; >350 cycles No difference Miscarriage 6 RCT; 1 MA; >1,000 cycles No difference LBR 8 RCT; 1 MA; >1,200 cycles No difference Liu et al. Reprod Biol Endocrinol. 2012; 10:107 ANDROFERTANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2015 ANDROFERT
- 33. Vaisbuch et al. Reprod Biomedicine Online 28: 330-‐5, 2014. Worldwide prac3ces favor longer dura3on LPS ANDROFERTANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2015 ANDROFERT
- 34. Luteal-‐placental shit on P produc3on occurs around 7-‐12th gesta3onal week 0 100 200 300 400 500 600 700 800 900 0 10 20 30 40 50 60 70 80 4 5 6 7 8 9 10 E2(pg/mL) P(ng/mL) Gestational age in weeks P E2 Scott et al. Fertil Steril 1991; 56:481 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2015 ANDROFERT
- 35. Bleeding before P discon3nua3on consequence (not a cause) of non-‐ pregnancy state • Reflect lack of a viable pregnancy rather than deficient LPS • Usually seen in women with lower estradiol levels Onset of menses following HCG (day 0) in non-pregnant womenn = 63 Roman E et al. Hum Reprod. 2000 ANDROFERTANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2015 ANDROFERT
- 36. Modified LPS in GnRH-‐a trigger (fresh ET) No. follicles day OPU* 1,500 IU hCG at OPU & 1,000 OPU+5 & LPS with P gel 90 mg bid ≤ 14 1,500 IU hCG at OPU + LPS with P gel 90 mg bid OR Freeze all 15-‐25 Freeze all >26 *Modified from Humaidan et al. Hum Reprod. 2013;28(9):2511-‐21 ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2015 ANDROFERT 14h 14h 20h 48h0 20 h 4h GnRHa Natural LH surge Luteal phase defect 1
- 37. P agents and routes Effec3ve-‐ ness Safety Pa3ent-‐ centeredness Intramuscular ✔✔✔ ✔ ✔ Oral ✔✔ ✔ ✔ Subcutaneous ? ? ? Vaginal pressaries/ tablets ✔✔✔ ✔✔✔ ✔✔ Vaginal gel ✔✔✔ ✔✔✔ ✔✔✔ ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2015 ANDROFERT
- 40. Conclusions • Our ul5mate goal is to deliver the highest quality in infer5lity care – Consider safety and pa9ent-‐centeredness, in addi9on to effec9veness, when choosing methods for trigger and LPS • These quality dimensions offer an unique opportunity to beoer individualize trigger and LPS according to different pa5ent segments using novel tools and devices Novel treatments to triggering final follicular matura3on and suppor3ng luteal phase ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 40 2015 ANDROFERT
- 41. Thank you спасибо Obrigado This presentation is available at http://www.slideshare.net/ sandroesteves