Triggers and Luteal Support What, Why and How? Paul Brezina, MD/MBA Director of Reproductive Genetics: Fertility Associates of Memphis Consulting Gynecologist: St. Jude Children's Research Hospital Assistant Clinical Professor: Vanderbilt University School of Medicine Director of clinical genetic applications: advagenix, llc

Disclosures Advagenix LLC Minority Partner Director of Clinical Genetic Applications PGS PGD Preconception Carrier Screening Non Invasive Prenatal Testing Other Genetic Testing

Case: “Jenny and Bob T” 32 year old G0 Male factor infertility AFC = 25 AMH = 3.1 FSH= 6.2 LH = 5.9 E2=42 BMI = 28

Big Questions What is the best protocol? What is the best trigger Pregnancy outcomes Cost Safety What is the best trigger hCG Lupron What is the best luteal support? Injectable progesterone Vaginal progesterone

Progesterone: What’s the big deal? Maintenance of early pregnancy depends on the production of progesterone by the corpus luteum Between 7 and 9 weeks of gestation the developing placenta takes over the progesterone production

Luteal Phase Deficiency Progesterone Estrogen Fetus Placenta Corpus Luteum Ovary Uterus HCG

Luteal Phase Deficiency Progesterone Estrogen Fetus Placenta Corpus Luteum Ovary Uterus

So…. We treat most everybody with progesterone IUI RPL IVF Why is it different in IVF?

(Removes Granulosa Cells) Luteal Support in IVF Fresh Embryo Transfer IVF Frozen Embryo Transfer IVF Extra Progesterone Added Estrogen Progesterone Added Progesterone Estrogen Ovary Ovary Fetus Fetus Placenta HCG Placenta Uterus Uterus Retrieval (Removes Granulosa Cells) Supplementation Replacement

Fresh IVF Progesterone Progesterone support is superior to no support Best method of support: Debated Optimal support Work well Minimal side effects Ease of administration Hubayter ZR, Muasher SJ. Luteal supplementation in in vitro fertilization: more questions than answers. Fertil Steril 2008; 89(4):749–758 Yanushpolsky EH. Luteal phase support in in vitro fertilization. Semin Reprod Med. 2015 Mar;33(2):118-27.

Fresh IVF Progesterone IM Progesterone Pro Long track record “It has to be getting in” Cons Big Needle Disturb surrounding tissue Vessels (Hematoma) Nerves Vaginal Progesterone Pro Ease of use (no needles) No disturbance of surrounding tissues Excellent outcome data Cons Less long term data Administration errors Messy Hubayter ZR, Muasher SJ. Luteal supplementation in in vitro fertilization: more questions than answers. Fertil Steril 2008; 89(4):749–758 Yanushpolsky EH. Luteal phase support in in vitro fertilization. Semin Reprod Med. 2015 Mar;33(2):118-27.

Fresh IVF Progesterone: In our center In our center we use Vaginal progesterone as 1st line for fresh ET We still utilize IM Progesterone if patient prefers

Frozen ET Progesterone IM Progesterone Pro Long track record “It has to be getting in” Cons Big Needle Disturb surrounding tissue Vessels (Hematoma) Nerves Vaginal Progesterone Pro Ease of use (no needles) No disturbance of surrounding tissues Cons Less long term data ? Efficacy concerns Administration errors Messy Hubayter ZR, Muasher SJ. Luteal supplementation in in vitro fertilization: more questions than answers. Fertil Steril 2008; 89(4):749–758 Yanushpolsky EH. Luteal phase support in in vitro fertilization. Semin Reprod Med. 2015 Mar;33(2):118-27.

Triggers GnRH FSH LH E2 Progesterone

Lupron Down Regulated Cycle Triggers Lupron Down Regulated Cycle Antagonist Cycle Lupron Trigger GnRH GnRH FSH LH FSH LH HCG Trigger E2 Progesterone E2 Progesterone

Lupron Trigger Principally utilized to prevent OHSS Only several case reports with Lupron trigger Only with antagonist cycles Reduced pregnancy rates with FRESH transfers Some data shows improvement with aggressive E2 and P4 luteal support Some have utilized low dose hCG concurrently with Lupron trigger Reported lower OHSS rates while preserving rates of pregnancy success. Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Hudson C. Comparison of "triggers" using leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin. Fertil Steril. 2011 Jun 30;95(8):2715-7. Griffin D, Benadiva C, Kummer N, Budinetz T, Nulsen J, Engmann L.Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders. Fertil Steril. 2012 Jun;97(6):1316-20. Lin MH, Wu FS, Lee RK, Li SH, Lin SY, Hwu YM. Dual trigger with combination of gonadotropin-releasing hormone agonist and human chorionic gonadotropin significantly improves the live-birth rate for normal responders in GnRH-antagonist cycles. Fertil Steril. 2013 Nov;100(5):1296-302. Casper RF. Basic understanding of gonadotropin-releasing hormone-agonist triggering. Fertil Steril. 2015 Apr;103(4):867-869. Shapiro BS, Andersen CY. Major drawbacks and additional benefits of agonist trigger-not ovarian hyperstimulation syndrome related. Fertil Steril. 2015 Apr;103(4):874-878. Youssef MA, Van der Veen F, Al-Inany HG, Mochtar MH, Griesinger G, Nagi Mohesen M, Aboulfoutouh I, van Wely M. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist-assisted reproductive technology. Cochrane Database Syst Rev. 2014 Yding Andersen C, Vilbour Andersen K. Improving the luteal phase after ovarian stimulation: reviewing new options. Reprod Biomed Online. 2014 May;28(5):552-9. Engmann L, Benadiva C. Agonist trigger: what is the best approach? Agonist trigger with aggressive luteal support. Fertil Steril. 2012 Mar;97(3):531-3 .

hCG Trigger Standard method of triggering Any type of IVF stimulation cycle Exposure to OHSS Coasting May minimize dose of hCG trigger Seyhan A, Ata B, Polat M, Son WY, Yarali H, Dahan MH. Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger with the addition of 1500 IU hCG. Hum Reprod. 2013 Sep;28(9):2522-8 Lin YH, Huang MZ, Hwang JL, Chen HJ, Hsieh BC, Huang LW, Tzeng CR, Seow KM. Combination of cabergoline and embryo cryopreservation after GnRH agonist triggering prevents OHSS in patients with extremely high estradiol levels--a retrospective study. J Assist Reprod Genet. 2013 Jun;30(6):753-9.

Case: “Jenny and Bob T” 32 year old G0 Male factor infertility AFC = 25 AMH = 3.1 FSH= 6.2 LH = 5.9 E2=42 BMI = 28

Big Questions What is the best protocol? What is the best trigger Pregnancy outcomes Cost Safety What is the best trigger hCG Lupron What is the best luteal support? Injectable progesterone Vaginal progesterone