Synchronization of Slowly Developing Embryos Restores Implantation Success Richard T. Scott, Jr, MD, HCLD Clinical and Scientific Director, Reproductive Medicine Associates of New Jersey Professor and Fellowship Director, Reproductive Endocrinology Sidney Kimmel Medical College, Thomas Jefferson University Progesterone and clinical outcomes Serum Progesterone on day of HCG administration 2 critical breakpoints Could exogenous LH be the cause? 1.27 2.86 Silverberg KM, et al. J Clin Endocrinol Metab. 1991; 73:797 803
Late follicular rise in progesterone Retrospective study 4032 patients P 4 1.5 ng/ml associated with lower ongoing pregnancy rates Bosch E et al. Hum Reprod. 2010; 25:2092 100 Why Do We Attain Elevated Progesterone Levels in the Follicular Phase? 1. Excessive LH Stimulation Exogenous LH/hCG induced luteinization Failure of the GnRH analog to suppress endogenous LH surges 2. High Response Normal Progesterone production per follicle, with the elevation reflecting accumulation from large numbers of follicles 3. A result of excessive FSH stimulation
Is the Prevalence of Progesterone Elevations Different in GnRH ant and GnRH a cycles? % cycles with P > 1.5 ng/ml Clinical Pregnancy Rate % 30 25 20 15 10 5 0 40 35 30 25 20 15 10 5 0 Antagonist Agonist <1.5 > 1.5 Progesterone (ng/ml) Papanikolaou et al Hum Reprod 2012; 27:1822 8 RCT N=190 Mean age 32 years Stimulation 150 300 IU recfsh No LH/hCG Management not altered by presence of P elevation Prevalence not altered by choice of analog Outcomes diminished by P >1.5 ng/ml Follicular Progesterone Elevations Circulation The Two Cell Theory Progesterone DHEA SO 4 Estradiol C21 C19 C21 C19 C18 Cholesterol Theca Cell C27 Androgen Granulosa Cell C21 C27 LH R FSH R Cholesterol
Follicular progesterone elevations DHEA Inadequate Excessive exlh RE DEFINING THE EFFECT OF EXOGENOUS LH ACTIVITY IN FOLLICULAR STIMULATION: AN ANALYSIS OF 10,280 CYCLES VALIDATING THE IMPORTANCE OF exlh IN PREVENTING A PREMATURE RISE IN PROGESTERONE 60 50 40 % 30 20 10 0 % Progesterone Elevation (>1.5 mg/ml) Werner et al. Fertil Steril in press 2014 * Colors separate statistically definable groups
Ovarian Response versus Elevated Late Follicular Progesterone Levels (>1.5 ng/ml on day of hcg) 100 90 80 70 60 P<0.001 50 40 P<0.001 30 P=0.03 20 10 0 FSH Only 0 0.3 0.3 0.6 >0.6 Ratio of administered LH/FSH Werner et al. Fertil Steril in press 2014 % Cycles with Progesterone Rise Differences between response groups Werner et al. Fertil Steril in press 2014
Ovarian Response versus Elevated Late Follicular Progesterone Levels (>1.5 ng/ml on day of hcg) Griesinger et al Fertil Steril 2013; 100:1622 8 N=1866 Ovarian Response versus Elevated Late Follicular Progesterone Levels (>1.5 ng/ml on day of hcg) P=NS *All comparisons significantly different except that for > 18 oocytes N=1866 Griesinger et al Fertil Steril 2013; 100:1622 8
Luteinization on the Day Prior to Oocyte Retrieval and Pregnancy Rates 52% 50% 48% 46% 44% 42% 40% Delivery rate 0 2 2 4 4 6 >6 Serum P4 day AFTER hcg administration 38% Live birth rates after IVF are reduced by both low and high progesterone levels on the day of human chorionic gonadotropin administration Overall Data Adjusted Data Santos Ribiero et al Hum Reprod 2014; 29:1698 1705 Adjusted for Peak E2, number of COC s, patient age, number of embryos transferred, and stage of embryo development
DHEA Administration Increases Progesterone Production Progesterone ng/ml 6 5 4 3 2 1 0 DHEA None DHEA Strauss et al JARG 2014; 31:645 9 Case report of cancer patient with POI Patient with ovarian tissue transplantation Followed sequentially on and off DHEA for intervals of months DHEA 25 mg po tid NO change in E2 levels. Does this mean that DHEA induces luteinization? Beware of DHEA Interference in your P Assay Patients receiving DHEA have elevated DHEA SO 4 levels These levels may falsely elevate P levels Assay dependent Forman JARG 2014
A Physiologic Explanation of Impaired Endometrial Receptivity During Stimulated Cycles What goes wrong? www.origio.com Late follicular rise in progesterone Retrospective study 4032 patients P 4 1.5 ng/ml associated with lower ongoing pregnancy rates Bosch E, et al. Hum Reprod. 2010; 25:2092 100
Progesterone and the Endometrial Transcriptome Leuprolide acetate 1 mg/d td sc Estradiol 0.2 mg/d td 40 mg/d IM 10 mg/d IM 5mg/d IM 2.5 mg/d IM Adapted from S. Young, MD, PhD Progesterone Pharmacokinetics Adapted from S. Young, MD, PhD
Meta analysis of late follicular P levels and clinical outcome Summary Three studies included GnRH antagonist cycles Limited sample size Outcomes reduced with late follicular P elevation Hamdine et al Fertil Steril 2014; 102:448 54 Progesterone and the Endometrial Transcriptome Adapted from S. Young, MD, PhD
Revisiting SUSTAINED the IMPLANTATION Window of RATES Receptivity DECLINE OUTSIDE OF OPTIMAL WINDOW 18 16 Implantation Rate (%) 14 12 10 8 6 4 2 0 1 0 1 2 Day Relative to Normal Synchrony Prapas et al Hum Reprod 1998 13:720 3 Delayed Implantation versus Poor Embryo Quality Wilcox et al NEJM 1999
Start with an Endometrium That is Normal in Every Measurable Way ERA Pattern and Contractility Integrins Selectin Every other molecular marker you can imagine Are there other things to think about with endometrial receptivity? Ovulation Onset of LH Surge Embryonic Window of Implantation Progesterone Rise Endometrial Window of Implantation time
Synchronous Dysnchronous Ovulation Onset of LH Surge Embryonic Window of Implantation Progesterone Rise Endometrial Window of Implantation time Rise in P 4 with time after hcg administration 7 6 5 4 Serum P4 3 <6 6 7 7 8 8 9 9 10 10 11 11 12 12 13 >13 Time in hours from hcg administration 2
Embryonic Endometrial Synchrony Revisited Ovulation hcg administration Embryonic Window of Implantation Progesterone Rise 24h Franasiak et al ASRM 2013 Endometrial Window of Implantation time Fresh day 5 embryo transfer 70% 60% p <.001 64% p <.001 56% 50% 40% 44% 30% 20% 18% 10% 0% Franasiak et al ASRM 2013 <35 35 D5 M B1 D5 B2 B6
Fresh day 6 embryo transfer 70% 60% 50% 52% p<.05 63% p <.005 48% 40% 30% 32% 20% 10% 0% Franasiak et al ASRM 2013 <35 35 D5 M B1 D5 B2 B6 Frozen synchronous cycle Progesterone Start Endometrial Window of Implantation time
Frozen day 6 embryo transfer 70% 60% 57% p=0.5 60% p=0.3 50% 40% 30% 20% 10% 0% Franasiak et al ASRM 2013 37% <35 35 D5 M B1 D5 B2 B6 42% Progesterone and Impaired Implantation: A Study of Euploid Embryos 70 Sustained Implantation Rate (%) 60 50 40 30 20 10 0 < 0 0 1 2 3 4 5 6 7 8 9 10 11 12 >12 Hours Relative to Closure of the Window All patients had normal P levels prior to the administration of hcg
Older patients are more likely to have slow embryos 70% 60% Proportion of "Slow" Blastocysts P<0.0001 50% 40% 30% 31% 46% 20% 10% 0% Forman et al ASRM 2013 <35 years old 35 years old Obstetrical Outcomes Following Fresh versus Cryopreserved Embryo Transfer Fresh embryos at increased risk for Preterm birth Low birth weight Small for gestational age Wennerholm et al Hum Reprod 2013 28:2545 53
The supraphysiologic milieu which accompanies superovulation impact low birth weight risk 35 30 25 20 % 15 Fresh ET Cryo ET Retrospective review of SART data 2004 2006 56,792 neonates 10 5 0 Low Birth Wt Term LBW Preterm LBW Fresh embryo transfer at increased risk for LBW Embryonic Endometrial Synchrony It take two..