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Progesterone rise and IVF success
Sandro C. Esteves, MD., PhD. Medical Director, ANDROFERT
Andrology & Human Reproduc=on Clinic Campinas, BRAZIL
20th Na>onal Conference of the Indian Society for Assisted Reproduc>on -‐ Chennai 2015
Learning objec>ves At the comple>on of this presenta>on, par>cipants should be able to: 1. Review the reasons why progesterone levels
rise in s>mulated cycles 2. Appraise the impact of progesterone
eleva>on (PE) on the day of hCG in cycle outcome
3. Cri>cally discuss the clinical importance of measuring P on the day of hCG for decision making
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2015
ANDROFERT
Does progesterone rise on the day of hCG nega>vely affect implanta>on rates?
a. True b. False c. Uncertain
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2015
ANDROFERT
P levels rise in the late follicular phase in natural cycles
Speroff L et al. 5th Edi>on
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2015
ANDROFERT
Progesterone ng/mL
LH
FSH
Adapted from Smith (Endocrinology 1993) In: Leão & Esteves Clinics 2014
95% P produced
intrafollicularly
CYP17 not present ✖ LH
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2015
ANDROFERT
Devroey et al. Fer/l Steril 2012; 97(3): 561-‐72
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2015
ANDROFERT
Within the hCG dose of 0-‐150 IU/d, supplementa>on with hCG increase late follicular phase P4 levels LH ac/vity in hMG prepara/ons is driven by hCG content
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2015
ANDROFERT
Why do progesterone levels rise in late follicular phase in s>mulated cycles? Due to supraphysiological s>mula>on of granulosa cells The higher the number of GCs under s3mula3on, the higher the P levels
Follicular P rise associated with: N follicles, N oocytes, E2 levels and total FSH dose
Intrafollicular P is a terminal product. In humans, expression of CYP17 within intra-‐follicular ovarian compartment is negligible Wickenheisser et al. 2006; Nguyen et al. 2013; Bosch et al. 2010; Xu et al, 2012; Kolibianakis et
al 2012; Vene>s et al. 2012; Griesinger et al 2013; Ezcurra & Humaidan 2014
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2015
ANDROFERT
Clinical evidence of nega>ve effect of progesterone eleva>on on the day of hCG
Fresh Frozen-‐thawed Donor/recipient 63 studies; N =
55,199 9 studies; N =7,229
8 studies; N = 1,330
LBR/OPR CPR CPR
0.8-‐1.1 OR: 0.72 (0.56 – 0.94)
OR: 1.03 (0.79 – 1.34)
OR: 1.18 (0.76 – 1.84)
1.2-‐1.4 OR: 0.64 (0.53 – 0.77)
OR: 0.83 (0.62 – 1.32)
OR: 1.61 (0.64 – 4.05)
1.5-‐1.75 OR: 0.62 (0.57 – 0.69)
OR: 1.13 (0.97 – 0.69) -‐
1.9-‐3.0 OR: 0.67 (0.55 – 0.81)
OR: 1.03 (0.84 – 1.27)
OR: 0.51 (0.12 – 2.19)
P ng/mL
Vene>s et al., Hum Reprod Update 2013
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2015
ANDROFERT
Clinical evidence of nega>ve effect of progesterone eleva>on on the day of hCG
Xu et al, 2012 (N=11,055) GnRH agonist Differen>al effect based on N oocytes retrieved
Ovarian response
N oocytes
Serum P threshold (ng/mL)
Poor ≤4 1.5 Intermediate 5-19 1.75
High ≥20 2.25
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2015
ANDROFERT
Bosch et al. 2010 (N=4,032) Irrespec>ve of GnRH analogue; Cut-‐off = 1.5 ng/mL
Griesinger et al. Fertil Steril 2013
6 RCT, N=1866; Antagonist cycles OPR not impaired in high responders with P eleva>on
Clinical evidence of a differen>al effect of PE on the day of hCG based on ovarian response
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2015
ANDROFERT
• P eleva>on had no effect on oocyte/embryo quality and PRs
Miller et al. 1996
• P eleva>on associated with N follicles and retrieved oocytes but not with CPR (>1.5 ng/mL)
Yding Andersen et al. 2011
• OPR not different between groups (cutoff=1.5 ng/ml); No impact of early or late GnRH antagonist ini>a>on
Hamdine et al. 2014
Clinical evidence of NO effect of PE on the day of hCG
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2015
ANDROFERT
Requena et al., 2850 cycles; High Responders
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2015
ANDROFERT
High P levels associated with high
estradiol levels
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2015
ANDROFERT
Requena et al. Reprod Biol Endocrinol 2014
u Live birth rates NOT significantly different between cycles with and without PE (>1.5 ng/ml) [OR: 0.78, 95% CI:0.56–1.09]
u N oocytes and female age main confounders
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2015
ANDROFERT
In a mul>variable model, PE vs LBR: 1. No impact in poor and high responders 2. Nega>ve impact in normal responders
Vene>s C A et al. Hum Reprod. 2015;30:684-‐691
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2015
ANDROFERT
Summary evidence on PE on the day of hCG pregnancy outcome in IVF
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2015
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2015
ANDROFERT
Never measure 60%
Cut-‐off 1.5 ng/ml
(10%)
Cut-‐off based on N oocytes (30%)
Rou>ne measurement
40%
Real life prac>ces among professionals within the same ins>tu>on (Androfert; n=10)
How oqen do P4 levels rise in s>mulated cycles?
7.4%
8%
17% Vene>s et al. 2015 Griesinger et al. 2013 Vene>s et al. 2013
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2015
ANDROFERT
How clinically important is P eleva>on in s>mulated cycles?
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2015
ANDROFERT
Transforma>on of the OR:0.64 (95% CI: 0.54–0.76) to absolute pregnancy rate reduc>on
(APRR) with 95% CIs (dored lines)
Vene>s et al., Hum Reprod Update 2013
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2015
ANDROFERT
= 10% (95% CI: 6%-14%)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2015
ANDROFERT
✖ ✖
10% pregnancy reduc>on Expected: 18 preg. (44x0.4)
Observed: 16 pregnancies
Overall reduc>on (2/400): 0.50%
70% cycles 6-‐18 oocytes N cycles PE (PE rate 6.3%): 44
Unit with 1000 cycles/year 40% average pregnancy rate
Shall we rou>nely measure P4 levels in s>mulated cycles?
We have to monitor 1000 cycles and intervene in 44 cycles (with high P) in order to poten>ally save 2 pregnancies by “freeze-‐all” and subsequent FET… …assuming our vitrifica>on program delivers the same PR as compared with fresh transfers.
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2015
ANDROFERT
This implies that NOT preventing P elevation would have
theoretically led to a decrease in overall pregnancy rate of less
than 1.0 percentage points (that is, from 40.0% to 39.5%
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 24 2015
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2015
ANDROFERT
It is a great fuss about something
of lirle importance
Conclusions (1)
• 95% circula>ng progesterone produced by GC in ovarian intrafollicular compartment – LH ac/vity (hCG or LH) does not reduce follicular progesterone
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2015
ANDROFERT
• P measured in blood is the sum of the P secreted by mul>ple follicles – It not necessarily relates to worsening of cycle outcomes
Conclusions (2)
• Conflic>ng data on what P levels detrimental to implanta>on in fresh transfers – P levels above 1.5 ng/mL not cri/cal to pa/ents with high cohorts
• Clinical relevance of rou>ne measurement of progesterone on the day of hCG ques>onable – Freeze-‐all policy should not be adopted in all cycles with late P4 levels above 1.5 ng/ml
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2015
ANDROFERT
Thank you
This presentation is available at http://www.slideshare.net/
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