progesterone rise and ivf success

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


ANDROFERT

P levels rise in the late follicular phase in natural cycles

Speroff L et al. 5th Edi>on


ANDROFERT

Progesterone ng/mL

LH

FSH

Adapted from Smith (Endocrinology 1993) In: Leão & Esteves Clinics 2014

95% P produced

intrafollicularly

CYP17 not present ✖ LH


ANDROFERT

Devroey et al. Fer/l Steril 2012; 97(3): 561-‐72


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


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


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


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


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


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


ANDROFERT

Requena et al., 2850 cycles; High Responders


ANDROFERT

High P levels associated with high

estradiol levels


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


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


ANDROFERT

Summary evidence on PE on the day of hCG pregnancy outcome in IVF


ANDROFERT


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


ANDROFERT

How clinically important is P eleva>on in s>mulated cycles?


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


ANDROFERT

= 10% (95% CI: 6%-14%)


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.


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%


ANDROFERT


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


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


ANDROFERT

Thank you

This presentation is available at http://www.slideshare.net/

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