Principles and Practices of Individualization in ART
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Transcript of Principles and Practices of Individualization in ART
Principles and Prac-ces of Individualiza-on in ART
Sandro C. Esteves, MD., PhD. Medical Director, ANDROFERT
Andrology & Human Reproduc=on Clinic Campinas, BRAZIL
Learning Objec-ves
1. Individualiza-on: a quality concept 2. How to individualize COS to different
pa-ent subgroups 3. How to individualize triggering 4. How to individualize luteal support
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2015
ANDROFERT
Why individualize?
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2015
ANDROFERT
Maximize beneficial effects of treatment Minimize complica-ons and risks
Why individualize?
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 4 2015
ANDROFERT
Top 3 clinical dimensions for quality improvement in infer-lity care
• Effec-veness: Technical aspects to deliver the best possible outcome (e.g. pregnancy, live birth, cumula=ve LBR)
• Safety: Complica=ons (OHSS), adverse effects, risks (pa=ent & offspring), errors/mistakes
• Pa-ent-‐centeredness: Informa=on and pa=ent involvement, competence and aPen=on of clinic and staff, accessibility, coordina=on and integra=on, emo=onal support
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2015
ANDROFERTDancet et al. Hum Reprod 2011; Mainz Int J Qual Health Care 2013
How stakeholders value the top 3 quality dimensions of infer-lity care
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2015
ANDROFERT
0% 50% 100%
Doctors & embryologists
Nurses
Pa-ents Safety
Effec-veness
Pa-ent-‐centeredness
Dancet et al. Hum Reprod 2013
Lack of psychological support and poor quality of service ~60% treatment discon-nua-on
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2015
ANDROFERT
22 studies 21,453 pa=ents 8 countries
Individualiza-on is a quality concept
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2015
ANDROFERT
Safety
Pa-ent-‐ centeredness
Effec-veness
How to individualize?
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2015
ANDROFERT
Individualizing S-mula-on Protocols
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2015
ANDROFERT
• Clinical characteris-cs
• Ovarian biomarkers
Iden-fy who is who
• Pa-ent-‐centered • Effec-ve • Safe
Protocol
AMH ~ AFC > FSH > Age
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2015
ANDROFERT
Popula-on Cutoff Sensi-vity Specificity Accuracy
AMH
ng/m
L
High-‐responder1 2.1 85% 79% 0.82
Poor responder2 0.82 76% 86% 0.88
*Beckman-‐Couter genera-on II assay; 1>20 oocytes retrieved; 2≤4 oocytes retrieved Leão RBF, Nakano FY, Esteves SC. Fer5l Steril 2013; 100 (Suppl.): S16
AMH & AFC should be internally validated
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 13 2015
ANDROFERT
Quality-‐based individualiza-on in COS
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2015
ANDROFERT
High responders*
Normal responders*
Low responders*
Biom
arkers Safety
Pa-ent-‐ centeredness
Effec-veness
*expected
High responders
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2015
ANDROFERT
• Main goal: Safety • Clinical quality indicator: OHSS • Protocol of choice*: Antagonist (flexible; cetrorelix) Tailored recFSH (112.5-‐150 IU/d; follitropin alfa; pen injector)
*Androfert, Brazil
GnRH antagonists in high responders
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2015
ANDROFERT
9 RCT; 966 PCO women Rela-ve Risk Dura-on of ovarian s-mula-on -‐0.74 (95% CI -‐1.12; -‐0.36) Gonadotropin dose -‐0.28 (95% CI -‐0.43; -‐0.13) Oocytes retrieved 0.01 (95% CI -‐0.24-‐0.26) Risk of OHSS
Mild Moderate and Severe
20% vs 32% 1.23 (95% CI 0.67-‐2.26) 0.59 (95% CI 0.45-‐0.76)
Clinical PR 1.01 (95% CI 0.88; 1.15) Miscarriage rate 0.79 (95% CI 0.49; 1.28)
Pundir J et al. RBM Online 2012; 24:6-22
iCOS (n=118): rec-‐hFSH 112.5-‐150 IU + GnRH antagonist (flexible) cCOS (n=131): rec-‐FSH 150-‐225 IU + GnRH agonist (nafarelin)
39.3
18.5 14.0
57.0
14.3 14.7 4.8
56.0
0 10 20 30 40 50 60
Observed Excessive
Response (%)
Oocytes retrieved (N)
OHSS (%) Pregnancy (%)
cCOS iCOS *p<0.05
* *
Individualized vs conven-onal COS in high responders
Excessive response >20 oocytes retrieved; Mild/severe OHSS reported; Leão RBF, Nakano FY, Esteves SC. Fer5l Steril 2013; 100 (Suppl.): S16
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2015
ANDROFERT
*
Poor responders
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2015
ANDROFERT
• Main goal: pa-ent-‐centeredness • Clinical quality indicators:
– Compliance (drop-‐out rate) – Pa-ent burden (cancela-on rate)
• Protocol of choice*: Antagonist (flexible; cetrorelix) recFSH + recLH (follitropin alfa + lutropin alfa 2:1 ra=o: 300 IU recFSH + 150 IU recLH); from s=mula=on D1
*Androfert, Brazil
Pregnancy rates increased by 30% in poor
responders treated with
rLH+rFSH
Lehert et al Reprod Biol Endocrinol 2014, 12:17
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2015
ANDROFERT
Lehert et al 2012
Increase of ≈1 oocyte per 1,000
UI in poor responders
treated with rLH+rFSH
Lehert et al Reprod Biol Endocrinol 2014, 12:17
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2015
ANDROFERT
Individualized vs. Conven-onal COS in Expected Poor Responders (N=118)
72.0
3.5
45.0
20.0
46.6
4.8
23.3 26.8
0
20
40
60
80
Observed Poor Response (%)
Oocytes retrieved (N)
Cancella=on (%) Pregnancy/cycle (%)
cCOS (Long GnRHa + 300-‐450 IU recFSH alone) iCOS (GnRH antagonist + rFSH (225-‐300 IU) +rLH (75-‐150 IU))
Expected poor response: AMH<0.82 ng/dL; Observed poor response <5 oocytes retrieved;
Leão RBF, Nakano FY, Esteves SC. Fer5l Steril 2013; 100 (Suppl.): S16
*p<0.05
*
* *
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2015
ANDROFERT
Normal responders
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2015
ANDROFERT
• Main goal: effec-veness • Clinical quality indicators: number oocytes • Protocol of choice*: <35yr: Antagonist + recFSH
cetrorelix (flexible); 187.5-‐262.5 IU/d follitropin alfa pen injector
>35yr: Antagonist + recFSH/recLH cetrorelix (flexible); follitropin alfa + lutropin alfa
2:1 ra=o; 225-‐300 IU/d; from s=mula=on D1
*Androfert, Brazil
Nega-ve predictor
Posi-ve predictor
van Loendersloot et al. Hum Reprod Update 2010; 16: 577–589
Female Age (OR=0.95; CI: 0.94-‐0.96) Number of oocytes retrieved (OR=1.04; CI: 1.02-‐1.07)
Level
1a Predictors of pregnancy in IVF
14 studies >30,000 pa=ents
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2015
ANDROFERT
What is the optimum number of retrieved oocytes to
increase pregnancy rates ?
a. 4 to 8 b. 9-12 c. 13-17 d. The higher the better
0% 5%
10% 15% 20% 25% 30% 35% 40% 45%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 20 25 30 35 40
Live
birt
h ra
te (%
)
Oocyte number
Observed live birth rate Predicted live birth rate
Sunkara et al. Hum Reprod 2011
450,135 IVF cycles
Best chance of live birth is associated with ~15 oocytes
number of oocytes that best optimized LBR was 15
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2015
ANDROFERT
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2015
ANDROFERT
...irrespec-ve of age group
The higher the cohort size, the higher the chance of having euploid embryos
Ata et al. RBM Online (2012) 24, 614–620
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2015
ANDROFERT
Do you take into account the severity of male factor
infertility when planning COS?
a. Yes b. No c. Never though about it
41.4 47 43.3 20
100 64 61 34.2
Sperm retrieval (%)
2PN Fertilization
(%)
Top Quality Embryos (%)
Live Birth (%)
Non-obstructive (N=365) Obstructive (N=146)
P<0.01
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2015
ANDROFERT
3,412 cycles
Oocyte number and LBR at Androfert (ICSI cycles involving severe male factor)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2015
ANDROFERT
0%
10%
20%
30%
40%
50%
60%
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 20 25 Number of oocytes
Clinical pregnancy
Live birth
Each addi-onal warming cycle increases the chance of achieving a live birth
40.4% 48.0%
ET #3 (FET) 49
ET #2 (FET) 239
ET #1 (fresh) 822
50.5% +18.8%
+25.0% Female Age ≤38
332/822 63/239 17/49
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2015
ANDROFERT
Oocyte yield by gonadotropin
↑ 1.5 oocytes (GnRH antagonist cycles) Devroey et al., 2012
↑ 3.1 oocytes (GnRH antagonist) Bosch et al., 2008
↑ 1.8 oocytes (GnRH agonist cycles) MERIT Study, 2006
↑ 2.8 oocytes (GnRH agonist cycles) Hompes et al., 2008
↑ 2.1 oocytes (16 RCT; different protocols) Lehert et al., 2010
Higher with rec-‐FSH vs. hMG, HP-‐hMG, and uFSH
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2015
ANDROFERT
LH supplementa-on improves clinical pregnancy in women >35 yr
Hill et al. Fer5l Steril 2012
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2015
ANDROFERT
LH ac-vity by rec-‐LH vs hMG
Adapted from: Leao & Esteves. Clinics 2014; 69(4): 279–293.
Product LH ac-vity (IU/vial)
LH content* Purity
hMG 75 hCG ~5% HP-‐hMG 75 hCG ~70% Lutroprin alfa (rec-‐hLH) 75 LH >99% 2:1 Follitropin alfa + Lutroprin alfa (rec-‐hFSH + rec-‐hLH)
75 LH >99%
*hCG concentrated or added during purifica-on process (8IU hCG ~ 75IU LH)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2015
ANDROFERT
LH and hCG elicit different gene expression
LH hCG
LHR and FSHR expression (Trafficking of re=noic acid : RXRB, TTR, ALDH8A1) Meiosis and follicular matura-on (TRA : RXRB, TTR, ALDH8A1; IL11; AKT3)
Follicular development (IL11; AKT3) Cellular growth (RXRB, TTR, ALDH8A1; IL11;AKT3)
Ovarian stereodogenesis (TRA : RXRB, TTR, ALDH8A1)
Embryo development & survival (AKT3)
Aromatase inhibi-on (PPARS) Apoptosis
enhancement (DNAsi)
LH hCG
Grondal ML et al. FerFl Steril 2009; Menon KM et al. Biol Reprod 2004; Ruvolo et al. Fer=l Steril 2007
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2015
ANDROFERT
COS with LH ac-vity delivered by rec-‐LH vs hMG in IVF
Authors, yr. Design N Main findings Buhler & Fisher, 2011
Matched case-‐control
4719 Higher CPR in fixed 2:1 rec-‐FSH + rec-‐LH (31%) vs hMG (26%) and vs combo (rec-‐FSH + hMG, 25%); p=0.02
Fábregues et al, 2013
Cross-‐over study
66 Higher N oocytes in fixed 2:1 rec-‐FSH + rec-‐LH (9.8) vs HP-‐hMG (7.3); p<0.01. Higher N frozen embryos in recLH
Dahan et al, 2014
Observa=onal 201 Higher N oocytes in rec-‐LH (12) vs hMG (10); p=0.008. Higher CPR rec-‐LH (36% vs 20%; p=0.02)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2015
ANDROFERT
Individualizing trigger and LPS
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2015
ANDROFERT
High responders
Normal responders
Low responders
Safety
Pa-ent-‐ centeredness
Effec-veness
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 matura-on as surrogates for the mid-‐cycle LH surge
GnRHa
36-48 h
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2015
ANDROFERT
Day 8
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
One size trigger does not fit all
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 39 2015
ANDROFERT
Freeze-‐all embryo policy: is it for all? • Non-‐inferior in effec-veness in high-‐quality vitrifica-on programs, but…
• Safety – Increase ART unit workload – Perinatal outcome
• Higher rate of large for gesta-onal age (Wennerholm HR 2013)
• Pa-ent-‐centeredness – Psychological & cost burden
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 40 2015
ANDROFERT
Modified LPS for fresh ET in GnRH-‐a trigger
No. follicles day OPU 1,500 IU hCG at OPU & 1,000
OPU+5 & standard LPS ≤ 14
1,500 IU hCG at OPU + standard LPS 15-‐25
1,000 IU hCG at OPU + standard LPS or Freeze all 26-‐30
Freeze all >30 Humaidan et al. Hum Reprod. 2013;28(9):2511-‐21
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 41 2015
ANDROFERT
14h
14h 20h
48h 0 20 h
4h
GnRHa
Natural LH surge
Luteal phase defect
Individualizing trigger
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 42 2015
ANDROFERT
Normal & poor responders
rec-‐hCG u-‐hCG
hCG trigger
RCT N Effect
Oocytes retrieved 9 1409 MD: -‐0.04
95% CI: -‐0.69 to 0.61
Live birth 6 1,019 OR: 1.04 95% CI: 0.79 to 1.37
Miscarriage 7 1,106 OR: 0.69 95% CI: 0.41 to 1.18
Severe OHSS 3 549 OR: 1.49 95% CI: 0.54 to 4.1
Youssef et al. Cochrane Database Syst Rev. 2011; 13(4):CD003719 Databases searched up to January 2010
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 43 2015
ANDROFERT
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, 44 2015
ANDROFERT
Effec-veness 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. Fer5l Steril 2010; 94:2902-‐4
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 45 2015
ANDROFERT
RCT N Odds-‐ra-o
Local site reac-ons* 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, 46 2015
ANDROFERT
hCG preferences in treatment-‐experienced pa-ents 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, 47 2015
ANDROFERT
Why immature oocytes? 1. Follicles <13mm 2. LH receptor deficiency 3. Blood/intrafollicular level
barely achieved 4. Not enough -me for
intrafollicular hCG ac-on
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 48 2015
ANDROFERT
Trigger is the most important injec-on of the cycle
Weight (kgs) 55 64 90 Blood volume (lts) (7% of weight) 3.8 4.4 14
Fat (kgs) (essential 13.5% of weight) 7.4 8.6 27
hCG Blood Threshold
hCG Intrafollicular Threshold
Blood represents about 7% of the body mass or about 4.5 kg (volume ~ 4.4 liters) in a 64 kg (141 lb) person." Cameron, J.. Physics of the Body. 2nd Edition. Madison, WI:, 1999: 182.
Injecting hCG: Size and BMI
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 49 2015
ANDROFERT
What is the optimum interval between trigger and oocyte
retrieval?
a. 34 to 35h b. 35 to 36h c. 36-38h d. >38h e. Doesn’t matter much
63 73 76 79 82 Oocyte maturity %
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 51 2015
ANDROFERT
Individualizing LPS
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 52 2015
ANDROFERT
Normal & poor responders
Fresh ET FET
In FET cycles, all of the current methods of endometrial prepara-on appear to be equally effec-ve in terms of ongoing pregnancy rate*
• Meta-‐analysis of 20 compara=ve studies • ~13,000 cycles • Natural and ar=ficial cycles with and w/o GnRH agonist
• Safety & pa-ent-‐centeredness not addressed Groenewoud ER et al. Hum Reprod Update. 2013;19:458-‐70
*in eumenorrhoic pa-ents
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 53 2015
ANDROFERT
Luteal phase abnormal in s-mulated cycles
• Corpus luteum func-on dependent on pulsa-le LH release from pituitary
• Supraphysiologic steroid levels (by mul-follicular development) inhibits LH secre-on
• Low LH levels causes luteolysis, implanta-on failure and shortened luteal phase
Jones 1996; Albano et al 1998; Beckers et al 2000; Tavaniotou et al Hum Reprod 2000; Fauser & Devroey 2003; Trinchard-Lugan et al 2002; Sherbahn 2013
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 54 2015
ANDROFERT
LPS mandatory in s-mulated cycles
• hCG vs. Placebo or No treatment: Higher ongoing PR (OR=1.75; 95% CI: 1.09-2.81)
• Progesterone vs. Placebo or No treatment: Higher clinical PR (OR=1.83; 95% CI: 1.29-2.61) Higher ongoing PR (OR=1.87; 95% CI: 1.19-2.94) Higher live birth rates (OR=2.95; 95% CI: 1.02-8.56)
Level 1a
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 55 2015
ANDROFERT
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 LPS in s-mulated cycles
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 56 2015
ANDROFERT
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
Among vaginal P, patients prefer gel
7 RCT; 1 MA; >2,400
cycles
Easier to use; better adherence; lower discharge
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 LPS in s-mulated cycles
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 57 2015
ANDROFERT
1 hour
3 hours
2 hours
4 hours Time
Bioadhesion of vaginal P is essential because it takes ~4h to reach steady state in the uterus (first-pass effect)
Bulletti C et al. Hum Reprod 1997
aqueous
lipid
-ssue
micronized progesterone in an ‘oil-‐in-‐water’ emulsion (Crinone® 8%)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 58 2015
ANDROFERT
Similar outcome in low vs. high dosage Crinone 8% (90 mg/d) vs. 200-‐800 mg/d (capsules; tablets;
pressaries)
No. studies No. OR; 95% CI
Live birth 2 1485 1.01; 0.81-‐1.26
Clinical PR 12 4973 1.04; 0.92-‐1.17
Miscarriage rate 8 2350 1.27; 0.85-‐1.89
Mul-ple PR 4 905 0.95; 0.57-‐1.58
Van der Linden et al Cochrane 2011
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 59 2015
ANDROFERT
Vaginal P started at the -me of OPU reduces uterine contrac-ons at the -me 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. Fertil Steril 1999
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 60 2015
ANDROFERT
Luteal-‐placental shiw on P produc-on occurs around 7-‐12th gesta-onal 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 (n
g/m
L)
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, 61 2015
ANDROFERT
Principles and Prac-ces of Individualized ART at Androfert
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 62 2015
ANDROFERT
High responders
Normal responders
Low responders Cl
inical fe
atures + AMH Antagonist protocol; tailored COS rec-‐FSH
(112.5-‐150 IU) + tailored trigger (GnRHa or rec-‐hCG); tailored LPS (modified LPS or vaginal P gel OPU)
Antagonist protocol; tailored COS w/rec-‐FSH (<35yr) or rec-‐FSH+rec-‐LH 2:1 ra-o (>35 yr); rec-‐hCG trigger; LPS vaginal P gel
Antagonist protocol; recFSH + recLH 2:1 ra-o + rec-‐hCG trigger; LPS vaginal P gel
Principles and Prac-ces of Individualiza-on in ART
Conclusions • Individualiza-on is a quality concept • Safety, effec-veness and pa-ent-‐centeredness are important principles in a quality-‐based individualized infer-lity care
• Novel biomarkers combined with new devices & drug regimens can be used to deliver a high quality evidence-‐based individualized ART
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 63 2015
ANDROFERT