Novel treatments to trigger final follicular maturation and luteal phase support
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Transcript of Novel treatments to trigger final follicular maturation and luteal phase support
Novel treatments for triggering final follicular matura3on and
suppor3ng luteal phase
Sandro Esteves Medical & Scien3fic Director
ANDROFERT -‐ Brazil
Learning objec3ves At the comple3on of this presenta3on, par3cipants should be able to: • Appraise novel strategies to triggering the final follicle matura5on and suppor5ng the luteal phase as per a quality management perspec5ve
• Individualize trigger and luteal phase support according to different pa5ent segments
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2015
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“Process”: the only objec3ve and measurable aspect of quality
Process = Any activity or set of activities that uses resources to transform raw material, supplies and labor (inputs) into products or services (outputs)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 3 2015
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Quality of trigger and LPS methods can be measured, but how?
Using indicators for the most important quality dimensions in infer3lity care…
Safety Pa3ent-‐
centeredness
Effec3veness
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What are the most effec3ve, safest and pa3ent-‐centered strategies?
• Effec3veness: technical aspects to deliver the best possible outcome (e.g. pregnancy, live birth, cumula5ve LBR)
• Safety: complica5ons (OHSS), adverse effects, risks (pa5ent & offspring), errors/mistakes
• Pa3ent-‐centeredness: convenience, physical burden, invasiveness of techniques
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2015
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How to offer the most effec3ve,
safest and pa3ent-‐centered trigger and LPS methods?
Clinical Needs Standard Opera3ng Procedures
Results
• Agents • Route of administration • Dose • Timing
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2015
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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 matura3on as surrogates for the
mid-‐cycle LH surge
GnRHa
36-48 h
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2015
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Day 8
Trigger Prac3ces at Androfert
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2015
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High responders at risk of OHSS
Fresh ET + modified LPS
FRALL + blastocyst ET ar3ficial cycle
GnRH-‐a trigger (0.2 mg triptorelin)
High*, normal and poor responders
FRALL Fresh D3/D5
ET + standard
LPS
Rec-‐hCG trigger (250 mcg)
*Low OHSS risk
Propor3on of total immunoreac3vity (%) Pregnyl® Choragon® Profasi® Ovitrelle®
Intact bioac3ve hCG 50 30 96 >99 Hyperglycosylated hCG 0.6 4 0.5 <0.1 Free β subunit 6.2 8 2.4 <0.1 β-‐core fragment1 43 58 1.2 -‐-‐ Epidermal growth factor2 181-‐204 154 4-‐10 -‐-‐
Gervais et al. Glycobiology 2003;13:179-89; Yarram et al. Fertil Steril 2004;82:232-3
1degradation product of hCG; 2EGF is a contaminant (ng/5000IU)
Func3onally intact hCG and contamina3on in hCG formula3ons
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2015
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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, 10 2015
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Effec3veness of hCG trigger 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. Fer&l Steril 2010; 94:2902-‐4
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2015
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RCT N Odds-‐ra3o
Local site reac3ons* 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, 12 2015
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hCG preferences in treatment-‐experienced pa3ents 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, 13 2015
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2015
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RCT comparing rec-‐hCG (ovitrelle; 250 mcg) vs GnRH agonist (0.2 mg triptorelin) trigger in oocyte
dona3on cycles
12 11.4 8 7.5
67.8 71.1
rec-‐hCG GnRHa
N oocytes N mature oocytes %2PN
Galindo et al. Gynecol Endocrinol. 2009;25(1):60-‐6
N=257; p=NS
Reasons for trigger failure with hCG and GnRHa
Empty follicle: Ø hCG: 0.1%-‐2.0%1,2
Ø GnRHa: 0.6%-‐3.5%3,4
Root causes: • Human errors • High BMI • Low baseline LH levels* • Less bioac5ve LH*
1Quintans et al. 1998; 2Zegers Hochschild et al. 1995; 3Castillo et al. 2012; 4Kummer et al. 2013.
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2015
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*GnRHa
<34h 34-‐35h 35.5h >35.5-‐36h >36-‐38h
63% 73% 76% 79% 82%
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2015
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Oocyte maturity by interval between trigger (rec-‐hCG 250 mcg) and oocyte retrieval in
antagonist cycles
Androfert; N=2,230 cycles
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
GnRH-‐a trigger in IVF cycles
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2015
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Agents Effec3veness Safety Pa3ent-‐centeredness
Rec-‐hCG ✔✔✔ ✔✔ ✔✔✔
u-‐hCG ✔✔ ✔ ✔✔
GnRH-‐a ✔✔ ✔✔✔ ✔
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2015
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How to offer the most effec3ve, safest and pa3ent-‐centered trigger method?
Abnormal luteal phase in s3mulated cycles
• Supraphysiologic steroid levels (by mul3follicular development) inhibits LH secre3on
• Low LH levels causes luteolysis, shortened luteal phase, and may result in implanta3on failure
Jones 1996; Albano et al 1998;Tavaniotou et al 2000; Fauser & Devroey 2003; Trinchard-‐Lugan et al 2002; Sherbahn 2013
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2015
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Corpus luteum func3on depend on pulsa3le LH release from pituitary
Mid-‐cycle LH levels Natural cycle 6.0 IU/l
hCG trigger 0.2 IU/l GnRHa trigger 1.5 IU/l
Tavaniotou & Devroey, 2003; Humaidan et al. 2005
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2015
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Damewood et al., 1989; Gonen et al., 1990; Itskovitz et al., 1991;
Weissman et al., 1986 ; Bonduelle et al., 1988
In s3mulated cycles, there is a period of deficient LH ac3vity
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2015
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Day 6
Trigger
Luteal phase length (days)
hCG
Day 8
LH activity deficient period
Day 14
28-32h
GnRHa LH activity deficient period
Clinical Needs Standard Opera3ng Procedures
Pa3ent subgroups
How to offer the most effec3ve,
safest and pa3ent-‐centered LPS?
• Agents • Routes of administra3on • Dose • When to start • When to stop
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2015
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GnRHa trigger
§ Vaginal P gel 90 mg 2x/d
§ Onset day OPU § Cessa3on ~9th week if pregnancy
hCG trigger
§ Vaginal P gel 90 mg 1x/d
§ Onset day OPU § Cessa3on ~9th week if pregnancy
2
hCG bolus 1,500 IU (rec-‐hCG; 6 clicks pen of 250
mcg OPU)
§ Vaginal P gel 90 mg 1x/d
§ ET 5 days ater P § Cessa3on ~9th week if pregnancy
FET Ar3ficial cycle:
Transdermal estradiol step-‐up regimen
(100mcg/d up to 300 mcg/d)
3 1
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2015
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LPS SOP at Androfert standardized steps, which are used every time the task is done, to ensure the process is done the same way each time
In FET cycles, all of the current methods of endometrial prepara3on
appear to be equally effec3ve in terms of ongoing pregnancy rate*
• Meta-‐analysis of 20 compara3ve studies • ~13,000 cycles • Natural and ar3ficial cycles with and w/o GnRHa • Safety and pa3ent-‐centeredness not addressed
Groenewoud ER et al. Hum Reprod Update. 2013;19:458-70 *in eumenorrhoic patients
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 24 2015
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3
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 effec3veness of LPS methods
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 25 2015
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2
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
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 safety & pa3ent-‐centeredness of progesterone usage
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2015
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2
0
5
10
15
20
25
30
35
40
IM P Vaginal P
ng/mL
Endometrial Levels
0
0.5
1
1.5
2
2.5
3
3.5
IM P Vaginal P ng
P/m
g pr
otei
n
Serum Levels P<0.0001 P<0.0001
Ficicioglu et al. Gynecol Endocrinol 2004; 18: 240-3
P in oil (50mg) vs. P gel (vaginal; Crinone 8%)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 27 2015
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• Vaginal pessaries/tablets/suppositories – can be required t.i.d. – lay flat for 30 minutes following inser5on – messy, vaginal discharge
• vaginal itching and perineal irrita5on • CRINONE gel
– 90mg once daily dosage • some women may need 90mg twice daily
– no need to lay flat afer administra5on
Vaginal delivery op3ons
Lan VTN. Repro BioMed Online. 2008; Simunic V et al. Fer9l Steril. 2007 Ludwig M & Diedrich K. Acta Obs Gyn Scand. 2001; Penzias AS. Fert Steril. 2002.
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2015
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High vs low dosage vaginal delivery with applicator
Khan et al. Fer5l Steril 2009; 91:2245-‐50
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2015
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1 hour
3 hours
2 hours
4 hours Time
Vaginal bioadhesion essen3al because it takes ~4h to reach steady state in the uterus
(first-‐pass effect)
Bullek C et al. Hum Reprod 1997
aqueous
lipid
3ssue
micronized progesterone in an ‘oil-‐in-‐water’ emulsion (Crinone® 8%)
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2015
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Vaginal P started at the 3me of OPU reduces uterine contrac3ons at the 3me 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. Fer3l Steril 1999; Fanchin et al Hum Reprod 1998
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2015
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High uterine contrac3ons (UC) at the 3me of ET decrease IR
Similar outcome early vs. late cessa3on pregnancy test or clinical pregnancy vs. 6-‐7 week gesta5on
Outcome Evidence Conclusion
OPR 2 RCT; 1 MA; >350 cycles No difference
Miscarriage 6 RCT; 1 MA; >1,000 cycles No difference
LBR 8 RCT; 1 MA; >1,200 cycles No difference
Liu et al. Reprod Biol Endocrinol. 2012; 10:107
ANDROFERTANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2015
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Vaisbuch et al. Reprod Biomedicine Online 28: 330-‐5, 2014.
Worldwide prac3ces favor longer
dura3on LPS
ANDROFERTANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 33 2015
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Luteal-‐placental shit on P produc3on occurs around 7-‐12th gesta3onal 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 (p
g/m
L)
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, 34 2015
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Bleeding before P discon3nua3on consequence (not a cause) of non-‐
pregnancy state • Reflect lack of a viable pregnancy rather than deficient LPS
• Usually seen in women with lower estradiol levels
Onset of menses following HCG (day 0) in non-pregnant women n = 63
Roman E et al. Hum Reprod. 2000
ANDROFERTANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2015
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Modified LPS in GnRH-‐a trigger (fresh ET)
No. follicles day OPU*
1,500 IU hCG at OPU & 1,000 OPU+5 & LPS with P gel 90
mg bid ≤ 14
1,500 IU hCG at OPU + LPS with P gel 90 mg bid OR
Freeze all 15-‐25
Freeze all >26
*Modified from Humaidan et al. Hum Reprod. 2013;28(9):2511-‐21
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2015
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14h
14h 20h
48h 0 20 h
4h
GnRHa
Natural LH surge
Luteal phase defect
1
P agents and routes
Effec3ve-‐ness
Safety Pa3ent-‐centeredness
Intramuscular ✔✔✔ ✔ ✔
Oral ✔✔ ✔ ✔ Subcutaneous ? ? ? Vaginal pressaries/tablets ✔✔✔ ✔✔✔ ✔✔
Vaginal gel ✔✔✔ ✔✔✔ ✔✔✔
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2015
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Conclusions • Our ul5mate goal is to deliver the highest quality in infer5lity care – Consider safety and pa9ent-‐centeredness, in addi9on to effec9veness, when choosing methods for trigger and LPS
• These quality dimensions offer an unique opportunity to beoer individualize trigger and LPS according to different pa5ent segments using novel tools and devices
Novel treatments to triggering final follicular matura3on and suppor3ng luteal phase
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 40 2015
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Thank you спасибо Obrigado
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