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)


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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


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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


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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


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Day 8

Trigger Prac3ces at Androfert


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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


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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 *


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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


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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


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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


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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.


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*GnRHa

<34h 34-‐35h 35.5h >35.5-‐36h >36-‐38h

63% 73% 76% 79% 82%


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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


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Agents Effec3veness Safety Pa3ent-‐centeredness

Rec-‐hCG ✔✔✔ ✔✔ ✔✔✔

u-‐hCG ✔✔ ✔ ✔✔

GnRH-‐a ✔✔ ✔✔✔ ✔


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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


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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


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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


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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


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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


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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


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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


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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


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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%)


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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.


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High vs low dosage vaginal delivery with applicator

Khan et al. Fer5l Steril 2009; 91:2245-‐50


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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%)


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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


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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


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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


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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


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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


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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 ✔✔✔ ✔✔✔ ✔✔✔


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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


ANDROFERT

Thank you спасибо Obrigado

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Novel treatments to trigger final follicular maturation and luteal phase support

Health & Medicine

Transcript of Novel treatments to trigger final follicular maturation and luteal phase support