hCG vs. GnRH-agonist for final maturation of the oocytecme-utilities.com/mailshotcme/Material for...
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hCG vs. GnRH-agonist for final maturation of the oocyte
Ovarian Club
Paris 9.11.2019
Robert FischerFertility Center Hamburg
ISO 9001:2015
ISO 17025
PP Vorlage.potx
I receive honoraria for lectures from the MERCK Company
Layout
Physiology
Number of Oocytes
Quality of Oocytes
OHSS
Luteal Phase
Pregnancy rate
Empty Follicles
Dyn, dynorphin;ER, estrogen receptor; ME, median eminence;POA, preoptic area;PR, progesterone receptor. Skorupskaite K, at al. Hum Reprod Update. 2014;20:485-500.
Neuroendocrine control of final follicular maturation
POA/
infundibular
nucleus
Sex steroids
Gonads
GnRH
LH/FSH
ME
Pituitary
KiSS1
KiSS1
KiSS1
KiSS1
+
+
+
+
DynNKB
+− ER
PR
GnRH neurone
Kisspeptin
neurone
POA Infundibular nucleus
KND
neurone
ER PR
(sex steroid receptor)
NKB3R
(neurokinin B receptor)
Kiss1r/KiSS1R
(kisspeptin receptor)
KOR
(koppa opioid receptor)
+
−
hCG
• FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; hCG, human chorionic
• gonadotropin; IVF, in vitro fertilization; KND, kisspeptin/neurokinin B/dynorphin; LH, luteinizing hormone.
• Fritz MA, Speroff, L. Clinical gynecologic endocrinology and infertility. 8th ed. Philadelphia: Lipincott Williams & Wilkins; 2011.
• Kasum M, et al. Gynecol Endocrinol. 2017;33:583-7.
Final oocyte maturationSerum hormone levels from a natural cycle
LH surge
• Resumption of oocyte meiosis
• Follicular rupture and oocyte expulsion
• Luteinization
2 4 6 8 10 12 14 16 18 4 6 8 10 12 14
Time (days)
Ovulation
20
Time (weeks)
Implantation
FSH
LH
Progesterone
hCG
KND neurons
Neurokinin B
Neurokinin B
Kisspeptin
+
Dynorphin A
GnRHneurons
GnRH
pulse
GnRH
pulse
Neurokinin B
Role of FSH surge • Promotes formation of LH receptors
• Nuclear maturation
• Cumulus expansion
• Stimulates plasminogen activator leading to dissociation of the oocyte from the follicular wall
• Keeps the gap junctions open between the oocyte and cumulus cells
Eppig JJ. Nature 1979;281:483–484Strickland and Beers. J Biol Chem 1976;251:5694–5702Yding Andersen C. Reprod Biomed Online 2002;5:232–239Yding Andersen C, et al. Mol Hum Reprod 1999;5:726–731Zelinski-Wooten MB, et al. Human Reprod 1995;10:1658–1666
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Adding 450 IU FSH to hCG resulted in:
More oocytes
More normal fertilizations
Lamb et al F&S, 2011
Normal responders
• hCG trigger standard dosage: 6,500 IU rhCG
• Dual trigger: 0.2 mg triptorelin and 6,500 IU rhCG
• Lin MH, et al. Fertil Steril. 2013;100:1296-302.
Dual trigger with GnRH agonist and hCG improves LBR for normal responders
VariableControl
(hCG)
hCG +
triptorelin
p
value
Implantation rate, % 18.43 29.68 < 0.001
Clinical pregnancy rate per ET, % 40.11 50.79 0.047
Abortion rate, % 18.67 16.49 NS
LBR per ET, % 30.49 41.36 0.042
Blastocyst progression rate, % 55.6 52.9 NS
OHSS rate, % 0.005 0 NS
Outcomes of IVF/ICSI cycles
VariableControl
(hCG)
hCG +
triptorelin
p
value
Total dose of gonadotropins, IU 4,062 3,851 NS
Duration of stimulation, days 10.3 9.6 NS
E2 on trigger day, pg/mL 2,139 2,083 NS
Progesterone on trigger day, ng/mL 1.84 2.09 NS
Duration of GnRH-antagonist treatment, d 3.5 3.4 NS
Endometrial thickness on trigger day, mm 9.8 10.1 NS
Oocytes retrieved, n 10.10 12.36 < 0.01
MII oocytes retrieved, n 8.03 10.53 < 0.01
Embryos obtained, n 5.3 5.8 NS
Top quality embryos obtained, n 2.9 2.9 NS
Embryos transferred, n 2.84 2.79 NS
Embryos cryopreserved, n 1.60 1.97 < 0.01
Characteristics of ovarian stimulation
• *p < 0.05.• Haas J, et al. Fertil Steril. 2016;106:653-59.
hCG versus double trigger for final oocyte maturation in granulosa cells
hCG hCG + GnRH
agonist
0
0.5
1.0
1.5
2.0
FS
HR
/-a
ctin
mR
NA
hCG hCG + GnRH
agonist
0
0.5
1.0
1.5
LH
R/
-act
in
mR
NA
hCG hCG + GnRH
agonist
Am
ph
ireg
ulin
/-a
ctin
mR
NA
0
1
2
3*
hCG hCG + GnRH
agonist
0
1
2
3
4
5
Ep
ireg
ulin
/-a
ctin
mR
NA
*
FSHR LHR
Amphiregulin Epiregulin
• hCG induces luteinization of the granulosa cells, final oocyte maturation, and resumption of meiosis
• Final follicular maturation is usually triggered by one bolus of hCG (5,000–10,000 units)
– This is administered as close as possible to the time of ovulation (i.e. 36 hours before oocyte recovery)
• Orvieto R. J Ovarian Res. 2015;8:60.
hCG is a surrogate of the naturally occurring LH surge
Does the routine trigger meet our needs?
hCG AS TRIGGER
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The default, “gold standard”, trigger agent
Works fine for most patients
Usually followed by vaginal progesterone for luteal support
Is this the best we can have?
10,000 IU hCG
Natural mid-cycle LH surge
GnRHa trigger-induced LH
surge
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What are the problems with hCG as trigger?
Deviations from physiology:
No FSH surge
Long half life
Early luteal over-stimulation
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LH
cAMP (protein kinase A)
EGF-like (AR, β-cellulin, epiregulin)
Ras
ERK 1/2
FSH action Ovulation
Oocyte
maturation
COC
expansion
Follicle
rupture
Luteinization
PGE2/EP2
LH hCG
AR, amphiregulin;cAMP, cyclic AMP;COC, cumulus cell-oocyte complex; EBP, enhancer binding protein;EGF, epidermal growth factor; EP, epiregulin;PgE2, prostaglandin E2. Fan HY, et al. Science. 2009;324:938-41.
LH versus hCG signalling
C/EBPβ and
other factors
• Choi J and Smitz J. Mol Cell Endocrinol. 2014;383:203-13.
LH and hCG action on the same receptor: differences in intracellular signaling
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Induction of Ovulation with GnRH
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GnRH agonist for triggering of final oocyte maturationand ovulation
• Of interest in the late eighties/early nineties
( Hoff et al., 1983; Gonen et al., 1990; Itskovitz et al.,1988;1991)
• Not applicable in cycles down-regulated with GnRHa
• Renewed interest with the introduction of GnRH antagonist protocols
1st Interest Group Meeting on GnRHa triggering of
final oocyte maturation, Copenhagen, December 2009
Fertil &Steril
June 2014
ET, embryo transfer; w, week(s). Fauser BC, et al. J Clin Endocrinol Metab. 2002;87:709-15.
LH, FSH, estradiol, and progesterone levels following triggering of final oocyte maturation
0
400
800
1,200
1,600
2,000
E2 (pg/mL)
hCG
Triptorelin
Leuprorelin
0 4 8 12 24 OPU ET ET + 1w ET + 2w
Time (hours)
0
20
40
60
0 4 8 12 24 OPU ET ET + 1w ET + 2w
P (ng/mL)
Time (hours)
0
5
10
15
20
25
FSH (IU/L)
0 4 8 12 24 OPU ET ET + 1w ET + 2w
Time (hours)
120
80
40
0
200
300
100
hCG (IU/L)LH (IU/L)
LH hCG
LH triptorelin
LH leuprorelin
hCG
0 4 8 12 24 OPU ET ET + 1w ET + 2w
Time (hours)
hCG
Triptorelin
Leuprorelin
hCG
Triptorelin
Leuprorelin
Benefits of GnRH-a vs. hCG triggering
More MII oocytes Humaidan etal. Hum Rep. 2005
Higher fertilisation rate Oktay et al. RBM online 2010
Higher nuclear maturity Maman et al.Fertil Steril 2012
Higher LHR expression in Cumulus cells Borgbo et al.Fertil Steril 2013
-Different clusters according to ovarian reserve and type of triggering-VEGF lower after GnRH triggering
• 1. Fauser BC, et al. J Clin Endocrinol Metab. 2002;87:709-15.• 2. Kolibianakis EM, et al. Hum Reprod. 2005;20:2887-92. 3. Humaidan P, et al. Hum Reprod.
2005;20:1213-20. 4. Acevedo B, et al. Fertil Steril. 2006;86:1682-7. 5. Erb TM, et al. Fertil Steril. 2010;93:374-8.
GnRH agonist vs hCG
Studies Oocytes, n MII, nMII/
oocytes, n
Top quality
embryo, n
Fauser et al, 20021 = = =
Kolibianakis et al, 20052 = = =
Humaidan et al, 20053 = >
Acevedo et al, 20064 = = = =
Erb et al, 20105 > > >When effects are observed across studies, they are always in the same direction – consistently improved
366 Patients in 539 IVF cycles triggered with GnRHa or hCG
Oocyte number as a predictor forovarian hyperstimulation syndromeand live birth: an analysis of 256,381in vitro fertilization cycles
Ryan G. Steward, M.D.,a Lan Lan, Ph.D.,b Anish A. Shah, M.D., M.H.S.,a Jason S. Yeh, M.D.,a
Thomas M. Price, M.D.,a James M. Goldfarb, M.D.,c and Suheil J. Muasher, M.D.aFigure 2
Percentages of ovarian
hyperstimulation syndrome (OHSS)
and live birth (LB)
per retrieved oocyte numbers
per IVF cycle among
SART members
from 2008 to 2010.
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ORIGINAL ARTICLES: ASSISTED REPRODUCTIOn Fertility and Sterility
April 2014 : Vol.101;4;967-973
OHSS risk: GnRH agonist vs hCG trigger
Youssef et al., Cochrane Database Syst Rev 2014
GnRH-a Trigger and OHSS
Humaidan et al., Hum Reprod Update. 2011.
GnRH-a Trigger and Total Freeze• Griesinger et al., 2007, , 20 HIGH Risk Patients
(≥ 20 Follicles ≥ 11mm)
- Cumulativ ongoing pregrnancy rate 37 %
• Griesinger et al., 2011, 51 High Risk Patients
(≥ 20 Follicles ≥ 11mm)
- Cumulativ Pregnancy Rate 37 %
Garcia-Velasco F&S. 2012
Herrero et al.,F&S 2011
92 OHSS – Risk Patients(>20Foll. E2>4000pg/ml)
- 50% Pregnancy Rate und 32% Implantation Rate
GnRH antagonist cycle and GnRH agonist trigger to almost eliminate the risk of OHSS
Gold Standard in Egg Donation• Acevedo et al., F&S 2006
• Shapiro et al.,F&S 2007
• Bodri et al., F&S 2009
• Galindo et al.,Gyn.Endokrin. 2009
• Hernández et al., F&S 2009
• Melo et al., RBM online 2009
• Sismanoglu et al., ARG 2009
• Erb et al. F&S 2010
The Luteal Phase
Luteal phase progesterone in natural vs hCG triggered cycle
Adapted from Jones-1996 by Fauser and Devroey-2003
Serum concentrations of LH (hCG), FSH, E2, and P ( during triggering of final stages of oocyte maturation with two GnRH agonist or hCG
Fauser B C et al. JCEM 2002;87:709-715©2002 by Endocrine Society
Filicori et al., 1984
Correlation between LH and P4 during mid-luteal phase
Filicori et al.,
J. Clin. Invest, 1984
Mid-luteal LH levels
• 6.0 IU/l in natural cycle (Tavaniotou and Devroey 2003)
• 1.5 IU/l – GnRHa trigger (Humaidan et al., 2005)
• 0.2 IU/l – HCG trigger (Humaidan et al., 2005)
Physiology in COS• Supraphysiological steroid level (estradiol and progesterone)
in early-mid luteal phase exert a negative feed-back on the hypothalamic-pituitary axis reducing LH secretion in early luteal phase.
(Tavaniotou and Devroey, 2006; Tavaniotou et al., 2001)
▪ GnRHa triggering leads to significantly reduced total amounts of gonadotropins (LH and FSH) released by the pituitary due to profile and duration of surge.(Gonen et al., 1990; Itskovitz et al., 1991)
hCG trigger: price to pay
Supraphysiologic stimulation of CL in early luteal phase
Supraphysioloigc levels of E2 and P
Negative feedback at the pituitary level
Low endogenous LH secretion
Luteal phase defect
Need of luteal phase supplementation
Abnormal P production (peak P not with implantation)
Out-of-phase endometrium given high early luteal P
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OPU
hCG
Day 8
Day 6.5
hCG
hCG
The luteal phase reality after hCG trigger
LH activity deficiency period
Progesterone support needed appx. 8 days
OPU
LH
Day 8
Damewood et al., 1989; Bonduelle et al., 1988; Gonen et al., 1990; Itskovitz et al., 1991
28-32 hours
GnRHa
LH activity deficiency period
hCG
Early luteal phase after GnRHa trigger
GnRH agonist fortriggering of ovulation
and Fresh E.T.First trials low clinical pregnancy rate – high early pregnancy loss(Humaidan et al., 2005; Kolibianakis et al., 2005 Griesinger et al., Fertil Steril 2007; Hum. Rep. Update 2006)
Low live birth rate after GnRHa versus hCG triggering(Griesinger et al., Fertil Steril 2007)
Low reproductive outcome attributed to a luteal phase insufficiency despite supplementation with progesterone and estradiol
Different Strategies for Lut.Phase Support(after GnRH-a Triggering)
• E2+Progesterone :(i.m.) high dose until 10 weeks pregnancy
(Engmann et al. 2008)
• HCG :Multi Low-Dose 450 I.U. (Krause et al. 2006)
Single- Dose 1500 I.U. /Double Dose (Humaidan et al.2010;2013)
Dual –Triggering (GnRHa+1000 I.U. hCG,if E2<4000pg/ml)
(Shapiro et al.,2011; Engmann et al., 2012 )
Daily Micro-Dose (125 I.U.) hCG (C.Y.Andersen et al. 2015))
Luteal Phase Coasting (Kol et al.2016;Fatemi et al.2017&2018)
• Rec LH: Multiple Dose 300 I.U. (Papanikolaou et al. 2011)
• GnRH –Agonist :Multiple Dose daily (Pirard et al. 2006,2015)
(Bar Hava et al. 2016)
A new concept of Luteal support
0
50
100
150
200
250
300
0 24 48 72 96 120 144 168 192 216 240 264 288
hC
G (
IU/L
)
Time (hours)
125 IU hCG daily
1.500 IU hCG on OPU and OPU+5
10.000 IU hCG on ovulation triggerGnRHa trigger induced mid-cycle surge of LH
OPU OPU+2 OPU+4 OPU+6 OPU+7
hCG during the luteal phase with different dosing
FISCHER´S CONCEPT
Ongoing Pregnancy:GnRH agonist vs hCG trigger
Youssef et al., Cochrane Database Syst Rev 2014
GnRH agonist vs hCG trigger„From the clinical point of view,
the luteal support used is the
variable which affects the
pregnancy rate and not the
use of GnRHa trigger for final
oocyte maturation.Therefore ,
a meaningful comparison
between GnRHa and
HCG trigger
must be confined to
outcome measures
that are not affected by
the luteal support used.“
Results June2011-Dec.2012matched group for hCG trigger and
GnRHa trigger (Cycles1-3 No PBGS for RIF or AMA)) hGG trigger (n=680) GnRH-a trigger (n=664)
CPR /ET age <34 132/245 (53,9%) * 106/168 (63,1%)* I.R. 40.1% 45.2%CPR /ET age 35-39 63/143 (43,4%) * 79/145 (54,5%)*I.R. 29.7% 36.8%CPR /ET age >=40 3/26 (11,5%) * 12/41 (29,3 %)*I.R. 16.8% 22.1% OHSS EARLY ONSET 3% * 0
*) Significant(Fischer,Unpublished Data)
•• Beck-Fruchter R, et al. Hum Reprod.
2012;27:1357-67.
Incidence of EFS
The incidence of EFS is 0.045–3.4%; genuine EFS prevalence is 0–1.1% Author (year) No. of OPU cycles
No. of EFS cycles(genuine)
EFS prevalence (%) (genuine%)
No. of patients with EFS Recurrent EFS
Ben-Shlomo et al. (1991) 1,321 26 (NM) 2 (NM) 26 1/21
Harrison, Fawzy (1996) 1,418 1 (NM) 0.07 (NM) 1Ndukwe et al. (1996) 716 6 (0) 0.8 (0) 6Fiszbain et al. (1997) 376 9 (0) 2.4 (0) 9
Awonuga et al. (1998) 2,059 11 (3) 0.92 (0.58) 11 0/5Driscoll et al. (1998) 4,236 43 (NM) 1.01 (NM) 42
Quintans et al. (1998) 1,118 5 (0) 0.44 5Zreik et al. (2000) 3,004 57 (NM) 1.89 37 55/200
Aktas et al. (2005) 3,060 25 (14) 0.81 (0.45) 25 0/12Coskun et al. (2010) 5,238 NM (58) NM (1.1) 26 4/13
Reichman et al. (2010) 15,729 7 (0) 0.045 (0) 7
Griesinger et al. (2006) 51 1 (NM) 2 (NM) 1
Mesen et al. (2011) 12,359 11 (2) 0.089 (0.016) 11Baum et al. (2011) 8,292 163 (NM) 2 (NM) 136 16/101Castillo et al. (2012) 3,467 118 3.4 118
• Low hCG bioavailability resulting from variation in the absorption or clearance of hCG
• Variation in the threshold for follicular response to hCG
• Variation in the time needed from hCG exposure to maturation of oocyte–cumulus complexes
• Intrinsic defects in the biological activity of hCG preparation
• High BMI-Bad absorbtion.
• Incorrect injection
Beck-Fruchter R, et al. Hum Reprod. 2012;27:1357-67.
Causes of failure to retrieve oocytes
Other suggested aetiologies
• Ovarian aging
• Dysfunctional folliculogenesis due to
increased apoptosis
• Defective granulosa cell function
• Faulty oocyte development and maturation
• Strong attachment of cumulus cell
complexes to the follicular wall
• Dysfunctional ovulation induction
Inan MS, et al. Reprod Biomed Online. 2006;13:481-91.Yariz KO, et al. Fertil Steril. 2011;96:e125-30.
A genetic cause?
Empty follicle syndrome (EFS) GnRH-a versus hCG Trigger
Retrospektive Analyse of> 3000 Zyklen from 2009/2010
• 2034 Egg Donation Cycles and GnRHa Trigger
• 1433 IVF Cycles and hCG Trigger
• EFS Incidence: 3.5 % (GnRHa) versus 3.1 % (hCG) (NS)
Castillo, J C, Garcia-Velsaco J, Humaidan P, 2012
(2012)
Double trigger
• GnRH agonist: 40 hours prior to OPU
• hCG: 34 hours prior to OPU
This trigger combines the advantages of both
• Prolongation of the time between ovulation triggering and OPU
• GnRH agonist trigger with the consequent simultaneous induction of an FSH surge
Beck-Fruchter R, et al. Hum Reprod. 2012;27:1357-67.
OPU
−40h −36h −34h
ET
High responders
Normal
responders
Abnormal oocyte
maturation
Poor responders
hCG 5,000–10,000 IU
GnRH agonist
hCG 1,500 IU
h, hours. Orvieto Journal of Ovarian Research (2015) 8:60
Triggering final follicular maturation
HCG for triggering of ovulation
HCG has been used as a surrogate for LH for decades
effectively inducing:
• Final oocyte maturation
• Ovulation
• Luteinization of theca/granulosa cells
• Corpus luteum formation
due to structural and biological similarities with LH
HCG for triggering of ovulation - drawbacks
• Due to the longer half-life of hCG it is detectable up to 6 days following a single injection of 5000 IU
• Supraphysiological steroid levels (estradiol and progesterone), leading to disrupted luteal phase
• No FSH surge
• The sustained luteotropic effect may facilitate OHSS
GnRH-a trigger:Do we get what we need?
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Combined LH+FSH surge – yes
More Oocytes harvested-yes
Avoid negative impact of hCG on oocyte quality-yes
Avoid early luteal over stimulation - yes
Assure smooth luteal P rise to peak - yes
Assure peak P coincides with implantation window – yes
Avoid negative impact of hCG on endometrium receptivity-yes
Avoid OHSS-yes
Decrease patient burden - yes
How to use GnRHa triggerNo difference between different GnRHa types and
administration forms (Parneix et al., 1996)
Most commonly used GnRHa triggering doses:
• Buserelin 0.5mg s.c.
• Buserelin 0.2mg i.n.
• Triptorelin 0.2mg s.c.
• Leuprolide 1mg s.c.
Timing of bolus:
• Same as for hCG triggering (34-36 hours)
Which Patients can not be treated with GnRH-agonist Triggering
for Ovulation Induction?
Patients with-Hypogonadotrophic/ Hypogonadism(WHO I )
All Patients with -GnRH – Agonist (Long –Protocol)
• -
HAMBURG
Thank you for your time