GnRH antagonist in Ovarian stimulation for IVF/ET, Prof. Usama M.Fouda
-
Upload
umfrfouda -
Category
Health & Medicine
-
view
128 -
download
0
Transcript of GnRH antagonist in Ovarian stimulation for IVF/ET, Prof. Usama M.Fouda
GnRH antagonist in Ovarian stimulation for IVF/ET
Usama M. FoudaProfessor of Obstetrics and Gynecology , Faculty of medicine, Cairo University . Egypt
Introduction •Gn Rh is a decapeptide (10 amino acids) neurohormone that is secreated
by the hypothalamus in pulsatile pattern.
•GnRH stimulates the synthesis and secretion of the gonadotropins by the
pituitary gonadotopes. Low-frequency GnRH pulses lead to FSH release,
whereas high-frequency GnRH pulses stimulate LH release.
• A gonadotropin-releasing hormone analogue is a synthetic peptide drug
modelled after the human hypothalamic gonadotropin-releasing
hormone(GnRH).
• A GnRH analogue is designed to interact with the GnRH receptor and
modify the release of pituitary gonadotropins .
• Two types of analogues have to be distinguished;
Gn RH agonists
Gn RH antagonists
GnRH agonists cause initial stimulation of GnRH receptors (flare up )
followed by down-regulation of the pituitary GnRH receptors.
GnRH-antagonists cause immediate and dose-related inhibition of
gonadotropins release by competitive occupancy of the GnRH receptors in
the pituitary gland.
Structure of GnRH
1 2 43 65 98 107
pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2
activation of the GnRH receptor
regulation of GnRHreceptoraffinity
regulation ofbiologic activity
GnRH antagonists available in the market Cetrorelix (cetrotide , Serono ) and Ganirelix( Antagon , Organon ) .
Characteristics of GnRH antagonist
Ganirelix Fully effective
within 4 hours, with a half-life of about 13 hours
Cetrorelix Fully effective
within 8 hours, with a half-life of about 36 hours
Advantages of GnRH antagonist Immediate, reversible suppression of gonadotropin secretion which avoids
effects related to the initial flare up .
Endogenous inter-cycle FSH rise rather than FSH suppression, thus
resulting in a significant reduction in the effective dosage and shorter
treatment, than with GnRHa.
Lower incidence of OHSS.
In high risk cases for OHSS , Gn RH agonist can be used instead of HCG to
trigger ovulation .
Ideal regimen for patients with breast cancer undergoing controlled
ovarian stimulation , due to decreased risk of post-trigger oestradiol
exposure as well as OHSS risk.
Ideal regimen for cancer patients undergoing controlled ovarian
stimulation and gametes or embryo cryopreservation prior to
gonadotoxic therapy , because of the avoidance of an acute
stimulation of endogenous gonadotropins and the short duration of
treatment .
Disadvantages of GnRH antagonists
A) High intercycle endogenous FSH concentrations inducing secondary follicle
recruitment and leading to an asynchronous follicular development.
B) LH levels remain unsuppressed during the early follicular phase and enhance
E2 production.
c)High exposure of the genital tract to LH, E2 and progesterone levels during
the early follicular phase, might adversely affect the implantation rate
mainly by altering endometrial receptivity, leading to a worse reproductive
outcome.
Asynchronous follicular development
Advantages of GnRH agonist
A) Stable and low LH and P levels throughout the stimulation phase.
B)Suppression of endogenous FSH levels leading to a follicular cohort of all
small follilcles at the initiation of FSH stimulation resulting in a
synchronized follicular development.
Disadvantages of GnRH agonist
A. More time consuming and complex stimulation protocols.
B. Acute stimulation of gonadotropins and steroid hormones due to the flare
up effects ( more cyst formation).
C. Profound hypoestrogenemia due to downregulation ( hot flushes ).
D. More risk of OHSS.
GnRH antagonist protocols
A) Single dose protocol
GnRH antagonist ( 3 mg) is started on day 7 of ovarian stimulation .
B) Multiple dose protocols
• Fixed regimen: GnRH antagonist (0.25 mg )/daily from the 6th day of ovarian
stimulation .
• Flexible regimen : GnRH antagonist (0.25 mg) / daily when the follicles
reach a size of > 14 mm .
Single dose Vs. Multiple dose regimens
• No significant difference in pregnancy rates or in the inhibition of LH surge .
• Single-dose GnRH-ant protocol has the advantage of reducing the number
of injections.
• In 10 % of cases using the single dose regimen , additional daily dose of
antagonist is needed.
• In some cases 3 mg-dose may result in excessive and potentially harmful
suppression of endogenous LH.
Fixed Vs. Flexible regimens • Reduced number of antagonist injections and the duration of stimulation is
observed with the flexible regimen .
• Four RCTs have so far been performed comparing a fixed versus a flexible
protocol. Although currently the difference is not significant, all published
studies show a lower pregnancy rate in the flexible as compared to the fixed
protocol (odds ratio 0.70, 95% CI: 0.47– 1.05).
Al-Inany H, Aboulghar MA, Mansour RT, Serour GI: Optimizing GnRH antagonist administration: meta-analysis of fixed versus flexible protocol. Reprod Biomed Online 2005, 10(5):567–570.
Modifications of the standard GnRH antagonist protocol
Oral contraceptive pills pre-treatment
•It was suggested that oral contraceptive pills (OCP) pre-treatment may improve
synchronization of the recruitable cohort of ovarian follicles.
•A large meta-analysis showed no significant effect of OCP pre-treatment on
the probability of pregnancy in GnRH-ant cycles
•An increase of gonadotropin requirement, and a longer duration of treatment
was observed with the use of OCP.
Kolibianakis EM, Collins J, Tarlatzis BC, Devroey P, Diedrich K, Griesinger G: Among patients treated for IVF with gonadotrophins and GnRH analogues, is the probability of
live birth dependent on the type of analogue used? A systematic review and meta-analysis. Hum Reprod Update 2006, 12(6):651–671
GnRH agonist versus HCG for triggering final oocyte maturation
•Replacing HCG with GnRH agonist has been claimed to lead to a decreased
risk of developing OHSS in high risk patients .
• However, GnRH agonist administration induces an LH surge which is not
identical to that occurring in the natural cycle, especially regarding its duration.
•The existing literature suggests that a lower probability of pregnancy is to be
expected when a single dose of GnRH agonist is used instead of HCG for
triggering final oocyte maturation .
Griesinger G, Diedrich K, Devroey P and Kolibianakis EM (2005b) GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis. Hum Reprod Update 12,159–168.
GnRH-ant (antagonist) protocols Vs GnRH-a (agonist) long protocol
• Significantly less gonadotropin ampoule consumption and stimulation days
in GnRH-ant regimes.
• First two met-analyses revealed that the pregnancy rates tended to be
lower in GnRH-ant regimen .
• Subsequent larger meta-analyses revealed that there are no significant
differences in the pregnancy rates and the live birth rate between both
regimens .
• Lower mean number of cumulus-oocyte-complexes (COC) and 2
pronuclear (PN) oocytes were found in GnRH-ant group.
• LH and E2 concentrations, in early follicular phase were higher in GnRH-
ant regime as compared with GnRH-a regime, whereas the LH
concentrations on the day of hCG were comparable in both protocols .
• A premature LH rise was observed in 4.3% of GnRH-ant patients and in
3% of GnRH-a patients .
• OHSS was significantly higher in GnRH-a group (1.1% P = 0.03) .
Ongoing pregnancy rate is significantly lower in the antagonist group.( P =0.03 , OR 0.82 , 95% CI 0.68 to 0.97 )
Two folds decrease in the risk of OHSS with antagonist protocols
Citation Year Effect Lower Upper PValue
Albano 2000 ,829 ,444 1,547 ,556
European 2000 ,748 ,519 1,078 ,119
Olivennes 2000 ,799 ,336 1,901 ,612
North American 2001 ,777 ,470 1,284 ,324
Middle East 2001 ,973 ,604 1,568 ,910
Akman 2001 ,760 ,177 3,263 ,712
Hohmann 2003 ,929 ,398 2,169 ,865
Martinez 2003 1,569 ,307 8,011 ,587
Franco 2003 ,545 ,065 4,562 ,573
Hwang 2004 1,105 ,347 3,526 ,866
Sauer 2004 1,067 ,334 3,409 ,913
Xavier 2005 ,845 ,288 2,484 ,760
Loutradis 2005 ,704 ,271 1,827 ,469
Malmusi 2005 1,000 ,257 3,888 1,000
Marci 2005 10,358 ,533201,451 ,062
Cheung 2005 1,550 ,242 9,940 ,642
Check 2005 1,818 ,518 6,382 ,347
Barmat 2005 ,651 ,262 1,621 ,356
Bahceci 2005 ,839 ,436 1,613 ,598
Badrawi 2005 ,803 ,320 2,015 ,640
Schmidt 2005 1,000 ,181 5,533 1,000
Lee 2005 ,696 ,229 2,114 ,522
FixedCombined (22) ,859 ,722 1,021 ,085
0,1 0,2 0,5 1 2 5 10
Favor agonists Favor antagonists
Odds ratio:0.859p=0.085
LIVE BIRTH
Rate difference2.7%
3.0 ampoules less with GnRH antagonistsp<0.07
FSH requirement
COCs retrieved
1.2 COCs more with GnRH agonists
p<0.001
Review: GnRH Antagonists vs. GnRH agonistsComparison: 02 COCs Outcome: 01 COCs retrieved
Study Antagonists Agonists WMD (random) Weight WMD (random)or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI Year
Albano 166 8.00(4.90) 72 10.60(6.60) 5.97 -2.60 [-4.30, -0.90] 2000Olivennes 113 9.20(5.10) 36 12.60(7.40) 3.79 -3.40 [-5.99, -0.81] 2000Akman 20 4.50(1.63) 20 5.50(2.98) 6.63 -1.00 [-2.49, 0.49] 2001European 463 8.70(5.60) 238 9.70(6.20) 8.53 -1.00 [-1.94, -0.06] 2001Middle East 226 7.90(5.10) 111 9.60(6.80) 6.83 -1.70 [-3.13, -0.27] 2001Franco 14 10.50(6.50) 6 10.10(4.60) 1.38 0.40 [-4.61, 5.41] 2003Martinez 23 3.70(1.90) 21 5.60(4.30) 5.13 -1.90 [-3.90, 0.10] 2003Hwang 25 16.30(6.40) 27 17.60(5.90) 2.65 -1.30 [-4.65, 2.05] 2004Badrawi 47 9.68(5.28) 50 12.60(6.15) 4.44 -2.92 [-5.20, -0.64] 2005Bahceci 59 19.33(9.00) 70 21.60(11.00) 2.54 -2.27 [-5.72, 1.18] 2005Barmat 36 12.50(3.28) 41 15.00(4.50) 5.83 -2.50 [-4.25, -0.75] 2005Check 24 9.60(7.70) 30 17.60(10.10) 1.51 -8.00 [-12.75, -3.25] 2005Cheung 19 5.89(3.02) 21 5.62(4.17) 4.52 0.27 [-1.97, 2.51] 2005Loutradis 58 8.10(2.40) 58 8.70(3.00) 8.35 -0.60 [-1.59, 0.39] 2005Malmusi 18 2.50(1.20) 24 3.50(1.40) 9.03 -1.00 [-1.79, -0.21] 2005Marci 29 5.60(1.60) 26 4.30(2.20) 8.22 1.30 [0.27, 2.33] 2005Schmidt 14 8.90(0.90) 12 9.00(1.20) 8.90 -0.10 [-0.93, 0.73] 2005Xavier 53 10.10(4.60) 59 10.60(5.00) 5.73 -0.50 [-2.28, 1.28] 2005
Total (95% CI) 1407 922 100.00 -1.19 [-1.82, -0.56]Test for heterogeneity: Chi² = 48.11, df = 17 (P < 0.0001), I² = 64.7%Test for overall effect: Z = 3.70 (P = 0.0002)
-10 -5 0 5 10
Favor agonists Favor antagonists
Citation Year Rate1 Rate2 PValue Effect Lower Upper
Albano 2000 ,00 ,01 ,20 ,16 ,01 3,91
Badrawi 2005 ,04 ,04 1,00 1,00 ,15 6,82
Bahceci 2005 ,04 ,07 ,49 ,62 ,15 2,49
European 2000 ,01 ,02 ,07 ,33 ,10 1,17
Lee 2005 ,07 ,10 ,72 ,73 ,13 4,04
Middle East 2001 ,02 ,05 ,07 ,34 ,10 1,17
North American 2001 ,01 ,02 ,76 ,76 ,13 4,46
Olivennes 2000 ,02 ,05 ,25 ,34 ,05 2,35
RandomCombined (8) ,01 ,47 ,27 ,84
0,01 0,1 1 10 100
Favor agonists Favor antagonists
RR : 0.47~ 2 times less risk to be admitted due to OHSS with GnRH antagonists
Hospital admission due to OHSS
In conclusion
• The GnRH antagonist protocol is a short and simple protocol with a
comparable live-birth rate to GnRH agonists long protocol .
Furthermore , it is associated with less incidence of the OHSS.