GnRH Agonist vs GnRH Antagonist what to choose?

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Dr. Ritu S Santwani M.B.B.S, MD, FICOG
IVF -Infertility (Test Tube Baby) Specialist
Director -Pune TestTube Baby Center
Center Address:
Liberty , Phase -2, C-6 , Opp Lane -5
North Main Road, Koregoan Park
Pune – 411001
http://www.punetesttubebabycenter.com
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PUNE TESTTUBE BABY CENTER

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AntagonistGnRH agonist

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1984 GnRH Agonist
•Vast experience
•Numerous studies
1999 Antagonist
• Comparatively Lesser experience
•Fewer studies

THESE ARE TWO DRUGS USED
FOR THE SAME PURPOSE:
LH SUPPRESSION FROM
PITUTARY FOR PREVENTING
ENDOGENOUS LH PEAK SO WE
CAN TIME THE OOCYTE RETRIVAL
6PUNE TESTTUBE BABY CENTER

• The first report on use of GnRH agonist (buserelin) +
Gn for ovarian stimulation for IVF was in --- 1984
• Incidence of premature LH surge & subsequent
luteinization with Gn stim without GnRH agonist was
20 – 50 % ,leading to increased cancellation rates &
deleterious effects on fertilization/pregn rates.

• The receptors (R) after
intracellular synthesis are
randomly inserted into the cell
membrane.
• The R has 3 important
regions :
→ External -- to bind to the
hormone
→ Transmembrane region
→ Internal 8PUNE TESTTUBE BABY CENTER

1. Activated Calmodulin
+
2. Activated PKC
↓
Cause release of
Gonadotophins (FSH & LH)
FLARE UP 4 times FSH and 10
times LH release

• Over the time b/o over abundance
of agonists with longer half life,
the dimer form of receptors is
favored and the receptors go into
the cell and cannot come back
so
• Cannot respond to subsequent
pulses of GnRH
• Thus the gonadotrops become
desensitised and this is called
down regulation of GnRH
receptors

• DESENSITIZATION
• When the GnRH receptors
exposed to GnRH agonists for
a prolonged period, the cells
lose their ability to respond to
the stimulus with their original
sensitivity.
• Process is rapid & reversible.
• Process operates at both the
receptor level & by post
receptor modification

Agonist is the ---- Conventional
---- Time tested & trusted
---- More efficacious
---- Many modifications
“ OLD IS GOLD “

Many treatment schedules with the use of
GnRH agonists in ART have been designed.
It has to be tailored as per the patient profile.
The 2 most widely used GnRH agonist protocol
in COS for ART are :
→ Long Luteal Protocol
→ Short Protocol
13

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agonist
agonist
agonist
2 3 4
2 3 4 5 6 7 8 9 10 11 12
21 (luteal) 2 3 4 5 6 7 8 9 10 11
hCG
hCG
hCG
150 /225 FSH / hMG daily
150 rec FSH / 225 hMG daily
150/225 FSH / hMG daily

-- The GnRH agonist is started on Day-21 of
the cycle preceeding tt.
-- GnRH agonist is continued in parallel along
with Gn.
-- Gn started after pituitary downregulation
Some modifications :
→ Long Follicular
→ Early cessation/Stop
→ Long Luteal Mini-dose

-- They utilize the initial temporary
flare effect of the agonist to
promote follicular recruitment
during menstruation before the
supressive action takes over.
-- More suitable for older patients
or poor responders.
Some modifications :
→ Ultrashort
→ Micro-dose Flare

The long mid-luteal protocol
has consistently been reported
to be more effective than
short or ultra-short protocols as
far as pregnancy rates are
concerned & the most recent
Cochrane review has confirmed
these.
Disadvantages : Higher cost as
more Gn used
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Agonists offers many advantages over
Antag..
Agonist long protocol : (Advantages)
1) Stable & low LH & P4 levels
throughout the stimulation phase.
2) Suppression of endogenous FSH
levels leading to a follicular cohort of
all small follicles at the initiation of
FSH stimulation
→in a synchronized follicular
development

3) Agonist use is associated with ↑ HOXA 10 expression, so ↑ endometrial receptivity.
(Orvieto et al., 2008a )
4) Significantly higher number of oocytes and higher proportion of mature MII oocytes was
retrieved per patient randomized, in the GnRH agonist group Depalo et al. Reproductive
Biology and Endocrinology 2012
5) So increased chance of pregnancy in current as well as subsequent cycles with cryo-
preserved embryos.
6) Better programming of treatment schedule. Reduces the cycle cancellation rates (2%)
7) Can be used to induce final maturation & ovulation instead of hCG in antagonist protocol
8) Very good protocol for normal responders

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1) Longer pretreatment period required
2) Initial “flare up” of FSH & LH may lead to ovarian cyst formation.
3) Excessive follicle selection leading to higher incidence of OHSS, especially
in PCOS patients.
4) Over suppression in poor responders requiring a higher dose of
Gonadotropins or a poor response.
5) Higher incidence of multiple pregnancy.
6) Luteal phase support is required.
7) Increased total gonadotropins dose per
treatment cycle.
8) Higher cost
9) Daily administration

1) LH levels remain unsuppressed during the early follicular
phase, so ↑ LH, E2 & P4 as well.This adversely affects
endometrial receptivity, so pregnancy rates too.
2) High intercycle endogenous FSH concentration induces
secondary follicular recruitment, leading to asynchronous
follicular development.
22

• Patients with an unfavorable prognosis (patients with repeated
IVF failure )
GnRH agonist protocol was superior, showing a significantly
higher clinical pregnancy rate, when compared with the
antagonist protocol
(20.8% versus 14.5%; P < 0.02).
Orvieto et al., 2009)

GnRH agonist Antagonist

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GnRH antagonists versus
agonist protocols in non
obese women with polycystic
ovarian syndrome showed
similar embryological &
clinical efficacy of both
protocol.
Kurzawa et al, J Assist Reprod Genet 2008

No difference between the two
protocols
In terms of quality of oocyte
morphology or oocyte dysmorphism.
Conclusion –
Oocyte dysmorphism was not
influenced by the type of pituitary
suppression.
Cota et al, Reprod Bio Endocrinol 2012

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Marci et al compared ovarian stimulation in women with high & normal body
mass index (BMI) in both agonist & antagonist protocols.
 Patients with BMI >25kg /m2 were found to require a higher amount of
goandotropins in the agonist protocol compared to those with normal BMI.
Conclusion
 Obesity could impair the ovarian response to gonadotropins
 In patients with normal BMI clinical pregnancy rates were similar with both
protocols
Marci et al, Gynecol Endocrinol 2012

Clear advantage was gained in duration of stimulation with
GnRH-anta in poor ovarian responders undergoing IVF,
although there was no statistical difference in the number of
oocytes retrieved, the number of mature oocytes retrieved,
the CCR and CPR between GnRH-ant and GnRH-a protocols.
Comparisons of GnRH antagonist versus GnRH agonist protocol in
poor ovarian responders undergoing IVF Danhua Pu1,2,jie Wu1,2,*
and Jiayin Liu1,2 Human reproduction 2011

• A randomized prospective study compared an antagonist protocol with
a long agonist protocol in poor responders and concluded that there
were no significant difference in the cycle cancellation rates, duration of
stimulation, dosage of gonadotropins (a fixed dose was used), and mean
numbers of mature follicles, oocytes, and embryos obtained .
Cheung L-P, P-M, Lok I, Chiu T, Yeung S-Y, Tjer C-C, Haines C.GnRH
antagonist versus long GnRH agonist protocol in poor
respondersundergoing IVF: a randomized controlled trial. Hum Reprod
2005;20:616 –21
• The implantation rates were similar but the pregnancy rate was higher,
though not statistically significant, in the antagonist group.

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Not the preferred protocol
Why???
Down regulation of the hypothalamic pituitary ovarian axis prior
to gonadotrophins leads to over suppression of ovaries & hence
prolongation of follicular phase & increase in the number of
gonadotropins ampoules required for stimulation or poor
response.

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No difference between both protocols regards pregnancy
losses.
No difference in major congenital malformations.
Neonatal outcome was also similar
Boerrigter et al, Human Reprod 2002

1a

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Various meta analysis have found no significant difference in the
live birth rates between the two protocols.
They concluded that the probability of live birth was not
dependent on the type of protocol used for stimulation
Kolibianakis et al Human Reprod Update 2006,
Tur Kaspe I & Ezcurra 2009

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Recent Cochrane review no significant difference between the
two protocols in terms of clinical pregnancy rates (CPR).
(odds ratio 0.86, AI – 95% confidence interval 0.69-1.08)
Al Inany et al, Cochrane data base Syst Rev 2011

GnRH Agonist vs GnRH Antagonist what to choose?

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