Dr Frank Quinn

Clinical Director
IVF Australia
Overview

• Introduction
• GnRH agonists and antagonist Mode of Action
• Antagonist vs Agonist efficacy
• GnRH antagonist protocols
♦ Multiple and single dose antagonists
♦ Fixed versus flexible start
♦ Cycle Programming

• GnRH antagonists and Poor Responders

• Summary
Native GnRH and its Analogues

pyro Gly
Glu His Trp Ser Tyr Gly Leu Arg Pro NH2

Chemically modify native GnRH to form:

Agonists - initial stimulatory phase

followed by suppression

Antagonists - immediate suppression

GnRH Agonist vs Antagonists: effect
on LH levels

30
25
20
LH (IU/L)

Agonist
15
Antagonist
10
5
0
-6 0 6 12 18 24 30 36 42 48
Hours
 1 2 3 4 5 6 7 8 9 10
pyro Gly
GnRH Glu His Trp Ser Tyr Gly Leu Arg Pro NH2

First-Generation
AcD- D-4F D-Trp
Nal-Arg Nal Phe Ser Tyr D-Arg Leu Arg Pro D-Ala

Second-Generation
AcD- D-4Ci D-Pal D-Glu
Nal-Glu Nal Phe Ser Arg (AA) Leu Arg Pro D-Ala

Third-Generation

Ganirelix AcD-
Nal
D-4Ci D-Pal
Phe Ser Tyr
D-4Aph
(Et2)
Leu
L-4Aph
(Et2) Pro
D-Ala

AcD- D-4Ci D-Pal

Cetrorelix Nal Phe Ser Tyr D-Cit Leu Arg Pro D-Ala
The GnRH antagonists available:
cetrorelix and ganirelix

2 REGIMENS
• Multiple dose (0.25mg/day)
♦ cetrorelix, ganirelix

• Single dose (3mg)

♦ cetrorelix
PROTOCOLS
• !!!
 Comparison of the long agonist and the
antagonist protocols
more
physiologic
no hormonal antagonist
antagonist no cyst administration
multiple dose protocol formation
withdrawal
gonadotropin administration

less gona-
dotropins

flare up pituitary
effect suppression
gonadotropin administration
agonist
long protocol agonist administration
longer
treatment

pre-treatment cycle treatment cycle

GnRH antagonists vs agonists
Advantages and Questions?
DEMONSTRATED QUESTIONS
• Shorter treatment • Outcome same as
Agonists?
• Less Injections
• Best protocol?
• Less OHSS
• Cycle
• Less FSH Programming?
• More patient friendly • Need for LH?
Is the outcome the same for
GnRH antagonist and GnRH
agonist protocols?
Antagonists vs Agonists
in ART
GnRH ant protocol used
more in older patients
and following initial
treatment failure

BUT: in young patients

with tubal infertility
• A literature search identified 22 RCTs comparing GnRH
antagonists and GnRH agonists that involved 3176 subjects.
♦ Where live birth was not reported, an effort was made to contact the
corresponding authors to retrieve the missing information.

• Dramatic reduction in the duration of analogue treatment

♦ –17.88 days; 95% CI, –20.41 to –15.36)

• Significantly reduced duration of FSH stimulation was

present in the antagonist group.
♦ –3.04 ampoules; 95% CI, –6.27 to +0.19).

• Significantly less oocytes were retrieved in the antagonist group.

♦ –1.19 COCs; 95% CI, –1.82 to –0.56).
• No significant difference was present in the probability of
live birth between the two GnRH analogues
♦ [odds ratio (OR), 0.86; 95% confidence intervals (CI), 0.72 to
1.02].

• Significantly lower OHSS requiring hospitalisation in the

antagonist group
♦ OR, 0.46; 95% CI, 0.26 to 0.82;

• In conclusion, the probability of live birth after

ovarian stimulation for IVF does not depend on the
type of analogue used for pituitary suppression.
• 6 trials fulfilled the inclusion criteria. There was no
difference between GnRH-ant and GnRHa (long and flare-
up protocols) with respect to
♦ cycle cancellation rate, number of mature oocytes and clinical
pregnancy rate per cycle initiated, per oocyte retrieval and per
embryo transfer.

• In the two trials that had used GnRH-ant versus long

GnRHa, a significantly higher number of retrieved oocytes
was observed in the GnRH-ant protocols [P = 0.018;
WMD: 1.12 (0.18, 2.05)].
• In the four trials that had used GnRH-ant versus flare-up
protocols, a significantly higher number of retrieved
oocytes (P = 0.032; WMD: −0.51, 95% CI −0.99, −0.04)
was observed in the GnRHa protocols.
Franco et al RBM online 2006
• Poor Responders: 8 studies, with 575 patients treated with
GnRHa or antagonist for ovarian stimulation in RCT.
♦ Long agonist protocol in poor responders is associated with
significantly fewer oocytes retrieved compared with GnRH-ant
protocol (OR 0.41, 95% CI: 0.0–0.83, P = 0.05)
♦ likelihood of clinical pregnancy higher after antagonist use;
however, this did not reach statistical significance (OR 1.28, 95%
CI: 0.84–1.96; P = 0.25;

• PCOS: Four studies identified with 305 patients.

♦ duration of stimulation shorter using GnRH-ant (OR -0.86, 95% CI
-1.14 to -0.59, P < 0.01),
♦ non-significant lower consumption of gonadotropins
♦ No significant difference in number of oocytes retrieved or
likelihood of clinical pregnancy
Griesinger et al RBM online 2006
 hCG 3 foll
17mm diam

Day 6 FSH stim

Day 2 menses GnRH ant

R-hFSH Vag P4

Papanikolaou et al NEJM 2006

 Single Blastocyst Single Cleavage
stage embryo
Age 30.4±3.6 30.5±3.2
FSH used (IUs) 1704±574 1699±515
Oocytes 12.5±7.1 13.9±8.1
Implantation rate % 38.7 27.4
% Clinical Preg 34.3 24.0
% Live Birth Rate 33.1 22.2
Papanikolaou et al NEJM 2006
Which is the best Antagonist protocol?

• Fixed daily
♦ Day 1 or 6 FSH

• Fixed single dose

♦ Day 7 FSH

• Flexible daily/single dose

♦ Follicle 14 or 15 mm

• OC pre-treatment
♦ 4-5 day interval before
starting FSH
Administration of GnRH
antagonist according to follicle
size (flexible protocol) vs a
fixed day of stimulation
• No significant difference in clinical pregnancy rate
between fixed and flexible protocols
• Reduction in IU’s FSH with Flexible Protocol
• No difference in oocytes
recovered
• Pregnancy/cycle 21.8
vs 31.1% in flexible vs
fixed 0.25mg antag
protocol arm
• In absence of foll ≥
15mm on stim day 6
ongoing preg rate lower
• Patients receiving
GnRH-ant on FSH day
Conclusion: Slow responders
8 or later had lower
pregnancy rates have lower pregnancy
potential
Flexible vs Fixed Day Administration
of GnRH antagonists

• General Rule: To reduce risk of

premature luteinisation in flexible
protocol start GnRH antagonist no
later than follicle size 14 mm
• If > 6 follicles 11-13 mm diameter
start GnRH antagonist (Kim et al
2005)
GnRH antagonist and Cycle
Programming with Oral
Contraceptive / oral E2
 Cycle programming in Cetrorelix
protocols using oral contraceptives

18 to 28 days 5 days

oral contraceptive pill GnRH ant 0.25mg

- 30µg ethinylestradiol
- 150 µg desogestrel

FSH
sunday friday

last pill stimulation

start

Fischl et al 2001, Obruca, et al. Human Reprod 2001;16(Suppl 1):89

 Cycle Programming in Cetrorelix
Multiple Dose Protocol Using OCs

With OCs Without OCs

Patients (n) 75 75
Ampoules of FSH* 22.1 ± 6.5 20.1 ± 4.7
Days of FSH* 11.4 ± 2.7 10.6 ± 2.0
Mean number of
5.8 6.3
oocytes
Mean number of
2.5 2.3
embryos transferred
Clinical
39.7% 41.2%
pregnancies/ET
No. weekend OPUs 0/68 6/66
Obruca,
Fischl etetalal.
2001,
Human
Obruca,
Reprod
et al.
2001;16(Suppl
Human Reprod
1):89
2001;16(Suppl 1):89 *Mean ± SD
• 425 patients randomised to receive OC pretreatment or
not with r-hFSH starting day 2 (menses) or 5 days after
stopping OC. GnRH antag started stim day 6
• Ongoing pregnancy rates per started cycle in the non-
OCP and OCP group were 27.5% and 22.9%, respectively
[95% confidence interval (CI) of the difference: -3.7 to
+12.8].
• Pregnancy loss was significantly increased in the OCP
(36.4%) compared with the non-OCP group (21.6%),(95%
CI of the difference: -28.4 to -2.3).
♦ Due to oversuppressed LH levels?
• Randomised controlled study in 185 patients from16 US centres
• OC pill administered from day 1 of previous cycle
• R-hFSH (follitropin alfa multi dose) 225 IU started on 5th day after stop
of OC pill
• FSH Dose adjustment from stim day 6
• Single dose GnRH antagonist (cetrorelix) 3mg or daily GnRH
antagonist 0.25 mg (ganirelix) administered when lead foll >=14mm
♦ If hCG not administered 4 days after 3mg Cetrorelix daily 0.25mg
Cetrorelix initiated

• 250 mcg r-hCG (Ovidrel) admin when 1 foll >=18mm, 2 foll >= 16mm
and E2 150 pg/ml per mature foll
• Vaginal progesterone(Crinone) admin from day of or day after oocyte
retrieval Fertil Steril 2005 84: 108 - 117
• No difference in outcome characteristics between Single
dose 3mg and multi dose 0.25 mg
• Use of OCP programming and flexible dosing of GnRH
antagonist associated with acceptable outcomes of 46%
pregnancy rate per cycle

Wilcox et al Fertil Steril 2005 84: 108 - 117

• Oral 17β E2 (4mg each pm) from day 20 to day 2 of next cycle
• Multidose r-hFSH 225 IU from day 3
• Lead follicle >13mm Cetrorelix 3mg admin
• More synchronised follicle cohort, higher oocyte yield
Possible benefits of oral contraceptives
in GnRH antagonist protocols

• Cycle programming for optimal timing of oocyte

pick-up
• Synchronise Follicle cohort
♦ Avoid rapid emergence of dominant follicle

• Can benefit poor responders

♦ Cheung et al 2004
Is it necessary to increase the
FSH dose when starting the
GnRH antagonist?
 hCG

R-hFSH

GnRH ant

R-hFSH

GnRH ant
 Control Step-up
Age 31.8 31.4
FSH used (IUs) 2,540 ± 567 2,662 ± 593
Oocytes 14.6 ± 7.5 16.7 ± 10.4
Embryos 2.1 ± 0.4 2.2 ± 0.5
Replaced
Live Birth Rate 56.7% 60.0%
Can GnRH agonist be used to
trigger final follicular
maturation?

YES
Is the use of GnRH agonist to
trigger final follicular
maturation associated with
similar pregnancy rates as
hCG?
• No significant difference in number of oocytes
retrieved (–0.94,–0.33–0.14), fertilization rate
(0.15,–0.09–0.38)
• No conclusion can be drawn as regards OHSS
incidence after GnRH agonist triggering.
• GnRH agonist administration is associated with a
significantly reduced likelihood of achieving a
clinical pregnancy (0.21, 0.05–0.84;P=0.03).
• The odds of first trimester pregnancy loss is
increased after GnRH agonist triggering.
What are the criteria for
administering hCG in a GnRH
antagonist Protocol?
 Typical Follicle and E2 Patterns Following
GnRH-a Down Regulation or GnRH-ant
Administration

Agonist Antagonist
Follicular Diameter Plasma E2 (pg/ml)
25
3000
20
15
2000 *
E2 1000
10
5 0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

1 3 5 7 9 11 13 Cycle Day
Leading follicle emerges E2 higher in early stim phase
earlier in in antag cycle in antag cycle

Scott et al 2001 * Agonist > Antagonist

 RBM online
2005

Higher (P > 0.02) pregnancy and implantation rate when

hCG criteria when ≥ 3 foll 17mm (early hCG) vs late
hCG group (hCG admin 2 days later)
Is there a need to add LH in a
GnRH antagonist Protocol?
Is there a need to add LH in a GnRH
antagonist Protocol?

• If rapid LH suppression has a detrimental effect would be

most apparent in single dose 3mg cetrorelix protocol
• Sauer et al 2004 in multicentre study using 3mg flexible
protocol (+OCP) reported no benefit of LH
supplementation (150 IU r-hLH dy 6 FSH) on MII oocytes
or pregnancy rate vs no supplementation or GnRH agonist
protocol
• Cedrin et al 2004 in multicentre study using 3mg flexible
protocol (+OCP) reported no benefit of LH
supplementation (75 IU r-hLH dy antag) on oocytes or
delivery rates
Women aged 32 yrs treated with Cetrotide 0.25mg from
foll>= 14mm and randomised to receive 75 IU r-LH or no LH
at same time
No sig difference (except higher E2) in outcome parameters

Eur J Obstet Gyn 2006

Is there a need for luteal phase
support a GnRH antagonist
Protocol?
Is there a need for luteal phase support
a GnRH antagonist Protocol?

• Due to immediate
reversability of GnRH
antagonist action – no need?
• Controlled ovarian
stimulation leads to short
luteal phase (Jones et al
1981)
• Inadequete luteal phase
(Albano et al 1998)
• Abnormal endometrial
development (Kolibianakis et
al 2003)
• 201 patients received rFSH / GnRH antagonist and randomized
for luteal support from day 1 after oocyte retrieval to either
♦ 600 mg of micronized progesterone vaginally (n = 100,
progesterone group) or
♦ 600 mg of micronized progesterone and 4 mg of E2 valerate orally
(n = 101, progesterone/E2 group).

• Twenty-six ongoing pregnancies were achieved in the

progesterone (26%) and 30 in the progesterone/E2 group (29.7%).
(Difference: 3.7 and 95%, CI: –15.8 to 8.6%).
• In conclusion, the addition of E2 to progesterone in the luteal phase
after stimulation with rFSH and GnRH antagonist does not appear to
increase the probability of pregnancy.
GnRH antagonists in Poor
Responder Patients
GnRH antagonists may be associated with
- simpler stimulation protocols,
- lower gonadotropin requirements,
- reduced patient costs,
- shorter downtimes between consecutive cycles.
Greatest advantage of GnRH antagonists is the ability to assess
ovarian reserves immediately prior to starting gonadotropin
stimulation.
The ability to respond to cycle-to-cycle variation in antral follicle
counts may allow the optimization of oocyte yield and reduce cycle
cancellation rates.
• 63 patients ave. 36 yrs
received OCP pre-treatment
• Long Luteal Agonist or
Cetrotide fixed dose 0.25mg
daily from day 6 FSH
• R-hFSH 300iu daily
• No differences in oocytes
retrieved
• More embryos transferred in
Cetrotide group with a trend
to higher pregnancy rate per
cycle (16.1 vs 9.4%)

Human Reprod 2005

 Placido et al Fertil Steril 2006

• 300 IU r-hFSH (Gonal-f)

• GnRH antag (Cetrotide) 0.25mg from foll size 14mm or short agonist protocol
• 150 IU r-LH from foll size 14mm
• More mature and fertilized oocytes in GnRH antag group
The Use of GnRH Antagonists in Ovarian
Stimulation Protocols: Summary

• Single and multiple dose GnRH antagonist protocols are equally effective
and patient friendly

• Antagonist protocols are as effective as Classic Long GnRH agonist

• Flexible administration of Antagonist (no later than follicle size 14mm) is

effective

• OC (or E2) programming improves cycle management and reduces LH

secretion.

• Supplemental LH in normogonadotrophic patients is not required

Use of Antagonist in poor responders associated with more embryos for

An Ideal GnRH antagonist protocol
today

FIXED FLEXIBLE

MENSES PROGRAMMED

GnRH ant 0.25mg

hCG
5 Days Leading follicle size
14mm

OC FSH progesterone

1 2 3 4 5 6 7 8 9 10 11 12 13