Gnrh Agonist

Types of protocols
 Protocols

Long Short Ultra short

1.Short /Flare
1.Long Follicular 2.Microflare
2.Long Luteal
-Minidose protocol
-Stop protocol

3.Long Follicular
Depot
4. Long Luteal
Depot
5. Ultra long
 Long Follicular Protocol
Gnrh Agonist daily Gonadotropins

28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Blood tests and scan Hcg Trigger

E2<50 pg/ml When criteria for

LH<5miu/ml trigger is fulfilled
All follicles<10 mm
 Long Luteal Protocol
Gnrh Agonist
Daily Gonadotropins

19 20 21 22 23 24 25 1 2 3 4 5 6 7 8 9

Blood tests and scan Hcg Trigger

E2<50 pg/ml When criteria for

LH<5miu/ml trigger is fulfilled
All follicles<10 mm
 Long Follicular Depot Protocol
Gnrh Agonist Depot Gonadotropins

28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Blood tests and scan Hcg Trigger

E2<50 pg/ml When criteria for

LH<5miu/ml trigger is fulfilled
All follicles<10 mm
 Long Luteal Depot Protocol
Gnrh Agonist
Depot Gonadotropins

19 20 21 22 23 24 25 1 2 3 4 5 6 7 8 9 Till Hcg criteria is reached

Blood tests and scan Hcg Trigger

When criteria for

E2<50 pg/ml
trigger is fulfilled
LH<5miu/ml
All follicles<10 mm
 Ultralong Protocol
Gnrh Gnrh Gnrh
Agonist Agonist Agonist Gonadotropins
Depot Depot Depot

1st month 2nd month 3rd month 1 2 3 4 5 6 7 8 9 Till Hcg criteria is reached

Blood tests and scan Hcg Trigger

E2<50 pg/ml When criteria for

LH<5miu/ml trigger is fulfilled
All follicles<10 mm
 GnRH Minidose Protocol
Gnrh Agonist Gonadotropins
Daily
OPU

19 20 21 22 23 24 25 26 27 28 1 2 3 4 5 6 7

Blood tests and scan Hcg Trigger

E2<50 pg/ml When criteria for

LH<5miu/ml trigger is fulfilled
All follicles<10 mm
Stop Protocol
 GnRHa Stop protocol
• Based on the assumption, that after discontinuation of the
GnRH-a the endogenous LH concentrations remain low for 10
to 14 days
• Pituitary recovery and resumption depends on dose and route
of administration
• Paradoxical drop in LH/E2 after stopping agonist
 GnRH Stop Protocol
Gnrh Agonist Gonadotropins
Daily

OPU

19 20 21 22 23 24 25 26 27 28 1 2 3 4 5 6 7

Blood tests and scan Hcg Trigger

E2<50 pg/ml When criteria for

LH<5miu/ml trigger is fulfilled
All follicles<10 mm
Stop GnRH-a protocol
• ADVANTAGES
– more convenience for the patient (fewer injections),
– cost reduction,
– reduced exposure of the developing follicles to the GnRH-a
itself----lessened the suppression of the ovarian
responsiveness to COH
– Flexibility to start Gonadotropin on a suitable day as
compare to flare protocol

• DISADVANTAGES

- risk of premature LH surge

Short/Flare protocol
 SHORT/FLARE UP PROTOCOL
• FLARE- Endogenous FSH & LH produced enhance the stimulatory
effect
• Eliminates excessive ovarian suppression

• Pituitary desensitisation generally achieved in 5 days

• Effective in poor responders

PHYSIOLOGICAL BASIS
Brief initial agonist phase-
FLARE mimics follicular
phase FSH surge

Later- suppression of
premature LH surge
 Short/Flare Protocol
Gnrh Agonist Daily Gonadotropins

OPU

Pretreatment with OC pills 1 2 3 4 5 6 7 8 9 10 11 12 13

Blood tests and scan

Hcg Trigger
E2<50 pg/ml
LH<5miu/ml When criteria for
All follicles<10 mm trigger is fulfilled
ADVANTAGES

Reduces excessive
suppression

Shortens the stimulation

time

Reduced amount of
GnRH-a

Less amount of Gn

Reduces the total cost of

IVF
 Increases
intrafollicular
androgen levels
• GnRH agonist
induced flare
• LH in early
follicular phase
Androgen rich Less fertilization &
environment implantation capacity
• Folliculogenesis affected- • Over aging of
inhibition of meiosis oocytes & Quality of
inhibiting factors
• CEILING THEORY- LH oocytes poor
inhibits GC proliferation &
atresia of less mature
follicles
Increase in follicular progesterone levels

Reduced flexibility

DISADVANTAGES
Micro-dose Flare Protocol
MICRODOSE GnRH-a FLARE PROTOCOL

• OCPs 14-21days

• Small doses of GnRH-a 40µg BD s/c

• Reduced chances of progesterone and

androgen rise in early follicular phase
• Useful in poor responders
• Several investigators have reported an
improved outcome with doses as low as 20-40
mcg of LA twice daily in poor responders
 Micro-Flare Protocol
Gnrh Agonist Daily Gonadotropins

OPU

OCP for 21 days from 2nd day

of cycle
22 23 24
Till Hcg criteria is reached

Blood tests and scan

Hcg Trigger
When criteria for
trigger is fulfilled
E2<50 pg/ml
LH<5miu/ml
All follicles<10 mm
 ULTRA-SHORT PROTOCOL
• GnRH-a is given for only 3 days with flare up
method
• LH is suppressed till mid cycle

• Helps retrieve more oocytes with minimal risk

of premature LH surge
 Short/Flare Protocol
Gnrh Agonist Daily Gonadotropins

OPU

Pretreatment with OC pills 1 2 3 4 5 6 7 8 9 10 11 12 13

Blood tests and scan

Hcg Trigger
E2<50 pg/ml
LH<5miu/ml When criteria for
All follicles<10 mm trigger is fulfilled
Long agonist vs Antagonist
protocol
Long agonist versus Antagonist protocol

There is moderate quality evidence that the use of GnRH antagonist compared with
long-cour se GnRH agonist protocols is associated with a substantial reduction in
OHSS without reducing the likelihood of achieving live birth
Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD001750.
 Long agonist versus Antagonist in POR
Study typ protocol Result
e
Prapas, 2013 RCT 362 pts por CPR similar.
1) 162pts-Long agonist More cancellations
2) 168 pts- antagonist but not significant in
Antagonist
Sunkara et al RCT 110 PTS No of oocytes
2014 1) LONG- Naferelin 400 mcg 200 retrieved -long >
mcgfrom 21 day short agonist regimen
Gnd-450 iu after 2 wks , long agonist =
2)Flare- Nafarelin 200mcg from day 2 antagonist regimens .
f/b gnd-450 iu Dur. of stimulation
3)Cetrorelix 0.25 mg fixed protocol and total gnd dose
-long agonist>short
agonist and
antagonist regimens.
The ongoing PR was
8.1% with long and
short agonist
regimens and 16.2%
with the antagonist
regimen
Long versus short protocol
37 RCTs, 3872 women

Included 37 RCTs (3872 women), one ongoing trial, and one trial awaiting
classification.
These trials made nine different comparisons between protocols. Twenty of the RCTs
compared long protocols and short protocols.
Only 19/37 RCTs reported live birth or ongoing pregnancy.

Siristatidis CS et al Cochrane review 2015

 Gonadotrophin-releasing hormone agonist protocols for
pituitary suppression in assisted reproduction (Review)
LIVE BIRTH RATE
LONG VERSUS SHORT PROTOCOL

There was no evidence of a difference in live birth and ongoing pregnancy rates
between the two protocols (odds ratio (OR) 1.30, 95% confidence interval (CI) 0.94
to 1.81; 12 RCTs, n = 976 women, I² = 15%, low quality evidence)
Siristatidis CS, Gibreel A, Basios G, Maheshwari A, Bhattacharya S.
Cochrane Database of Systematic Reviews 2015, Issue 11. Art. No.: CD006919.
 CLINICAL PREGNANCY RATE
CONTD...

There was evidence of an increase in clinical pregnancy rate (OR 1.50, 95% CI 1.18 to
1.92; 20 RCTs, n = 1643 women, I² = 27%, moderate quality evidence) in the long
protocol group when compared with the short protocol group (Analysis 1.2; Figure 6).
The subgroup of studies including poor responders only also showed a difference in
clinical pregnancy rates (OR 3.12, 95% CI 1.39 to 7.02; four RCTs, n = 232 women, I² =
0%, moderate quality evidence), favouring the long protocol
• No. Of oocytes retreived- Significant difference in
favor of long protocol(six studies, but lot of
heterogenity)
• Number of ampoules of gonadotrophins- significant
differance in favor of long protocol
• Cycle cancellation rate- No difference
SHORT VERSUS ANTAGONIST
CYCLE
Merviel et al. Reproductive Health (2015) 12:52
• 48 POR patients

48 POR patients

24 patients 24 patients
Micro flare Gnrh antagonist
Leupride acetate Fixed protocol
40 mcg bd Cetrorelix 0.25 mg
Study Typ Protocol Result
e
Demirol RCT 90 PTS No of oocytes retreive were mord
2010 1) Microflare in flare protocol.Implantation rate
2) Antagonist greater in microflare.cpr and
fertilization rate were similar

Sunkara et al RCT 110 PTS No of oocytes retrieved -long >

2014 1) LONG- Naferelin 400 mcg
200 mcgfrom 21 day
Gnd-450 iu after 2 wks
2)Flare- Nafarelin 200mcg from
day 2 f/b gnd-450 iu
3)Cetrorelix 0.25 mg fixed
protocol
short agonist regimen , long
agonist = antagonist regimens .
Dur. of stimulation and total gnd
dose -long agonist>short agonist
and antagonist regimens.
The ongoing PR was 8.1% with
long and short agonist regimens
and 16.2% with the antagonist
regimen
 Gnrh antagonist vs short protocol-meta-analysis of 3 studies-2009

The duration of stimulation (WMD: 0.52 days, 95% CI: 1.48 to þ0.44; fixed effects model)
and the number of ampoules of gonadotropins required (WMD: þ4.11 ampoules, 95% CI:
28.82 to þ37.03) were not significantly different between women down-regulated with a
short agonist protocol and those treated by an antagonist protocol.

However, significantly less COCs were retrieved (WMD: 1.07 COCs, 95% CI: 1.78 to 0.36)
in women who received GnRH antagonists compared with those who received GnRH
agonists.
How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review
and meta-analysis Dimitra Kyrou, M.D., Efstratios M. Kolibianakis, M.D., M.Sc., Ph.D., Christos A. Venetis, M.D.,
M.Sc., Evangelos G. Papanikolaou, M.D., M.Sc., Ph.D., John Bontis, M.D., Ph.D., and Basil C. Tarlatzis, M.D., Ph.D.2009
Gnrh flare vs Antagonist protocol

Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD004379

Gnrh agonist Continued versus
Stop protocol
 Gonadotrophin-releasing hormone agonist protocols for
pituitary suppression in assisted reproduction (Review)
Long continous vs Stop protocol Live birth

There was no evidence of a difference in the number of live birth and ongoing
pregnancies when GnRHa was stopped compared with when it was continued
(OR 0.75, 95% CI 0.42 to 1.33; three RCTs, n = 290 women, I² = 0%, low quality
evidence)

Siristatidis CS, Gibreel A, Basios G, Maheshwari A, Bhattacharya S.

Cochrane Database of Systematic Reviews 2015, Issue 11. Art. No.: CD006919.
Luteal versus Follicular long
protocol
 Gonadotrophin-releasing hormone agonist protocols for
pituitary suppression in assisted reproduction (Review)
Long follicular versus long luteal protocol

Siristatidis CS, Gibreel A, Basios G, Maheshwari A, Bhattacharya S.

Cochrane Database of Systematic Reviews 2015, Issue 11. Art. No.: CD006919.
 Conclusion:
There is no difference in
• Live birth rate
• Clinical pregnancy rate
• No. Of oocytes retreived
• Cycle cancellation rate

Siristatidis CS, Gibreel A, Basios G, Maheshwari A, Bhattacharya S.

Cochrane Database of Systematic Reviews 2015, Issue 11. Art. No.: CD006919.
Ultra-short vs short protocol
 82 PATIENTS Leupride 40
mcg bid was
used in both
protocols
41
ULTRA- SHORT AGONIST- 41
ANTAGONIST MICRO-FLARE

The implantation and clinical pregnancy rates

were similar between the two groups
There was no difference between the mean
number of mature oocytes retrieved in the two
groups.

J Turk Ger Gynecol Assoc. 2010; 11(4): 187–193.

 Protocol of choice

Normo-
PCOS POR Endometriosis
responders
• Antagonist • Microflare • Depot • Antagonist
protocol • Short protocol • Long agonist
• Antagonist • Ultralong
protocol
• Mild
stimulation
• Long agonist
 Conclusion
• Hyper-responders-
Antagonist protocol of choice
(Al- Inany cochranne study 2016)
• Endometriosis, aenomyosis
Ultralong , Long depot
(Alberqueue cochrane review 2015)
Normoresponders
Antagonist= Long agonist> Short agonist protocol
Sirsitadis cochrane review, Al Inany review
Poor Ovarian responders
Inconclusive evidence
Pandian cochrane study 2010,
• Leuprolide has a half life of 90 minutes
whereas nafarelin's half life is 3-4 hours,
triptorelin's half life is 4,2 hours. Leuprolide is
50-80 times, nafarelin 200 times, triptorelin
36-144 times more powerful than the natural
GnRH (2,3).