Presentation given in 2017. Management of infertility using assisted reproductive technologies. What is the role of antagonist in IUI and IVF - tips and tricks to optimize its use.

1. Dr. Anuradha Katragadda
ANU TEST TUBE BABY CENTER

2. GnRH – antagonist. In IUI & IVF
1. GnRH-antagonist protocols when compared to GnRH-agonist
protocols for IVF
a) Higher success rates
b) Lowered risk of OHSS
c) All of the above
2. GnRH-antagonist in IUI is recommended
a) Routinely to improve success rates
b) Not safe to use antagonist to post pone IUI
c) Can be used to reduce risk of OHSS

4. The ‘I - IVF Baby’ (early days of IVF)
Birth of Louis Brown – July, 1978
‘Steptoe & Edwards’, the pioneers
of In-Vitro-Fertilization (IVF)
Result of a single oocyte
retrieved in a natural cycle laparoscopically
Performed for tubal factor

6. Time-line of major Mile Stones
Initial experience with unstimulated cycles
- Yielded on average 0.7 Oocytes / retrieval
- Overall PR of 6 % / initiated cycle
Stimulated IVF cycles with HMG
- Extensively studied at Jone’s Institute (1982)
- 1980 – 83;
- Recovery of 2.1 – 2.6 Oocytes / retrieval
- PR 23.5 – 30 %

7. Revolution / Evolution –
Ovarian Stimulation Drugs
Ovarian stimulation
An integral part of ART
Each phase had -
Own ‘gold standard’
stimulation
A large armamentarium of
pharmaceutical agents
To utilise in treatment
protocols
The initial regimens:
clomiphene citrate.
Urinary gonadotropins were later
added to the ovulation induction
regimen alone or in combination with
clomiphene citrate.
In the late 1980s- early 1990s:
addition of a GnRH agonist to achieve
pituitary modulation.
1990s-
Development of Recombinant
Gonadotrophins, GnRH antagonists.

8. Conventional IVF (GnRH –
analogue cycles)
Prevalent problem
- 20 % of IVF cycles cancelled;
- Premature LH surge & ovulation
Pituitary desensitization
- Administration of GnRH-a (1984)
- Incidence of premature ovulation 2 %
- However, raise in incidence of potentially ‘life-
threatening’ OHSS (Nugent et al, 2000)
GnRH – antagonist (1990’s)
-More friendly protocol

9. ‘WHY-CONVENTIONAL PROTOCOLS’
(to tackle premature LH Surge)
Gonadotropins used to stimulate follicle growth
1
Stimulation of many follicles results in higher E2 levels
2
LH surge occurs before complete follicle maturation
3
Developmental arrest of oocytes and cycle cancellation
4

10. Majority of
RCTS clearly
show that -
Combination of
exogeneous gonadotropin
+ GnRH-a
Associated with
increased PRS as
compared to
use of Gonadotropins
with out a GnRH-a

12. GnRH-agonist protocol

13. Era of GnRH-agonist
dominant IVF cycles
• Prolonged treatment
• More no. of injections
• Occurrence of side-effects
• Extended widening of FSH window
no. of mature follicles &
retrieved oocytes
• ed risk of OHSS

14. ‘Friendly-IVF’ – GnRH-ant.
protocol
• dose related
inhibition of
Gonadotropin
release
Causes
immediate
&

15. ‘competitive occupancy of GnRH receptors in pituitary’

17. Third generation decapeptide
GnRH agonist with amino acid modifications at
1,2,3,6 & 10
2 Compounds 2 Regimens
Cetrorelix Flexible
Ganirelix Fixed
GnRH ANTAGONISTS

19. van Loenen AC, et al. Semin Reprod Med. 2002 Nov;20(4):349-64.
GnRH Agonist versus Antagonist

20. Agonist Antagonist
LH Suppression Not immediate Immediate & reversible
Flare up effect on
pituitary hormone
Yes No
Risk of Ovarian Cyst Present Absent
OHSS risk High Low
Treatment duration Long Short & Simple
Gonadotropin Usage More Significant less
Estrogen withdrawal
symptoms (Hot flushes,
loss of libido & Weight
gain)
Present Absent
LPS requirement ++++++ +++
Differences in Agonist &
Antagonist protocols
Expert Opin. Drug Metab. Toxicol. (2009) 5(10)

21. Controlled Ovarian Stimulation
Protocols Using GnRH Antagonists
GnRH antagonists induce a rapid decrease in LH
and FSH, preventing and interrupting LH surges
Their properties do not require a desensitization
period, and this allows their use in the late
follicular phase.
GnRH antagonists could replace GnRH agonists in
controlled ovarian stimulation without their side-
effects and their long desensitization period.
Hum Reprod Update. 2002 May-Jun;8(3):279-90.

23. COS - Complications
Multiple Pregnancy
Increased incidence of
heterotopic pregnancies
OHSS

24. ‘ Loss of control over COH ’
 Only after overstimulated ovaries
‘ exposed to hCG inj ’
OHSS
C U L P R I T
HMG HCG

25. Ovarian Hyperstimulation
An iatrogenic complication
Significant increase globally
Incidence of moderate cases ≈ 5 %
Incidence of cases requiring admission
hospitalization ≈ 2 %
Devastating consequence of OHSS is a serious
threat to life –3 maternal deaths 100,000

26. OHSS - Future
Design individualized treatment
protocols
In-Vitro maturation of oocytes
Artificial ovary
‘ Mild ’ stimulation for IVF
Single embryo transfer (SET)

28. Segmentation of IVF
OHSS can be ‘erased’ by applying ovarian stimulation
using a combination of GnRH-antagonist with
GnRH-agonist trigger
- freeze all

29. Agonist - Trigger
Possibility of luteal phase
defect Reduced pregnancy
rates
1.Rescue of luteal phase
2.‘Freeze all’ – a safe
alternative

30. The Patient-friendly Protocol
Segmentation of IVF –
- Freeze-all &
Frozen embryo cycle
‘The balance between the desire for
pregnancy
and patient’s safety is a top priority’.

34. Is antagon protocol-
a universal protocol
NO-ONE-SIZE FITS ALL

35. Antagonists -Treatment
Strategies
First-line treatment:
Patients undergoing first-line controlled
ov. Stimulation
PCOS – High risk of OHSS
More patient friendly protocol
Reproductive Biology and Endocrinology201311:20

36. Antagonists in IVF –
‘where-else’
In cycle with increased risk of OHSS –
continuation of Antagonist after Oocyte
Recovery
Poor ovarian reserve
Oocyte donors
Fertility preservation

37. Combines benefit
of stimulatory
effect of
microdose flare on
endogenous FSH
with
benefit of immediate
suppression of
GnRH-antagonist
Poor
responders –
‘the agonist-
antagonist
protocol’

38. Fertility preservation
Conventional protocol
May cause significant delay of cancer
treatment
‘Random – start – cos’
Stimulation - on - presentation
Estrogen sensitive malignancy
(i.e. endometrial or ER positive breast ca)
Letrozole 2.5 – 10 mg depending on E2 levels
started with stimulation until trigger

39. Patient Populations Benefiting From
GnRH Antagonist Protocols
Patients undergoing first-line controlled ovarian stimulation
Patients who have not responded to other controlled ovarian
stimulation regimens, including those with gonadotropin-releasing
hormone agonist
Patients with a poor prognosis
Oocyte donors
Patients at risk for ovarian hyperstimulation syndrome
Patients with polycystic ovarian syndrome
Fertility preservation
Reproductive Biology and Endocrinology201311:20

40. GnRH – ant. In IUI
IUI – Ist line treatment
Rationale –
Increase no. of fertilizable gametes
Perfectly timed insemination
Various therapeutic approaches –
Different ov. Stimulation protocols
Double insemination

41. Factors influencing IUI
success
Appearance of premature LH peaks
Significantly reduce possibility of
success
Spontaneous ovulation
Range from 24 – 35 % of initiated
cycles

42. GnRH-analogues in IUI
(To avoid premature luteinization)
GnRH-a is not recommended
Prolonged adminstration of injection
Risk of excessive follicular stimulation and
OHSS
Higher cost and
inconvenience
GnRH-antagonists –
Deep and immediate suppression
More pronounced for LH than for FSH

43. i. Posssibility of
improving
flexibility and
reducing
treatment
cancellation rate
ii. Allows
Gonadotrophin
stimulation to be
extended
Advantages
of inhibiting
LH peak –
GnRH
antagonist

46. Clinical PR higher in
multifollicular cycles
in comparison to
monofollicular
cycles
Most important
determinant is
perfect timing of
insemination in
relation to
Ovulatory trigger
(44 – 48 hrs) &
Semen preparation
(2 – 3 hrs)
Impact of
GnRH-
antagonist
addition on PR
in IUI with
Gonadotrophin
stimulated
cycles

47. GnRH-antagonist – IUI –
planning ahead
To avoid weekend
inseminations
For logistical
reasons
Reducing
overload on
hospital
emergency
team
GnRH antagonist –
Timing ovulation for IUI
Allows Gonadotrophin
stimulation to be
extended –
Enables appropriate
development of
more than 1 follicle

48. Expect
unexpected
To avoid
premature
luteinisation &
improve
gestation
rates
‘Rescue IVF’ – IUI
converted to IVF
Cycle cancellation
‘Rescue IVF’
Management of multifollicular recruitment

49. ‘Rescue - IVF’
• Conversion of high response
Gonadotrophin IUI cycles to – IVF
• To reduce incidence of multiple
pregnancy and OHSS
• Reduces emotional stress
• IUI – converted to – DIPI

52. Conclusions
Shorter and patient friendly
OHSS free clinic – segmentation of IVF
Individualise protocols
Fertility preservation – ‘softer protocol’
Random – start - cos

53. conclusions
 Addition of GnRH – antagonist to gonadotrophin
stimulated IUI cycles – higher PR in
multifollicular cycles compared to
monofollicular cycles
 Routine use of GnRH-antagonist in COS – IUI
protocols is not indicated
 GnRH-antagonist treatment could allow flexible
timing of HCG injection and insemination
 Decreases the need of extensive cycle monitoring
and avoiding IUI during weekends
 Role of GnRH-antagonist in preventing OHSS in
COS-IUI is worth considering

54. GnRH – antagonist. In IUI & IVF
1. GnRH-antagonist protocols when compared to GnRH-agonist
protocols for IVF
a) Higher success rates
b) Lowered risk of OHSS
c) All of the above
2. GnRH-antagonist in IUI is recommended
a) Routinely to improve success rates
b) Not safe to use antagonist to post pone IUI
c) Can be used to reduce risk of OHSS