agonist trigger state of art

1. Gonadotropin-releasing hormone agonist
(GnRHa) trigger State of the art

3. objectives
 Luteal phase physiology, a comparison between HCG trigger
and GnRHa trigger
 Safety and efficacy of GnRHa trigger
 Limitations of GnRHa trigger
 GnRH trigger and the optimal luteal phase support
 GnRHa trigger and segmentation (freeze all)
 Conclusions

4. Luteal phase physiology,
a comparison between HCG trigger and GnRHa trigger

5. A. Stimulated IVF/ICSI cycles triggered with HCG
 HCG binds to the same receptor as LH
 HCG (5000–6500-10,000 IU) has been administered
successfully for many decades as a substitute for the
endogenous LH surge to induce final oocyte
maturation

6. In controlled ovarian stimulation (COS) cycles
The early luteal supra-physiological steroid level
(progesterone (P) and estradiol (E)) induces a negative
feedback on the endogenous LH secretion by the
pituitary, resulting in low LH levels and a subsequent
disruption of the luteal phase, necessitating luteal phase
support (LPS),

7. When comparing the luteal steroid level of the natural
cycle with that of the HCG triggered stimulated cycle
significant differences exist due to the significantly
longer half-life of hCG as compared to LH

8. As the endogenous LH level of the HCG triggered cycle
is significantly reduced, the function of the corpus
luteum (CL) relies completely on the exogenously
administered LH activity in the form of HCG

9. At the time of implantation,
HCG levels deriving from the ovulation trigger, start
decreasing, which affects the endogenous P
production from the CL negatively. Thus, from
this point, onwards until the increase in endogenous
HCG production from an implanting embryo
exogenous P supplementation is mandatory

10. B-Stimulated IVF/ICSI cycles triggered with GnRHa
GnRHa trigger is only possible in GnRH antagonist co-
treated IVF/ICSI cycles,
GnRHa has an affinity coefficient two to Fifty times higher
than that of the endogenous GnRH for the GnRH
receptor

11. In a GnRH antagonist co-treated cycle a bolus of
GnRHa will displace the GnRH antagonist from the
receptor, inducing a flare-up of gonadotrophins (LH
and FSH), which activates oocyte maturation

12. Unlike the natural mid-cycle surge of gonadotropins
which has three phases, lasting for 48 h, the GnRHa
induced surge consists of two phases, only, with a
short duration of 24–36 h

13. This results in a reduced total amount of circulating LH
(and FSH) released after GnRHa trigger compared to
the natural cycle However, the concomitant release
of FSH induced by GnRHa trigger – unlike hCG
trigger –may add further physiological benefits as
recently reviewed

14. Indeed previous studies reported a higher maturity rate
of oocytes and a lower incidence of empty follicle
syndrome after GnRHa trigger As for HCG triggered
cycles,

15. early luteal phase supra-physiological levels of P and E
produced by multiple CL induce a negative feedback
on the endogenous LH secretion, which after the
initial flare-up will result in a CL demise and a short
luteal

16. a possible direct luteolytic action of GnRHa has
previously been proposed, and data from in vitro
studies suggested that GnRHa is able to initiate the
apoptosis cascade in granulosa cells

17. Due to significant differences in circulating LH activity
during the early luteal phase induced by GnRHa
trigger compared to HCG trigger and the natural
cycle, an intensive or modified LPS policy is
mandatory to obtain optimal pregnancy rates after
GnRHa trigger and fresh transfer

18. Safety and efficacy of GnRHa trigger
 OHSS prevention
 Oocyte maturation
 Implantation affection
 Patient tolerance

19. GnRHa trigger effectively reduces OHSS rates (shorter half-
life of the endogenously secreted LH compared to the
long acting LH activity after an HCG trigger –
approximately 33 h versus 6–10 days respectively)
which results in a defective CL formation and a decrease
in the release of vasoactive peptides such as VEGF
OHSS PREVENTION

20. Higher oocyte maturity rate in Gnrha triggered IVF
cycles has been reported
The physiological background for this finding has been
suggested to be a result of EGF-like peptides which
have been shown to be potent mediators of oocyte
maturation.
Oocyte maturation

21. Good quality oocytes and embryos are obtained from
GnRHa trigger as seen in the reproductive outcomes
of oocyte donation cycles which are now solely
performed using GnRHa trigger from either fresh or
segmented frozen thawed cycles

22. In contrast, earlier studies claimed a deleterious impact on early
embryo development when a bolus of HCG was used for trigger,
especially in recombinant FSH (rFSH) stimulated cycles
This hypothesis was based on an exaggerated intra-follicular shift
in steroids from androgens and E to P, mediated by high
concentrations of HCG in theca cells
Implantation affection

23. Some studies reported a potential negative impact of hCG on
endometrial receptivity The average level of serum hCG in hCG
triggered cycles is approximately 120 IU/l during the early luteal
phase, slowly decreasing to 4–6 IU/l on day 6 This supra-
physiological LH activity level during the early luteal phase might
hamper successful implantation due to interference with specific
actions mediated by hyperglycosylated hCG (H-hCG) produced by
the implanting embryo

24. after GnRHa trigger, the early to mid-luteal phase
steroid level appears to be closer to the
physiological range Moreover, GnRH receptors are
expressed in extra-pituitary tissue including the
endometrium, and the use of GnRH antagonists
results in inhibitory intracellular events on
transforming growth factor-b (TGF-B) pathway, inter-
leukin-1b (IL-1b) and vascular endothelial growth

25. In this aspect, earlier studies reported that the use of a
mid-luteal bolus of GnRHa resulted in a significant
improvement in implantation rates

26. Thus, it was hypothesized that a mid-luteal bolus of
GnRHa might displace the GnRH antagonist bound
to the endometrial GnRH receptor, activating the
down-regulated receptors and resulting in the up-
regulation of pro-implantation factors

27. Patient tolerance
Regarding tolerance to treatment, it has been
described that hCG trigger results in a significant
increase in fluid retention and ovarian volume, which
causes significantly more early luteal phase
abdominal pain, bloating and discomfort.

28. In contrast, GnRHa trigger is associated with less
ascites accumulation in the cul de sac reduced
ovarian volume and reduced discomfort and, thus, a
higher patient convenience

29. Limitations of GnRHa trigger

30. The luteal phase after GnRHa trigger is impaired, thus
it is crucial to modify the LPS after fresh transfer.
The mean mid-luteal LH level of the natural cycle is
approximately 6 IU/L whereas it is approximately 1.5
IU/L after GnRHa trigger

31. This level is insufficient to support the function of the
CL, leading to CL demise, implantation failure or
early pregnancy loss in fresh ET cycles using a
standard LPS.

32. After the introduction of the GnRHa trigger, two main policies
have been suggested.
One strategy is to administer exogenous steroid support, in terms
of P and E.
Another strategy is to stimulate the endogenous steroid support
by adding LH activity either in the form of a small bolus of HCG
after the initial trigger or by adding daily recombinant LH
injections during the luteal phase, aiming at rescuing the CL
function

33. GnRH trigger and the optimal luteal phase
support

34. A recent Cochrane meta-analysis concluded that
GnRHa trigger for final oocyte maturation should be
restricted to segmentation cycles, oocyte donation
cycles, and fertility preservation cycles

35. However, this conclusion was flawed due to the fact
that the studies included in the meta-analysis used
different types of LPS,or no LPS at all after GnRHa
trigger

36. Indeed, the LPS in GnRHa trigger is the crucial variable
which affects the reproductive outcome and not the
use of the GnRHa trigger per se .

37. Interestingly, despite the above mentioned conclusion, the
Cochrane review included a Forest plot in which a stratification
for LPS with and without LH activity was performed.
Importantly, in this analysis there was no significant difference in
ongoing pregnancy rates between GnRHa with modified LPS
and HCG trigger

38. Management of the luteal phase in GnRHa
triggered fresh transfer cycles

39. the physiological advantage of the GnRHa trigger
concept is the complete dissociation between the
trigger and the early LPS which allows for
individualization of the luteal phase; a concept
different from HCG trigger in which hCG apart from
inducing oocyte maturation will also cover the early
luteal LH activity deficiency.

40. Following the initial research, the exploration of the
most optimal modified LPS after GnRHa trigger
successfully resulted in a non significant difference
in reproductive outcomes between GnRHa trigger
and hCG trigger, however, with an almost elimination
of OHSS.

41. This fact urged the Copenhagen GnRH Agonist
Triggering Workshop Group to suggest a
“time for a change in practice” in trigger policies in
Assisted Reproduction Techniques

42. A. Corpus luteum rescue: endogenous steroid production
The use of HCG as a surrogate for LH activity to promote the
endogenous steroid production by the remnant corpora lutea
was recently referred as “The European approach” Over
the years, the main effort has been to find the minimum HCG
dose needed to rescue the corpora lutea until the HCG
produced by the implanting embryo covers the luteal LH
activity deficiency without increasing the risk of OHSS

43. GnRHa trigger and early luteal phase support with low
dose HCG combined with a standard luteal phase
support: the European concept
It is physiologically plausible that a refractory period
may occur after the initial GnRHa trigger, during
which human granulosa cells do not respond to
subsequent LH-like exogenous stimulation.

44. Individualized modified luteal phase support according to ovarian response
fine-tuning was necessary to find the minimal dose of
hCG administered to secure optimal pregnancy rates
without increasing the OHSS incidence in the OHSS
low-risk group.

45. B-GnRHa trigger and luteal phase support with recombinant LH (rLH) combined
with a standard luteal phase support
The advantage of the use of recombinant LH (rLH) over
HCG for LPS after GnRHa trigger is the significantly
shorter half-life of rLH, which would potentially
reduce the risk of OHSS.

46. C-GnRHa and hCG trigger (Dual trigger) combined with a
standard luteal phase support
A significantly higher pregnancy rate and live-birth rate
was reported in the dual trigger group without an
increased risk of OHSS development in different
studies

47. GnRHa trigger and exogenous steroid support
Another LPS policy after GnRHa trigger was recently described as “The
American approach”
This approach is based on the luteal phase regimen used for oocyte
recipients who are treated with intensive LPS using intramuscular P
and transdermal or oral E after the transfer of donated oocytes.
Thus, this concept disregards CL function and relies solely on
exogenous LPS after GnRHa trigger

48. Once pregnancy is established, the American approach
recommends that intensive steroid support should be
continued until at least seven weeks of gestation and in most
cases 10 weeks of gestation, well beyond the luteo-placental
shift

49. Interestingly, the Engmann group evaluated factors predicting
the probability of successful outcome after GnRHa trigger when
the American approach was used. They subsequently reported
that a peak serum E2 levels above 4.000 pg/mL and serum LH
levels above 3,5 IU/L on the day of trigger were the most
important predictive factors for success in terms of pregnancy
rates

50. GnRHa trigger and the “Exogenous steroid free” luteal
phase
To avoid the inconvenience of either vaginal or intramuscular P
administration,
P levels achieved by this strategy of exogenous LH activity (hCG
or LH) administration could induce higher intrauterine P levels
and a more steady penetration to the endometrium than those
achieved with exogenous P regimens.

51. GnRHa trigger and segmentation (freeze all)

52. The segmentation (freeze all) policy was recently
proposed for all GnRH triggered IVF cycles
Although authors claim higher pregnancy and live birth
rates in frozen-thaw transfer cycles compared to
fresh transfer cycles with an almost elimination of
OHSS
there are concerns regarding segmentation that need
to be addressed.

53. Laboratories worldwide develop fast; however, not all
IVF units have an optimal cryopreservation program,
which is crucial for the success of segmentation.

54. In addition, a higher early pregnancy loss rate related
to frozen-thawed cycles has been reported as well as
ahigher risk of epigenetic changes Moreover,
religious ,ethical and financial reasons may preclude
a freeze all policy.

55. Finally, the early embryonic stage is a vulnerable time
in terms of epigenetic activity, and additional
manipulations (freeze-thaw)might induce irreversible
changes which only appear during adulthood

56. Thus, a segmentation policy should be adopted with
caution, and results from large long term follow-up
trials in children conceived as a result of frozen-thaw
embryo transfer are mandatory before a “freeze all“
policy can be advised as a first line treatment.

57. However, in OHSS risk patients the immediate benefits
from segmentation already outweigh the known and
unknown risks involved with this strategy

59. GnRHa trigger significantly reduces OHSS, and GnRHa
trigger with modified LPS secures fresh transfer in
the majority of patients with excellent reproductive
outcomes.

60. In OHSS high risk patients GnRHa trigger followed by
segmentation of the cycle will allow oocyte retrieval
with a minimal risk of early onset OHSS and good
reproductive outcomes in subsequent frozen-thaw
cycles.

61. Although the most optimal LPS in GnRHa triggered
fresh transfer cycles is still subject to investigation,
GnRHa trigger is likely to become the future gold
standard trigger concept in IVF.