This document discusses methods for final oocyte maturation in IVF treatment. It notes that human chorionic gonadotropin (HCG) has traditionally been used but gonadotropin-releasing hormone (GnRH) agonists can also be used to reduce the risk of ovarian hyperstimulation syndrome (OHSS). While GnRH agonists prevent OHSS, they are associated with lower pregnancy rates. However, combining a GnRH agonist trigger with low-dose HCG or vitrification of all embryos may optimize pregnancy rates while still preventing OHSS. The optimal luteal phase support when using a GnRH agonist trigger remains an area of ongoing research.

1. FINAL OOCYTE
MATURATION:
HCG VS GNRH
AGONIST
By
Dr. Abayomi Ajayi
by
Dr. Abayomi Ajayiby
Dr. Abayomi Ajayi

2. Significant advancement since Louise Brown was born 40 years ago.
Unstimulated cycle.

3. The introduction of COS using gonadotropins for multiple
follicular development, arguably the single most effective
measure ever taken for improving ART outcome 1,2.

4. Porter et al 1984 reported the introduction of GnRH agonist for
pituitary suppression to prevent spontaneous LH surge,
reducing cycle cancellation rate from about 35% 2.

5. The GnRH agonist long protocol was the gold standard of IVF since
the 80’s 4.
The attendant risk of OHSS and the not too convincing experience
with short, ultra short, flare, microflare and stop protocols in poor
responders pointed to the need for alternative methods of pituitary
suppression.

6. Itskovitz Eldor 5 reported the 1st established using the antagonist
protocol in 1998.
Though greeted with initial suspicion, the introduction of GnRH
antagonist for pituitary suppression in COS has become so
widespread in usage due to better knowledge and experience 6,7.

7. Initial concerns centred around: when to initiate it’s administration
7,8,11,12 single or multiple dosage 9 , whether to supplement the
follicular phase with LH 9, whether or not to increase the
gonadotropin dosage at antagonist initiation 10, as well as use of
OCP pre treatment 13

8. Traditionally, final oocyte maturation was done with HCG since it
shares the same α subunit and 81% of the amino acid residues with
the β in Of LH. Bind to the same receptors13

9. With the use of GnRH antagonist, it became possible to use GnRH
agonist for final oocyte maturation 11,14

10. The use of GnRH agonist to replace HCG is probably the only
proven method to reduce/prevent severe OHSS in high-risk
patients. As there is less release of EGF 2,15

11. Prevention of OHSS with use of GnRH agonist is however
associated with reduction in on-going pregnancy/ live birth rate
and increased miscarriage rates in fresh autologous cycles. 16,17,18,19

12. The reason for the poor pregnancy rate was initially a source of
controversy
1.Egg quality
2.Endometrial receptivity
Cochrane study 2011: 11 randomized control trials 1055 women (Yousef
M.A et al 2016)
8 studies – fresh autologous
3 studies - donor recipient cycles
↓ live birth rates in fresh autologous cycles
No difference in live birth rates in donor recipient cycles

13. Experience with donors have shown no significant difference in
number of retrieved oocytes, meta phase 11 oocytes, fertilization
rates and more importantly no difference in pregnancy and
implantation rates in the two groups of randomized recipients 22.
There was a significant difference in luteal phase length in the
donors (4.16 Vs 13.6 days) and in the rates of OHSS: None in the
agonist group33

14. These point to the current thinking that there is a luteal phase
deficiency in cycles where GnRH agonist is used as trigger 18,23.
The LH surge induced by GnRH agonist has been found not to be
identical to that which occurs in the natural cycle

25. Prediction of the risk of OHSS was then used to classify patients into
a)Low risk
b)Moderate risk
c)High risk
Aljawoan et al 25 reported that patients having with an antagonist
protocol triggered with more than 18 follicles or an estradiol
concentration > 5000pg|ml have a sensitivity of 83% with a
specificity of 84% for developing OHSS

26. Based on the low and high risk, the idea of personalized luteal
support was introduced: bid to optimize pregnancy rates and still
prevent OHSS
i.Low risk : < 14
ii.Moderate risk : 15-25
iii.High risk : >25

27. i. Use of low dose HCG : 1500IU
a) OPU day
b) 5 days after OPU
(2) Dual trigger; 1000/1500IU HCG + GnRHa (Mahajan N. et al 2016,
griffin 2017)
ii. Modified intensive luteal support : injectables + virginal
tablets/pessaries
iii. Cycle segmentation : freeze

29. Our aim as ART practitioners is to maximize the chance of the birth
of healthy baby/babies with minimum risk to the mother
OHSS is an iatrogenic and potentially fatal disorder that can
complicate ART due to multifollicular development that follows
COH
The introduction of GnRHa for trigger is the most effective way of
reducing OHSS

30. The problem is the lower on-going pregnancy/live birth rates associated
with the use of GnRHa trigger.
Recent experience show similar ongoing pregnancy rate when GnRHa
trigger is combined with low dose HCG compared to the
conventional dose of HCG (5,000-10,000) with much reduction in
OHSS rate.
Advancement in embryo cryopreservation especially Vitrification has
made it possible to “freeze” all thereby separate IVF from ET.
The ET can then be done in a natural or hormone replacement cycle.

31. Initial reports point to better pregnancy rates and reduced
OHSS as this circumvents the defficient luteal phase usually
associated with GnRHa trigger.
This might just be the gateway to the much awaited OHSS-
free clinic.
The search for the most optimal LPS for use in GnRHa trigger
is however on-going

32. It is now possible to routinely use GnRHa to replace HCG for
triggering ovulation in donor cycles
In regular ART, it can be used in case of OHSS threat
But since the optimal LPS in such a scenario is still controversial,
combination with cryopreservation(preferably Vitrification)
gives excellent results