The administration of human chorionic gonadotropin (hCG) for final oocyte maturation is an
accepted practice in in vitro fertilization (IVF) treatments. However, in high-responder
patients, it increases the risk of ovarian hyperstimulation syndrome (OHSS) due to its longer
half-life compared to the naturally secreted Luteinizing Hormone (LH) as well as increased
synthesis and secretion of vasoactive substances. Gonadotropin releasing hormone agonist
(GnRHa) triggering, as an alternative to hCG triggering for final oocyte maturation in
antagonist protocols, enables substantial decrease of this complication in high responders.
However, the main disadvantage of using GnRHa for induction of oocyte maturation is
significantly lower pregnancy rates compared with hCG triggering. The primary hypothesis is
luteal insufficiency due to increased luteolysis. In order to preserve a high pregnancy rates
after GnRHa triggering, several approaches for luteal-phase rescue have been investigated,
including low-dose hCG boluses, intensive P and E2 supplementation, and a ''freeze-all''
approach with frozen-thawed embryo transfers at subsequent cycles. Several previous case
reports have demonstrated that inadvertent administration of GnRH agonists during the luteal
phase doesn't harm pregnancies achieved through IVF and moreover might even support
implantation.
The mechanism by which GnRH agonist improve implantation rates is unknown. Several hypotheses
were suggested including promoting corpus luteum maintenance by secretion of LH from
pituitary gonadotropin cells, a direct effect on the endometrium and the embryo through GnRH
receptors and regulatory effect on hCG secretion by the placenta at the preimplantation
phase. In 2004, Tesarik et al, conducted a prospective randomized trial including 276 oocyte
recipients. Oocytes from each individual donor were divided to two recipients, one of whom
received a single dose of a GnRH agonist (0.1 mg triptorelin) 3 days after embryo transfer
and the other received placebo at the same time. Of note, the endometrium was prepared by
oral estradiol valerate treatment following by vaginal progesterone (Utrogestan) as widely
accepted. The results demonstrated significantly higher implantation and live birth rate in
the group treated with GnRH agonist compared to the control group with significantly higher
twin pregnancy rates while no difference in miscarriage and abortion rates was observed
between the two study groups. The authors concluded that GnRH agonist administration at the
time of implantation has a positive effect on embryo developmental potential. It's important
to note that this study evaluated the effect of a single dose of GnRH agonist in addition to
a conventional luteal support in a population of oocyte recipients that are not at risk for
OHSS and tend to have higher implantation and pregnancy rates also without GnRH agonist
supplementation. A study by Pirard et al. was the first to evaluate the administration of
GnRH agonist alone for luteal support compared to compared to the standard treatment with
vaginal progesterone. The study group included 35 patients who were treated with antagonist
protocol. Intranasal GnRH agonist (Buserilin) was given for final oocyte maturation and
luteal support was achieved by administration of intranasal GnRH agonist for up to 16 days
after the oocytes retrieval. The control group included 18 women treated with a long GnRH
protocol for pituitary suppression. Final oocytes maturation was achieved by administration
of 10000 units of hCG and vaginal progesterone was used for luteal support. Implantation and
pregnancy rates were higher among the study group compared to the control group however, no
statistical significance was achieved. Progesterone levels on day 5 were significantly lower
while LH levels were significantly higher during all the luteal phase in the study group
compared to the control group. The authors concluded that intranasal administration of
Buserelin is as effective as standard progesterone treatment for providing luteal phase
support in IVF/ICSI antagonist protocols. To our knowledge, the only study, so far that
evaluated the efficacy of GnRH agonist treatment for luteal support in high responder
patients with increased risk for OHSS was conducted by Bar-Hava et al. It included 46 women
at risk for OHSS that were treated with GnRH antagonist protocol for pituitary suppression.
The final oocyte maturation was achieved by GnRH agonist (Triptorelin) and a daily intranasal
GnRH agonist (Nafarelin 200 micrograms twice daily) was administered for luteal support for
two weeks following the oocytes retrieval. 52% clinical pregnancy rates were obtained while
no cases od OHSS or other substantial adverse effects were observed.
The main disadvantage of the study is the lack of a comparison to a control group. To the
best of our knowledge, no study so far compared administration of GnRH agonist at the same
protocol described by Bar-Hava et al. to intensive estrogen and progesterone treatment for
luteal support among women treated with GnRH antagonist protocol and GnRH agonist triggering
for final oocytes maturation. A randomized controlled trial in an infertility population at
increased risk for OHSS, will enable us to evaluate the efficacy of GnRH agonist treatment
compared to standard treatment for luteal support and to determine the best treatment
approach in the high responder population undergoing a fresh embryo transfer new approach
undergoing a fresh embryo transfer following GnRHa triggering.
The aim of the current study isto compare the efficacy of GnRH agonist versus estrogen and
progesterone supplementation for luteal support in high responders undergoing fresh embryo
transfer following GnRHa triggering.