Gonadotropin-releasing hormone agonist ovulation trigger—beyond OHSS prevention


REVIEW ARTICLE

Gonadotropin-releasing hormone agonist ovulation trigger—beyond
OHSS prevention

Juan Carlos Castilloa, Thor Haahrb,c, Mar�ıa Mart�ınez-Moyaa and Peter Humaidanb,c

aDepartment of Human Assisted Reproduction, Instituto Bernabeu, Alicante, Spain; bDepartment of Clinical Medicine, Aarhus University,
Aarhus, Denmark; cThe Fertility Clinic Skive, Skive Regional Hospital, Skive, Denmark

ABSTRACT
In this review the advantages of the gonadotropin-releasing hormone agonist (GnRHa) trigger are dis-
cussed beyond those immediately associated with ovarian hyperstimulation syndrome (OHSS) preven-
tion. The GnRHa trigger concept has sparked the development of novel protocols, enriching the
assisted reproductive technology (ART) armamentarium for the benefit of present and future patients.
Thus, GnRHa trigger already has a pivotal role, not only for the standard in vitro fertilisation (IVF)
patient, but also for patient groups like oocyte donors, cancer patients, patients with poor ovarian
reserve, and patients with immature oocyte syndrome and empty follicle syndrome. Herein, we discuss
the importance of the GnRHa-elicited midcycle FSH surge and the potential improvement in oocyte
yield and embryo competence.

ARTICLE HISTORY
Received 1 November 2019
Revised 11 February 2020
Accepted 27 February 2020

KEYWORDS
Cancer; GnRH trigger; hCG;
IVF; oocyte donation;
ovulation trigger

GnRHa trigger—improving oocyte yield and
embryo competence?

In assisted reproductive technology (ART), hCG has been
extensively used as a surrogate for the midcycle luteinizing
hormone (LH). Due to its biochemical components and simi-
lar biological dynamics of LH, hCG binds to and activates the
same receptor as LH, the LH/hCG receptor, thus ensuring
excellent exposure of the follicle to LH activity. In contrast,
when hCG is used for ovulation trigger there is a complete
lack of the midcycle FSH surge and activity as seen during
the natural midcycle surge of gonadotrophins (1). Until
recently, clinicians have been relying solely on LH activity-
dependent triggering of final oocyte maturation and, thus,
have taken it for granted that the natural midcycle FSH surge
was biologically redundant. However, since the early days of
comparisons between gonadotropin-releasing hormone
agonist (GnRHa) trigger and hCG trigger in in vitro fertilisa-
tion (IVF), studies reported the retrieval of more metaphase II
(MII) oocytes and embryos after GnRHa trigger (2–4). Thus,
Kol and Humaidan in 2010 questioned this paradigm, sug-
gesting that the complex process of final follicular matur-
ation and ovulation in IVF cycles might benefit from the
synchronised interaction of both LH and FSH activity (5).
Although the exact role of the FSH midcycle surge is not
fully understood, it is known to: 1) promote nuclear oocyte
maturation (6); 2) favour cumulus–oocyte communication,
enhancing the network of gap junctions within the cumulu-
s–oocyte complex (7); 3) stimulate cumulus expansion (8);

and 4) favour the release of proteolytic enzymes involved in
ovulation (plasmin) (9).

As observed previously, the surge of gonadotrophins eli-
cited by a bolus of GnRHa differs from that of the natural
midcycle of gonadotrophins in duration and profile. It has
also been shown that the elicited flare of LH as well as FSH
resembles the natural midcycle surge of gonadotrophins and
was found to effectively stimulate final oocyte maturation
and ovulation (10), leading to the development of compe-
tent embryos as recently demonstrated in PGT-A cycles (11).
Moreover, studies in oocyte donors (12) and oncologic fertil-
ity-preservation patients (13,14) demonstrated a significant
increase in MII oocytes and the number of good-quality
embryos in GnRHa-triggered cycles as compared with hCG-
triggered cycles. Nonetheless, it is worth noticing that others
have not corroborated these findings (15–17).

Based on the previous observations, Lamb and co-workers
explored the possible benefits of adding FSH to the hCG trig-
ger bolus in a randomised placebo-controlled trial in a total
of 188 IVF cycles (18). Thus, apart from the hCG trigger
bolus, a total of 95 patients received 450 IU of FSH, whereas
the remaining 93 patients received a placebo. There were
higher retrieval rates (70% versus 57%) as well as fertilisation
rates (63% versus 55%) in the FSH group of patients.
Following the same line, Lin et al. (19) retrospectively ana-
lysed data from 376 normo-responder patients, undergoing
GnRH-antagonist co-treatment, of whom a total of 191
received the so-called ‘dual trigger’ approach (20) compared
with 187 patients receiving hCG only. More MII oocytes were

CONTACT Juan Carlos Castillo jcastillo@institutobernabeu.com Department of Human Assisted Reproduction, Instituto Bernabeu, Av. Albufereta 31,
03016 Alicante, Spain
� 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

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retrieved within the dual trigger group (10.53 versus 8.03),
and live-birth rates per embryo transfer were higher as well
(41% versus 30%), suggesting a beneficial effect of adding
FSH activity at the moment of final follicular maturation in
IVF. More recently, the same group published a similar study
(21), this time focussing on patients with diminished ovarian
reserve (n ¼ 427). The dual trigger group had higher oocyte
fertilisation rates (73.1% versus 58.6%), clinical pregnancy
rates (33.0% versus 20.7%), and live birth rates (26.9% versus
14.5%) when compared with the hCG-only trigger group. Of
note, the pregnancy loss (17.4% versus 37.0%) and embryo
transfer cancellation rate (6.1% versus 15.4%) were lower in
the dual trigger group.

Taken together, the available data show how modifica-
tions in the trigger strategy based on physiology may have
potential benefits for oocyte/embryo competence. At the
time of trigger, it seems that FSH activity enhances a proper
resumption of the meiotic processes of the oocyte, thus add-
ing clinical value by improving oocyte recovery and fertilisa-
tion, and by improved pregnancy rates. Although the specific
mechanisms need further exploration, these findings make
the introduction of an FSH surge in addition to the surge of
LH activity in IVF an attractive option for further improve-
ment of success rates in IVF (5,18).

Immature oocyte syndrome

In the human species, oocytes are created only during a
small period of time during foetal life, after which they arrest
in meiosis I (MI) until exposed to FSH and LH later in life.
Generating embryos during IVF depends on multiple varia-
bles, and one of utmost importance is obtaining MII oocytes
after the ovulation trigger. As noted previously, during ovar-
ian stimulation (OS) for IVF, this process was traditionally
induced by hCG which binds to the LH receptor acting as a
surrogate for the natural midcycle LH surge. In this aspect,
immature oocyte syndrome has been defined as a condition
with more than 25% immature oocytes at retrieval after OS,
despite the correct administration and timing of hCG (22).
The aetiology of this obscure phenomenon is unknown, but
has profound consequences for the couple, including a sig-
nificant reduction in the chance of conceiving during IVF
treatment (23).

Following a recent case report, describing a successful
pregnancy by use of the dual trigger concept (20) in a
patient with a history of immature oocyte syndrome (24), a
retrospective study by Griffin et al. in 2012 reported the
results of 27 women with a previous history of immature
oocyte syndrome after hCG triggering (25). In the subse-
quent cycle, patients were triggered with a combination of
GnRHa and hCG. By such means the number of MII oocytes
increased compared with the previous cycle, resulting in the
development of more transferable embryos. The odds of a
mature oocyte retrieved for patients who received a dual
trigger was 2.51 times higher, after controlling for confound-
ing factors. The authors speculated that the retrieval of more
MII oocytes might be associated with the presence of a
surge of FSH/LH in addition to the hCG activity; yet the

ongoing pregnancy rate per transfer was still disappointingly
low (17.4%). In contrast, another small-size retrospective
study of patients previously having a low proportion of MII
oocytes (66%), despite normal response to OS, and who
were subsequently submitted to a ‘double trigger’, reported
not only a significantly higher number of mature oocytes
(6.5 versus 3.6), but also an encouraging 50% clinical preg-
nancy rate (26). The ‘double trigger’ involves co-administra-
tion of GnRHa and hCG for final oocyte maturation, but at
40 and 34 h, prior to OPU, respectively (26).

Taken together, the presence of an FSH surge in addition
to the LH and hCG surge seems to be a valuable tool in the
armamentarium for the treatment of patients with immature
oocyte syndrome. However, larger studies are needed to val-
idate the reported retrospective results prior to its routine
implementation.

Empty follicle syndrome following hCG trigger

Empty follicle syndrome (EFS) was first described in 1986 in
four patients in whom no oocytes were retrieved after appar-
ently normal follicular development and appropriate oestra-
diol levels after OS (27). EFS is still a disturbing and
challenging situation in IVF clinical practice, and the inci-
dence varies among studies, ranging from 0.59% to 3.5%
(28,29). Moreover, EFS seems to be associated with PCOS,
GnRH-antagonist co-treatment (30), and diminished ovarian
reserve (31). Interestingly, Revelli et al. suggested that EFS
might not be a constant condition. Thus, in a study of 43
patients undergoing a second stimulation after EFS in the
first cycle, a total of 37 patients (86%) obtained MII oocytes,
although the stimulation protocols were similar, and a hCG
trigger was used for the second cycle too (32). This could be
caused by cycle-to-cycle variations in oocyte quality.
However, a contribution from the statistical phenomenon
‘regression to the mean’ could also play a role as it is
defined by the fact that an extreme variable in the first
measurement is more likely to be closer to the mean in the
next measurement.

In contrast, several case reports suggest a different pic-
ture. Thus, Lok et al. described a case presenting with two
consecutive EFS (33). First, in a long GnRHa down-regulation
protocol and subsequently in a GnRH antagonist protocol,
both were triggered with 10,000 IU urinary hCG. In a second
attempt, a single dose of GnRHa was used for final follicular
maturation. Nine MII oocytes were retrieved from 10 follicles,
and eight of these fertilised normally. Two good-quality
embryos were used for fresh transfer, and four embryos were
cryopreserved. A similar case has been described by Deepika
et al. (34), with two consecutive EFS cycles with adequate
follicular development and hormonal levels, and an unevent-
ful oocyte pick-up after the use of an hCG trigger. In a third
attempt, using GnRH antagonist co-treatment, the dual trig-
ger option was chosen. A total of 10 MII oocytes were
retrieved, and subsequently two-good quality blastocysts
were transferred, leading to one successful live birth.
However, the most puzzling case was described by Beck-
Fruchter (35). Herein, the authors reported a case of a young

UPSALA JOURNAL OF MEDICAL SCIENCES 139



woman with a normal karyotype and primary infertility of
25 months, submitted to IVF. After seven cycles including
either a long GnRHa down-regulation protocol or GnRH
antagonist co-treatment, resulting in normal follicular devel-
opment and oestradiol levels, very unfavourable outcomes
were obtained at retrieval, including four cycles with EFS and
three cycles with 1–4 immature oocytes only. Of note, in
these seven cycles rhCG (up to 13,000 IU) was used
for trigger.

In the final successful cycle, a ‘double trigger’ (GnRHa,
40 h prior to OPU; and hCG, 34 h prior to OPU) was used, 16
MII oocytes were retrieved, and a total of 11 embryos devel-
oped; two embryos were transferred, and nine were cryopre-
served; the fresh transfer resulted in the term birth of a
healthy child. In the cases of Lok et al. and Beck-Fruchter
et al. (33,35) it is difficult to clearly distinguish between the
effect of the dual trigger concept versus an isolated action
of the GnRHa bolus. Nevertheless, in view of the previous
hCG failures, it seems reasonable to assume that some form
of endogenous LH and/or the additive effect of the FSH
surge could have played a role for the successful outcome.

All these observations suggest that EFS is a genuine
entity. Albeit of obscure aetiology, EFS may represent a syn-
drome of impaired granulosa cell function, in which oocyte
meiotic maturation is not resumed, cumulus expansion does
not ensue, and the immature oocyte–cumulus complexes are
resistant to follicular aspiration (35). However, evidence is
mainly based on case reports and might suffer from publica-
tion bias. For the time being, it cannot be ruled out that in
some patients the FSH surge is needed for optimal resump-
tion of the oocyte meiotic processes, including EFS cases
after hCG trigger. Finally, it is important to note that EFS can
be encountered also after GnRHa trigger (28).

Ovulation trigger in oocyte donation cycles

According to the European IVF-monitoring Consortium,
oocyte donation cycles account for up to 32.4% of all ART
treatments in some countries (36). The oocyte donation is
usually performed in an altruistic manner by young and
healthy women. Even though important complications
account for less than 1% of all oocyte donation cycles (37),
moderate to severe ovarian hyperstimulation syndrome
(OHSS) might occur more frequently than anticipated,
0.87%�9.47% (37,38). As these patients do not proceed to
embryo transfer, the incidence accounts exclusively for early-
onset OHSS and are related to hCG trigger in the presence
of a high ovarian response.

The use of GnRH antagonist co-treatment followed by
GnRHa trigger has been shown to be the most advantageous
protocol for the oocyte donor in terms of safety and efficacy.
In oocyte donation cycles, outcomes after GnRHa trigger are
similar to those of hCG trigger. In 2009, Galindo et al.
reported similar oocyte maturation and fertilisation rates in
212 oocyte donors randomised to receive either GnRHa or
rhCG for trigger (38). Furthermore, although donors at high
risk of OHSS were excluded from randomisation, nine donors
had mild OHSS and one donor severe OHSS in the rhCG

group, whereas no OHSS cases were observed in the GnRHa
trigger group. Additional randomised controlled trials have
consistently reported similar outcomes. Importantly, the
pregnancy rates in recipients are similar to those seen after
hCG trigger (39,40). Further benefits for the oocyte donor
population include: shorter duration of the luteal phase,
reduced luteal phase discomfort and abdominal distension,
and reduced ovary volume. All these added benefits contrib-
ute to a more friendly process for the oocyte donor (41–43),
and GnRHa trigger should be the ‘gold standard’ for the
oocyte donor.

Ovarian torsion

Ovarian torsion (OT) happens when an ovary twists on its
attachment to other structures. The development of an ovar-
ian mass or ovarian enlargement is commonly related to the
development of OT and may affect up to 7.5% of women
who experience abdominal pain in emergency departments
(44). OS may result in ovarian conditions that predispose
patients to ovarian augmentation and torsion, with poten-
tially significant consequences, as OT may lead to necrosis
requiring ovariectomy, if left untreated.

In a recent retrospective cohort study (45), the incidence
of OT and its subsequent complications of IVF cycles were
explored. The analysis included more than 15,000 IVF cycles,
using either hCG trigger and fresh embryo transfer or GnRHa
trigger and elective frozen embryo transfer (eFET). As previ-
ously reported (46), OT was an infrequent complication (14
out of 15,577; 0.09%). It is worthy of note that of the 14
diagnosed OT cases, a total of 13 were diagnosed in the
hCG-triggered fresh embryo transfer group and 1 in the
GnRHa trigger eFET group (0.13% versus 0.018%, p < 0.049).
Importantly, although the total oocyte number obtained in
the GnRHa trigger group was higher than in the hCG trigger
group, the incidence of OT was lower in the former. The
authors correlated the lower OT rate to a lower OHSS rate in
the GnRHa trigger group compared to the hCG trigger group
(0.05% versus 2.4%, p < 0.001). In addition, others reported
that the ovary will gain its normal volume faster and closer
to the baseline prestimulation volume after GnRHa trigger
(47,48), which may further contribute to a reduction in OT
development.

Fertility preservation in cancer patients

According to the Global Cancer Observatory (https://gco.iarc.
fr/), breast cancer is the most common malignancy diag-
nosed in reproductive-age women worldwide, accounting for
approximately 30% of all new cases reported in 2018. Since
diagnostic tools and treatments have improved over the last
decade, fertility preservation in this specific group of patients
has gained importance. Considering the fact that a vast
majority of breast cancers are hormone-dependent (49),
attention has focussed on the supraphysiological oestradiol
levels occurring during OS prior to oocyte preservation.
Additionally, when hCG is used as a trigger agent, its luteo-
trophic effect will potentiate the function of multiple corpora

140 J. C. CASTILLO ET AL.

https://gco.iarc.fr/
https://gco.iarc.fr/


lutea, further increasing oestrogen levels during the
luteal phase.

In order to overcome these undesired effects of ovarian
stimulation and ovulation trigger in breast cancer patients,
OS protocols were developed involving the use of aromatase
inhibitors (in addition to exogenous FSH) and GnRHa trigger.
In their first small-size retrospective analysis Oktay et al.
explored the use of either GnRHa trigger or hCG trigger in
women with breast cancer who submitted to oocyte fertility
preservation before chemotherapy (50). GnRHa trigger
resulted in a considerable drop in luteal oestradiol levels
compared with hCG trigger. Furthermore, more MII oocytes
were retrieved, leading to the development of more 2PN
embryos after GnRHa trigger. The same group in an
extended analysis (13), including 129 breast cancer patients
(46 in the GnRHa trigger group versus 83 in the hCG trigger
group), confirmed their previous results in terms of more MII
oocytes (77.3% versus 67.6%, p ¼ 0.007) and a higher number
of cryopreserved embryos (7.7 versus 5.4, p ¼ 0.002) in the
GnRHa trigger group. More recently, a larger retrospective
cohort study (14) included 341 patient who underwent
oocyte freezing for fertility preservation (75.3% breast cancer
patients) and reported a higher number of MII oocytes and
embryos cryopreserved (11.8 versus 9.9, p ¼ 0.04; and 9.2 ver-
sus 6.4, p < 0.001) after GnRHa trigger.

Finally, the use of GnRHa trigger in the so-called ‘Random
Start Controlled Ovarian Stimulation’ protocol was published,
showing that GnRHa trigger effectively stimulates a flare of
FHS/LH also in the luteal phase (51). The random start proto-
col has the potential to shorten the time to oocyte retrieval
before oncology treatment.

In conclusion, on the basis of the reduced luteal oestro-
gen exposure after GnRHa trigger, the reduced risk of OHSS,
and the improved cycle outcomes, the available evidence
supports the use of GnRHa trigger in all women with breast
cancer undergoing fertility preservation.

Development of new protocols

In humans, the traditional model of follicular growth states
that a single cohort of antral follicles develops during the fol-
licular phase of a menstrual cycle. This classical theory of fol-
licular recruitment has been challenged by Baerwald et al. by
demonstrating the presence of two and even three wave-like
changes in folliculogenesis during one single menstrual
cycle, of which only one terminated in ovulation (52).

This new physiologic knowledge of folliculogenesis along-
side previous experiences in the Random Start Controlled
Ovarian Stimulation protocol paved the way for the develop-
ment of the so-called ‘double stimulation’ protocol. A double
stimulation protocol consists of two consecutive ovarian
stimulations, the second one performed in the luteal phase,
starting immediately after the first oocyte retrieval. This novel
approach was initially used with promising results in a group
of patients with poor ovarian reserve (53). From the double
stimulation, a total of 26 women had 1–6 viable embryos
cryopreserved, and 21 women underwent 23 cryopreserved
embryo transfers, resulting in 13 clinical pregnancies.

Importantly, in this novel protocol using GnRHa trigger in
the follicular as well as the luteal phase of ovarian stimula-
tion, it was found that the pituitary is able to respond
adequately to a GnRHa trigger during the luteal phase, even
in the presence of high circulating progesterone levels.
Nonetheless, the FSH and LH surge induced by the same
dose of GnRHa was higher after the first trigger compared
with the second trigger. Other investigators, exploring the
same concept of combined follicular and luteal phase OS, so-
called DuoStim, reached the same conclusions (54). It was
proposed that DuoStim would provide a better opportunity
of retrieving oocytes in patients with poor ovarian reserve, in
a shorter timespan as compared with conventional OS, and
also suggested its potential use in oncologic patients in
need of emergency fertility preservation. Finally, there is a
recent publication reporting on the concept of double ran-
dom ovarian stimulation, initiating OS regardless of the cycle
day, and proceeding immediately with a second stimulation
after the first retrieval in oncological patients (55).

Reason for caution

A substantial part of the literature in the field of GnRHa trig-
ger for the abovementioned patient sub-groups can be con-
sidered low-quality evidence. Hence, well conducted
prospective trials are awaited in this area of IVF.

Conclusions

GnRHa trigger has had a pivotal role in changing ovulation
trigger policies worldwide, not only for the standard IVF
patient, but also for patient groups like oocyte donors, can-
cer patients, patients with poor ovarian reserve, and patients
with immature oocyte syndrome or empty follicle syndrome.
Thus, GnRHa trigger plays an important role beyond OHSS
prevention. Moreover, the GnRHa trigger concept has
sparked the development of novel protocols, enriching the
ART armamentarium for the benefit of present and
future patients.

Disclosure statement

Not related to this manuscript, TH received honoraria for lectures from
Ferring, IBSA, Besins, and Merck. PH received unrestricted research
grants from MSD, Merck, and Ferring as well as honoraria for lectures
from MSD, Merck, Gedeon-Richter, Theramex, and IBSA. PH and TH are
listed as inventors in an international patent application (PCT/
UK2018/040882).

Notes on contributors

Juan Carlos Castillo is a senior consultant (MD PhD) at Instituto
Bernabeu, Alicante, Spain.

Thor Haahr is a medical doctor and a PhD student at the Fertility Clinic
Skive, and the Department of Clinical Medicine, Aarhus
University, Denmark.

Mar�ıa Mart�ınez-Moya is a consultant (MD) at Instituto Bernabeu,
Alicante, Spain.

UPSALA JOURNAL OF MEDICAL SCIENCES 141



Peter Humaidan is a senior consultant (MD, DMSc) and professor at the
Fertility Clinic Skive, and the Department of Clinical Medicine, Aarhus
University, Denmark.

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UPSALA JOURNAL OF MEDICAL SCIENCES 143


	Abstract
	GnRHa trigger—improving oocyte yield and embryo competence?
	Immature oocyte syndrome
	Empty follicle syndrome following hCG trigger
	Ovulation trigger in oocyte donation cycles
	Ovarian torsion
	Fertility preservation in cancer patients
	Development of new protocols
	Reason for caution
	Conclusions
	Disclosure statement
	References