Document Type : Review Article
Authors
1 Faculty of Medical Science, University of Southern Denmark, Odense, Denmark
2 Faculty of Medical Science, University of Southern Denmark, Odense, Denmark;The Fertility Clinic, Skive Regional Hospital, Skive, Denmark;Faculty of Health, Aarhus University, Aarhus, Denmark
Abstract
Keywords
In the natural cycle ovulation is induced by a
mid-cycle surge of luteinizing hormone (LH) and
follicle-stimulating hormone (FSH) from the pituitary
elicited by a rise in the late follicular phase
level of estradiol and progesterone. Ovulation
marks the transition from follicular phase to luteal
phase, characterized by the formation of a corpus
luteum which releases steroid hormones, including
progesterone and estradiol. Importantly, the steroid
production is totally dependent on the pulsatile secretion
of LH by the pituitary (
Apart from securing the function of the corpus
luteum, LH plays a crucial role during the luteal
phase by up-regulating growth factors like vascular
endothelial growth factor A (VEGFA) and
fibroblast growth factor 2 (FGF2). In addition,
cytokines are up-regulated and extragonadal LHreceptors
are activated in the endometrium. All
these factors are thought to enhance and support
implantation and early neo-vascularization (
The role of the previously described mid-cycle
FSH surge during the natural cycle is not fully understood;
however, FSH seems to promote oocyte
nuclear maturation, i.e. resumption of meiosis and cumulus expansion. Furthermore, FSH has been shown to induce LH receptor formation in the luteinizing granulosa cells, thus optimizing the function of the corpus luteum (
Following implantation, the embryo gradually begins to secrete human chorionic gonadotropin (hCG) into circulation, structurally and biochemically similar to LH (
Apart from progesterone, the corpus luteum produces other steroid hormones, including estradiol. Estradiol has a modulatory effect on the secretory endometrial progesterone receptor concentration and may serve to replenish and maintain a sufficient level of endometrial receptors to secure an adequate response to progesterone (
Controlled ovarian stimulation (COS) is a key component of modern IVF treatment, as the availability of multiple oocytes for fertilization increases the chance of pregnancy (
In the stimulated
HCG has been the golden standard for ovulation induction for decades, functioning as a surrogate for the mid-cycle LH surge. HCG binds to and activates the same receptor as LH, the LH/hCG receptor (
After triggering of ovulation, it is necessary to maintain the function of the corpus luteum in order to secure a good reproductive outcome. HCG has a significantly longer half-life than that of endogenous LH and the bolus injected to trigger ovulation can support the corpus luteum for 7-10 days. After this period hCG is cleared from the circulation, and the corpus luteum is now totally dependent on the endogenous LH production and the hCG produced by the implanting embryo. However, during the early/mid luteal phase the hCG secretion from the embryo to the maternal serum is limited due to an absence of direct vascular communication (
The best LPS strategy has yet to be defined, however progesterone administered either vaginally or intramuscularly is the first choice of treatment and is generally used for at least 15 days. Currently, the literature does not find any evidence for adding estradiol (
Regarding hCG triggering, the downside is that the trigger agent is very closely connected to the ovarian hyperstimulation syndrome (OHSS). This life threatening condition, characterized by massive enlargement of the ovaries and an increased vascular permeability, among others, is a iatrogenic complication following COS (
The best strategy to prevent OHSS has previously been to indentify high-risk patients before ovarian stimulation, followed by the use of an appropriate COS protocol (
With the introduction of the GnRH antagonist protocol for the prevention of a premature LH surge, it became possible to trigger ovulation with GnRHa. The GnRH antagonist occupies the GnRH receptor without causing down-regulation, and by injecting a single bolus of GnRHa, the antagonist is displaced from the receptor. This activates the receptor, inducing a flare-up of gonadotrophins (LH and FSH), which effectively stimulate the final oocyte maturation and ovulation. However, important differences exist regarding the profile and duration of the LH surge after triggering with GnRHa compared to that of the natural cycle. In the natural cycle, the LH surge is characterized by three phases with a total duration of ~48 hours. After GnRHa triggering, the surge consist of two phases, only, with a duration of ~24-36 hours leading to a significantly reduced amount of LH released (
Apart from an LH surge, GnRHa triggering also induces an initial secretion of FSH resembling that of the natural cycle. This more natural surge of gonadotrophins after triggering with GnRHa may explain why some authors reported retrieval of an increased amount of mature oocytes compared to hCG triggering (
The induced surge of gondotrophins results in an initial rise in the levels of progesterone and estradiol followed by a decrease during the next 24 hours prior to oocyte pick-up (OPU). Subsequently a second rise in the level of progesterone takes place as ovarian steroidogenesis shifts from follicular to luteal phase. In contrast, the estradiol level continues to fall (
After GnRHa trigger the circulating levels of progesterone and estradiol are significantly lower throughout the luteal phase as compared to those obtained after hCG triggering due to the shorter half-life of LH (~60 minutes) compared to that of hCG (>24 hours) (
The important clinical advantage of GnRHa triggering, however, is the reported significant reduction in or even elimination of OHSS (
As previously mentioned, the luteal phase after COS is defect due to supraphysiological steroid hormone concentrations inhibiting the LH secretion via negative feedback at the level of the hypothalamic-pituitary-gonadal-axis. As seen above the LH activity will be further compromised after GnRHa triggering due to the shorter duration of the endogenous induced LH surge and a potential weaker activation of the LH/hCG receptor. The result of this is a significant reduction in LH activity throughout the early/mid luteal phase leading to premature luteolysis and implantation failure (
In contrast, after hCG triggering, the luteal actions of LH will be covered by the bolus of hCG injected and then gradually by the hCG produced by the implanting embryo. Thus, supplementation with progesterone is sufficient to secure the reproductive outcome. However, after GnRHa triggering the lack of endogenous LH activity necessitates a modification of the standard luteal phase supplementation currently used after hCG triggering (
The initial randomized controlled trials (RCTs) reported a poor clinical outcome with an extremely high early pregnancy loss rate (EPL) when GnRHa was used to trigger final ovulation, despite the use of standard LPS with vaginal progesterone and oral estrogen (
After the first disappointing results, trials were performed to explore the possibility of correcting the luteal phase by injecting a small bolus of LH activity in the form of hCG. HCG in standard doses would increase the risk of OHSS, but by supplementing with a reduced dose, the treatment was thought to be safe, even for the OHSS high risk patient. Therefore, trials were conducted to explore the hypothesis that a small hCG bolus could rescue the luteal phase without increasing the risk of OHSS (
Humaidan et al. (
Following this study, the question to ask was: does GnRHa triggering followed by a bolus of 1500 IU hCG in a group of patients at risk of OHSS reduce the OHSS incidence compared with hCG trigger? This question was explored in a more recent study by Humaidan et al. (
No OHSS cases were seen in the group at risk of OHSS after GnRHa triggering despite supplementation with 1500 IU hCG, compared to an incidence of 3.4% in the group at risk of OHSS triggered with hCG. In contrast, two late-onset moderate OHSS cases were seen in the OHSS low-risk group triggered with GnRHa followed by two boluses of 1500 IU hCG, versus no cases of OHSS after hCG triggering. The authors concluded that future trials should focus on the minimal hCG activity needed for LPS in the low risk group to secure the reproductive outcome without increasing the risk of OHSS. The safety of the LPS protocol was previously tested among 12 hyper responders (
Using the same protocol, Radesic et al. (
These results were further corroborated by the conclusions of a recent international multicentre retrospective study. In this study Iliodromiti et al. (
In another effort to find the optimal dose of hCG necessary during the luteal phase after GnRHa triggering, Castillo et al. (
In another retrospective analysis, Shapiro et al. (
Finally, Kol et al. (
In conclusion, supplementation with hCG rescues the luteal phase after ovulation induction with GnRHa, resulting in reproductive outcomes similar to that of hCG. However, it still needs to be determined whether "dual-trigger", a single bolus of hCG or repeated low-doses of hCG is the best option. Regardless of the chosen protocol, it is crucial to individualize the luteal phase treatment with hCG according to the ovarian response to stimulation in an effort to reduce the risk of OHSS.
An alternative way of increasing the LH activity during the insufficient luteal phase after GnRHa triggering would be to administer repeated doses of recombinant LH.
This concept was explored in a proof-of-concept study performed by Papanikolaou et al. (
The authors in this small group of normo-responder patients concluded that rLH effectively secures a good reproductive outcome after triggering with GnRHa without any OHSS development. The study was the first to assess the concept of applying repeated doses of rLH as LPS to overcome the luteal phase insufficiency after GnRHa triggering and the results seem promising. However, larger RCTs are necessary to draw conclusions about the safety and efficacy of this protocol. Furthermore, an obvious limiting factor for the use of rLH for LPS is the high cost of this preparation.
As the standard LPS regimens turned out to be insufficient after GnRHa trigger (
The first report was by Engmann et al. (
This protocol resulted in DR and EPL rates comparable to those of hCG triggering. Furthermore, the study reported a total elimination of OHSS after GnRHa triggering despite the fact that PCOS patients were included, many of which were at high-risk of developing OHSS after ovarian stimulation.
An important question that needs to be explored is whether this protocol applies to normo-gonadotrophic patients. LH levels are significantly higher in PCOS patients during the follicular and luteal phases, due to a higher frequency and amplitude of the LH pulse. Further, in PCOS patients the hypothalamus has a reduced sensitivity to negative feedback from the ovarian steroid hormone concentrations, in particular progesterone (
In accordance with the results from Engmann et al. (
Although the results seem promising in terms of the reproductive outcome and the total elimination of OHSS among OHSS high-risk patients, the study by Shapiro et al. (
Moreover, there are some potential biases in the study by Engmann et al. (
Importantly, the abovementioned encouraging results are contrasted by others. In a previous study performed by Babayof et al. (
These findings are further supported by Orvieto (
An alternative approach to encounter the luteal phase insufficiency seen after GnRHa triggering is to segmentate the IVF cycle, i.e. to stimulate in one cycle, trigger with GnRHa and transfer in subsequent frozen-thaw cycles. This seems to be a very safe approach for patients at risk of OHSS and recent trials suggest similar pregnancy rates between fresh and frozen-thawed embryos (
The concept was recently explored in a RCT by Shapiro et al. including 177 patients (
To extend the indication, Shapiro et al. (
In summary, a freeze-all strategy further reduces the risk of OHSS and may be the best current option for patients with a very high risk of OHSS (
Many recent publications indicate that the time has come for a paradigm shift in the triggering policy of ART. HCG has been the gold standard for ovulation induction, however, after the introduction of the GnRH antagonist protocol for the prevention of a premature LH rise, triggering of final oocyte maturation and ovulation with a single bolus of GnRHa is definitely an alternative.
GnRHa triggering possesses important advantages over hCG triggering, mainly in terms of a significant reduction in-if not total elimination of OHSS. Following the initial disappointing clinical reports several subsequent studies implemented a modified luteal support in terms of supplementation with either LH activity or luteal steroids. Using the modified LPS, the reproductive outcome increased remarkably and is now comparable to that seen after hCG triggering. Although the modified LPS has had a significant positive effect on the reproductive outcome after GnRHa triggering without increasing the risk of OHSS, the most optimal LPS still has to be investigated.
Until the optimal luteal supplementation protocol has been defined an alternative option in patients with an extreme ovarian response or with a significant comorbidity is a freeze all strategy and transfer in a subsequent natural or stimulated cycle.