In stimulated IVF/intracytoplasmic sperm injection cycles, the luteal phase is disrupted, necessitating luteal-phase supplementation. The most plausible reason behind this is the ovarian multifollicular development obtained after ovarian stimulation, resulting in supraphysiological steroid concentrations and consecutive inhibition of LH secretion by the pituitary via negative feedback at the level of the hypothalamic–pituitary axis. With the introduction of the gonadotrophin-releasing hormone-(GnRH) antagonist, an alternative to human chorionic gonadotrophin triggering of final oocyte maturation is the use of GnRH agonist (GnRHa) which reduces or even prevents ovarian hyperstimulation syndrome (OHSS). Interestingly, the current regimens of luteal support after HCG triggering are not sufficient to secure the early implanting embryo after GnRHa triggering. This review discusses the luteal-phase insufficiency seen after GnRHa triggering and the various trials that have been performed to assess the most optimal luteal support in relation to GnRHa triggering. Although more research is needed, GnRHa triggering is now an alternative to HCG triggering, combining a significant reduction in OHSS with high ongoing pregnancy rates.
Stimulation of the ovaries for IVF treatment induces the growth of multiple follicles, resulting in the aspiration of several oocytes. During the early years of IVF treatment it became obvious that the stimulation per se induced an unphysiological hormonal level during the luteal phase – the phase after egg transfer – necessitating hormonal support with vaginally applied progesterone to obtain ongoing pregnancies. With the introduction of the gonadotrophin-releasing hormone (GnRH) antagonist protocol (short protocol) it became possible to perform final oocyte maturation with a GnRH agonist instead of human chorionic gonadotrophin (HCG). The first studies applying this concept, however, showed a very poor pregnancy rate, despite standard luteal-phase support with progesterone. This review discusses the reason for the poor results and the newest studies, using GnRH agonist instead of HCG, now showing a normalization of pregnancy rates due to modifications of the luteal-phase support and with the benefit of a protocol which has a reduced risk of ovarian hyperstimulation syndrome.
Introduction
With the introduction of gonadotrophins for ovarian stimulation in patients undergoing IVF treatment, it became obvious that the luteal phase of all stimulated IVF cycles was abnormal (Edwards et al., 1980) as compared with 8% of natural cycles (Rosenberg et al., 1980).
The aetiology of the luteal-phase defect in stimulated IVF cycles has been debated for more than three decades. Initially, it was argued that the removal of large quantities of granulosa cells during oocyte retrieval might negatively impact the function of the corpora lutea, leading to a luteal-phase insufficiency. However, this hypothesis was rejected when it was established that the aspiration of preovulatory oocytes in a natural cycle neither diminished the luteal-phase steroid secretion nor shortened the length of the luteal phase (Kerin et al., 1981).
As steroid-hormone production by the corpus luteum is totally dependent on the pulsatile secretion of LH by the pituitary (Devoto et al., 2000), it was suggested that the prolonged pituitary desensitization following a long gonadotrophin-releasing hormone-(GnRH) agonist (GnRHa) down-regulation to prevent a premature LH rise might result in circulating LH concentrations too low to support the corpora lutea, causing a luteal-phase defect (Smitz et al., 1992a, Smitz et al., 1992b). Thus, with the introduction of GnRH antagonists in IVF protocols it was anticipated that luteal-phase supplementation would be unnecessary due to the rapid recovery of the pituitary (within 2 days) after GnRH-antagonist discontinuation (Oberyé et al., 1999). However, subsequent IVF/intracytoplasmic sperm injection (ICSI) studies using GnRH antagonist co-treatment did not confirm this expectation. On the contrary, luteolysis was also induced prematurely after GnRH-antagonist co-treatment, resulting in a significant reduction in the luteal-phase length and a compromised reproductive outcome (Albano et al., 1998, Beckers et al., 2003). Thus, despite the rapid recovery of the pituitary in GnRH-antagonist protocols, luteal-phase supplementation was necessary (Dal Prato and Borini, 2005, Tarlatzis et al., 2006).
Finally, it was proposed that the triggering bolus of human chorionic gonadotrophin (HCG) administered for final oocyte maturation in stimulated cycles could potentially cause a luteal-phase defect by suppressing the LH secretion of the pituitary via a short-loop feedback mechanism (Miyake et al., 1979). However, this theory was questioned after the results of a cohort study, showing that the administration of HCG did not decrease luteal-phase LH concentrations in the natural cycle of normogonadotrophic women (Tavaniotou and Devroey, 2003).
Presently, according to recent research, the most plausible reason for the luteal-phase insufficiency seen after ovarian stimulation is the multifollicular development achieved during the follicular phase, resulting in luteal supraphysiological concentrations of progesterone and oestradiol which directly inhibit the LH secretion by the pituitary via negative feedback actions at the level of the hypothalamic–pituitary axis (Fatemi, 2009, Fauser and Devroey, 2003, Tavaniotou and Devroey, 2003, Tavaniotou et al., 2001). This has been shown to have a dramatic effect on the reproductive outcome (Humaidan et al., 2005, Humaidan et al., 2010) as LH plays a crucial role during the luteal phase not only for the steroidogenic activity of the corpus luteum (Casper and Yen, 1979), but also for the up-regulation of growth factors (Sugino et al., 2000, Wang et al., 2002) and cytokines (Licht et al., 2001a, Licht et al., 2001b), which are important for implantation. Apart from this, the activation of extragonadal LH receptors, expressed in human endometrium, is thought to enhance and support implantation (Rao, 2001, Tesarik et al., 2003).
Section snippets
Ovarian stimulation and the endometrium
During ovarian stimulation, an endometrial histological advancement has been observed on the day of oocyte retrieval when comparing with the endometrium from the ovulation day in natural cycles (Bourgain et al., 2002, Kolibianakis et al., 2002). The endometrial advancement has mainly been considered to be the result of the exposure of the endometrium to supraphysiological steroid hormones throughout the IVF treatment, independent of the type of GnRH analogue administered during the follicular
HCG triggering of final oocyte maturation
In the natural cycle, ovulation is induced by the mid-cycle surge of LH (and FSH) from the pituitary, elicited by an increasing late follicular concentration of oestradiol. More than 50 years ago, exogenous HCG (5000–10,000 IU) was successfully introduced as a substitute for the endogenous LH surge to induce final oocyte maturation. Sharing the same α subunit and 81% of the amino-acid residues of the β subunit, LH and HCG bind to the same receptor, the LH/HCG receptor (Kessler et al., 1979).
GnRHa triggering of final oocyte maturation
Previously, GnRHa was shown to effectively stimulate ovulation and final oocyte maturation, inducing an initial secretion of LH and FSH (flare-up), similar to that of the natural cycle, prior to down-regulation of the receptor (Gonen et al., 1990, Itskovitz et al., 1991). The GnRHa trigger concept gained some interest in the late 1980s and early 1990s. However, with the introduction of GnRHa for pituitary down-regulation prior to IVF/ICSI treatment (Porter et al., 1984), this concept was
GnRHa triggering and the luteal phase
During the natural cycle, the frequency of pulsatile LH release from the pituitary changes across the luteal phase, correlating significantly with progesterone concentrations (Filicori et al., 1986). Not only does LH play a crucial role for the steroidogenic activity of the corpus luteum, but also for the up-regulation of growth factors, such as vascular endothelial growth factor A, fibroblast growth factor 2, cytokines involved in implantation and stimulation of extragonadal LH receptors (
HCG bolus
Following the first disappointing trials after GnRHa triggering, a number of studies were performed in normoresponding as well as hyper-responding patients to explore the possibility of rescuing the luteal phase with a small supplementary bolus of LH-like activity in the form of 1500 IU HCG (Humaidan et al., 2006, Humaidan et al., 2010, Humaidan, 2009). The results of the first study confirmed the LH deficiency theory, as the luteal phase after GnRHa triggering was normalized not only in terms
Clomiphene citrate
Clomiphene citrate is a selective oestrogen receptor modulator and ovulation-inducing agent used for the initial treatment of a large majority of anovulatory infertile women (Cantineau et al., 2007). A direct endometrial adverse effect of clomiphene citrate administered during the follicular phase has been presumed, and interference with the oestrogen receptor-mediated endometrial oestrogen receptor and progesterone receptor induction has been implicated as plausible mechanisms for the negative
Conclusions
The luteal phase in all stimulated IVF cycles is disrupted. However, GnRHa triggering possesses advantages over HCG triggering in terms of an almost complete elimination of OHSS, the retrieval of more mature oocytes (Humaidan et al., 2005, Humaidan et al., 2010, Imoedemhe et al., 1991, Kol, 2004, Kol and Itskovitz-Eldor, 2000, Oktay et al., 2010, Orvieto, 2005), less luteal distension and discomfort for the patient (Garcia-Velasco et al., 2010) and luteal-phase steroid concentrations closer to
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2023, Handbook of Current and Novel Protocols for the Treatment of Infertility
Following the observations demonstrating comparable or even better oocyte\embryos quality following gonadotropin-releasing hormone agonist (GnRHa), compared to human chorionic gonadotropin (hCG) trigger, and the different effects of luteinizing hormone (LH) and hCG on the downstream signaling of the LH receptor, GnRHa is now offered concomitant to the standard hCG trigger dose to improve oocyte/embryo yield and quality.
Three different modes of concomitant administration of both GnRHa and a standard bolus of hCG (5000–10,000 units) prior to oocyte pick-up (OPU) are suggested: (a) dual trigger 35–37h prior to OPU is offered to normal responders patients, resulting in improved oocyte/embryo quality and IVF outcome; (b) double trigger GnRHa 40h and standard hCG added 34h prior to OPU is offered to patients demonstrating abnormal final follicular maturation despite normal response to COH, resulting in significantly higher number of oocytes retrieved, higher number of mature/metaphase-II (MII) oocytes, and proportion of MII oocytes per number of oocytes retrieved, with the consequent significantly increased number of top-quality embryos; and (c) double or dual trigger 34h before OPU is offered to poor responders patients, aiming to overcome premature luteinization, while achieving high yield of mature oocytes.
2022, Management of Infertility: A Practical Approach
The luteal phase is one of the most important events necessary for the establishment of a successful pregnancy. The endometrium is a dynamic tissue, and the window of implantation is known to be present between days 19 and 24 of a spontaneous cycle. Luteal phase defects have been extensively studied over the years, most often in assisted reproduction cycles (ART) where controlled ovarian stimulation requires the use of gonadotropin-releasing hormone analogs, as well as an ovulation trigger to achieve timed final oocyte maturation. Altogether, these treatments suppress pituitary secretion of luteinizing hormone, required for the formation and early activity of the corpus luteum. Higher pregnancy rates have been shown in ART cycles in patients who receive progesterone compared with patients who do not, but there is no clear consensus on which formulation to use or route of administration, time of initiation, and duration of treatment once pregnancy is achieved in different types of cycles (fresh and frozen). Fresh and frozen-thawed cycles are completely different in hormonal dynamics and luteal phase.
At present, we are faced with precision medicine, which leads us to analyze each case individually and to customize the luteal phase of fresh and frozen cycles. This concept of personalized medicine uses genetics or any other biomarker, together with diagnostic, prognostic, and therapeutic strategies precisely tailored to the requirements of each patient. Ultrasonographic measurement of the endometrium, serum progesterone levels on the day of embryo transfer, and endometrial receptivity tests appear to be the most widely used biomarkers in clinical practice. In this chapter we will discuss the multiple proposals to customize a patient's luteal phase support in ART.
Is body-mass index (BMI) associated with oocyte maturation in women at high risk for developing severe ovarian hyperstimulation syndrome (OHSS) who are triggered with gonadotrophin releasing hormone (GnRH) agonist?
Prospective observational cohort study. A total of 113 patients at high risk for severe OHSS (presence of at least 19 follicles ≥11 mm) pre-treated with gonadotrophin releasing hormone (GnRH) antagonists and recombinant FSH were administered 0.2 mg triptorelin to trigger final oocyte maturation. Patients were classified in two groups depending on their BMI: ΒΜΙ less than 25 kg/m2 (n = 72) and ΒΜΙ 25 kg/m2 or over (n = 41). Baseline, ovarian stimulation and embryological characteristics, as well as luteal-phase hormone profiles, were compared in patients classified into the two BMI groups. The main outcome measure was the number of mature oocytes.
A significantly higher number of mature (metaphase II) oocytes (19 [18–21] versus 16 [13–20], P = 0.029) was present in women with BMI less than 25 kg/m2 compared with those with BMI 25 kg/m2 or greater. The number of retrieved oocytes, the number of fertilized oocytes, oocyte retrieval, maturation and fertilization rates were similar in the two groups. A significantly higher dose of recombinant FSH was required for patients with BMI 25 kg/m2 or greater compared with patients with BMI less than 25 kg/m2 (1875 [1650–2150] IU versus 1650 [1600–1750] IU, P = 0.003) and the two groups displayed different luteal phase hormonal profiles.
Among women at high risk for developing severe OHSS who are triggered with a standard dose (0.2 mg) of the GnRH agonist triptorelin, women with BMI 25 kg/m2 or greater had significantly fewer mature oocytes, required a higher total dose of recombinant FSH compared with women with BMI less than 25 kg/m2.
Are the characteristics of the natural cycle or modified natural cycle (mNC), or live birth rates (LBR), affected by delaying frozen embryo transfer (FET) after a failed fresh IVF cycle?
In a retrospective study, conducted at a university-affiliated tertiary centre, 198 women aged 18–45 years undergoing their first FET cycle after a failed fresh embryo transfer attempt using an mNC were evaluated. Cycles were divided according to the time interval between oocyte retrieval and the start of the FET cycle into the immediate FET group (<22 days) and the delayed FET group (≥22 days). The main outcome measures were ovulation day and LBR.
The mean interval between oocyte retrieval and the start of the FET cycle was 15.6 ± 3.2 days in the immediate FET group and 84.8 ± 73.7 days in the delayed FET group (P < 0.001). Ovulation day was significantly delayed in the immediate FET group (day 17.1 ± 4.4 versus day 15.4 ± 3.7; P = 0.004). There was no difference between the immediate and delayed FET groups in terms of clinical pregnancy rate (CPR) (25.4% and 25.0%, respectively) or LBR (21.2% and 20.0%, respectively).
Natural-cycle characteristics are similar in immediate and delayed cycles, except for a slight delay in ovulation day. Deferring mNC-FET after a failed fresh IVF cycle does not improve the reproductive outcome. These results should encourage patients and clinicians who want to proceed with FET immediately after failure of fresh IVF.
In previous studies, double ovarian stimulation has usually been used when the first stimulation was carried out with a mild stimulation protocol or a GnRH-A protocol, and ovulation was triggered with GnRH-a (Kuang et al., 2014a; Ubaldi et al., 2016; Zhang et al., 2015). With the advantages of almost complete prevention of OHSS and inducing an endogenous surge of FSH in addition to the LH surge similar to the natural mid-cycle, the GnRH-a trigger for final maturation of oocytes has been considered a valuable and alternative strategy to classical HCG triggering (Humaidan et al., 2012; Kol and Itskovitzeldor, 2010). However, the GnRH-a trigger had a limitation, in that it could not be used in a GnRH-a pituitary down-regulation protocol, in which the flare-up effect of the GnRH-a trigger is blocked as GnRH receptors in the pituitary are already occupied.
Previous studies have shown that double ovarian stimulation could obtain more oocytes in women with poor ovarian response. This retrospective case–control study aimed to investigate the efficacy of double ovarian stimulation in older women. One hundred and sixteen women aged ≥38 years who received double ovarian stimulation were assigned to the study, with 103 divided into four groups according to follicular-phase ovarian stimulation protocols, including gonadotrophin-releasing hormone agonist short protocol (n = 27), gonadotrophin-releasing hormone antagonist protocol (n = 32), mild stimulation protocol (n = 21) and medrocyprogesterone acetate (MPA) pituitary down-regulation protocol (n = 23). Numbers of oocytes retrieved and available embryos after double ovarian stimulation were more than double those obtained after follicular-phase ovarian stimulation alone. In total 81.90% of patients had available embryos, and the cancellation rate decreased from 37.07% to 18.10%. Forty-eight cases underwent 50 cryopreserved embryo transfer cycles, with a 22.00% clinical pregnancy rate. The implantation rate (10.53% versus 10.67%) was similar between the embryos derived from first and second stimulations. The results suggest that double ovarian stimulation could increase the chances of achieving pregnancy by accumulating more oocytes/embryos in a short time, which might serve as a useful strategy for older women.
Moreover, 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 [21–23]. Taken together, 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 [1,24]. GnRHa trigger effectively reduces OHSS rates due to the 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 [25,26], which results in a defective CL formation and a decrease in the release of vasoactive peptides such as VEGF [6,27–29].
GnRH agonist (GnRHa) trigger for final oocyte maturation in GnRH antagonist co-treated IVF/ICSI cycles significantly reduces the risk of ovarian hyperstimulation syndrome (OHSS). GnRHa trigger followed by modifications of the standard luteal phase support (modified luteal phase support) secures fresh transfer in the majority of patients with excellent reproductive outcomes. In freeze all cycles (segmented cycles) GnRHa trigger allows oocyte retrieval with a minimal risk of early onset OHSS and good reproductive outcomes in subsequent frozen thaw cycles. Overall, two different luteal phase support strategies have been proposed when a fresh transfer is performed after GnRHa trigger. These involve either boosting the endogenous steroid production or adding exogenous steroids. The present review discusses the advancement of GnRHa trigger in fresh and segmented cycles and how a modified luteal phase support policy in fresh transfer cycles results in good reproductive outcomes as well as a high safety in terms of OHSS reduction. Finally, the new concept of an individualized luteal phase support policy taking the number of pre-ovulatory follicles into account when planning a fresh transfer in GnRHa triggered IVF/ICSI cycle is discussed.
Peter Humaidan is a specialist in reproductive endocrinology, professor and clinical director of the Fertility Clinic at Odense University Hospital, Denmark. He trained at the Sahlgrenska University Hospital, Gothenburg, Sweden, where he also completed a speciality degree in obstetrics and gynaecology. His research interests include reproductive endocrinology, the function of gonadotrophins, sperm chromatin integrity in relation to assisted reproduction and gonadotrophin-releasing hormone-(GnRH) antagonist co-treatment in ovarian stimulation. During recent years, his research has been focused on GnRHa triggering and prevention of ovarian hyperstimulation syndrome. He is a former board member of the Danish Fertility Society.
