Low-dose hCG supplementation after GnRH agonist triggering: don't be too quick on the trigger

Abstract

Induction of final oocyte maturation using a GnRH agonist was first described in the early nineties, though with the advent of the GnRH antagonist era it has gained ever increasing attention some two decades later (Humaidan et al., 2011). The primary motive for substituting the ‘classical’ hCG trigger is the complete elimination of clinically significant ovarian hyperstimulation syndrome (OHSS). When used alone (or with steroid-only luteal support) GnRH agonist triggering is undoubtedly themost efficient and powerfulwayof (secondary)OHSSprevention. So far there is no confirmedOHSS case in the literature that proves the opposite (Kol and Humaidan, 2012). This prevention occurs due to a massive, rapid and irreversible luteolysis leading to a practical, total elimination of clinically significant moderate/severeOHSS (Kol, 2004). Consequently when fresh embryo transfer is not planned this strategy has established itself as the first choice option in oocyte donor/fertility preservation cycles and before total freezing of oocytes or embryos (Bodri et al., 2010; Griesinger et al., 2011). However, if the primary goal is performing fresh embryo transfer then the challenge is to save the severely impaired luteal phase without increasing the risk of early/late-onset OHSS. After the discouraging results of initial trials only a few dedicated research groups have made further efforts to undertake research in this area (Humaidan et al., 2006; Engmann et al., 2008; Castillo et al., 2010; Papanikolaou et al., 2011b). Humaidan et al. developed the concept of a modified luteal support aimed at rescuing the impaired luteal phase by administering small boluses of luteotropic substances. This hypothesis was first tested in pilot studies, both in normal and high responders (Humaidan et al., 2006 Humaidan, 2009) and later in a randomized clinical trial (Humaidan et al., 2010). The first randomized trial (mainly involving normal responders) suggested that the reproductive outcome can be improved to the level of control patients with a single, low-dose (1500 IU) hCG bolus administered at the time of oocyte retrieval, without increasing the risk of OHSS (Humaidan et al., 2010). These encouraging results were also reproduced in a retrospective study by an Australian group (Radesic and Tremellen, 2011). Although Radesic and Tremellen used the aforementioned strategy with a fairly high OHSS risk population (without a pre-established upper limit of ovarian response) they were cautious enough to only perform mandatory single embryo transfer to reduce the risk of any late-onset OHSS. In the current issue of Human Reproduction the case series by Seyhan et al., report the combined experience from two geographically distant centres in Canada and Turkey with IVF patients at high risk of OHSS, who received the low-dose hCG rescue protocol. Despite using co-interventions (such as coasting and cabergoline administration) the authors reported a worryingly high rate (22%) of early onset severe OHSS requiring hospitalization. Although the presented retrospective case series is fairly small, the authors felt that it was important to highlight that early onset OHSS can still occur after applying the low-dose hCG rescue protocol. At first sight their findings are in blunt disagreement with most previously published studies that have also used low-dose hCG luteal support (single or multiple-bolus) following GnRH agonist trigger (Table I). However, at closer look notable differences can be observed. Among the four studies that were conducted in high OHSS risk patients Seyhan et al.’s 23 patients represent the highest ovarian response category with extremes of 49 and 65 oocytes retrieved. Moreover, although in one of the participating centres total freeze was considered in 33% of the cases, in the other fresh transfer was performed only transferring two to three embryos. Taken altogether these factors considerably influence the risk of early and late-onset OHSS. Although it was based on a very limited number of cases (5 versus 18) Seyhan et al. also suggested a threshold (≥18 follicles) based on the number of intermediate-sized (10–14 mm) follicles above which embryo/oocyte freezing is strongly recommended. This threshold (which was the only significant finding in this series) was based on the number of intermediate follicles and might be less practical for everyday clinical use than the total follicular count (Papanikolaou et al., 2006). Interestingly, in the design of a more recent randomized trial by Humaidan et al. on low-dose hCG support, patients with .25 follicles .11 mm were judged to be at too high risk and excluded from participation (www.clinicaltrials.gov: NCT00627406).