In the course of the ovulatory cycle, sufficient production of estradiol by the preovulatory follicle induces the mid-cycle LH surge, which is followed by a loss of gap junctions between the oocyte and cumulus cells, cumulus expansion, germinal vesicle breakdown, resumption of meiosis, and luteinization of the granulosa cells (Figs. 9.1, 9.2, 9.3, 9.4, and 9.5). Moreover, the consequent increase in progesterone synthesis facilitates the positive feedback action of estradiol to induce the concomitant mid-cycle FSH peak [1]. This peak FSH has several roles, including the assurance of an adequate complement of LH receptors on the granulosa layer and the synthesis of hyaluronic acid matrix that facilitates the expansion and dispersion of the cumulus cells, allowing the oocyte-cumulus cell mass to become free-floating in the antral fluid [1].
Fig. 9.1
Ovulation
Fig. 9.2
FSH curve
Fig. 9.3
LH curve
Fig. 9.4
Estradiol curve
Fig. 9.5
Progesterone curve
9.2 Human Chorionic Gonadotropin, a Surrogate to the Naturally Occurring LH Surge
As part of a standard/conventional controlled ovarian hyperstimulation (COH) regimen, final follicular maturation is usually triggered by one bolus of human chorionic gonadotropin (hCG) (5000–10,000 units), that is administered as close as possible to the time of ovulation (i.e., 36 h before oocyte recovery) [2]. Human chorionic gonadotropin, a surrogate to the naturally occurring LH surge, induces luteinization of the granulosa cells, final oocyte maturation, and resumption of meiosis (Fig. 9.6).
Fig. 9.6
LH/hCG receptor
Fig. 9.7
Evaluation of OHSS with abdominal transducer
Ovarian hyperstimulation syndrome (OHSS) almost always presents either 3–7 days after hCG administration in susceptible patients (early onset) or during early pregnancy, 12–17 days after hCG administration (late onset). Individualization of treatment according to the specific risk factor and the specific response in the current cycle with the option of freezing of all embryos, or replacement of only a single embryo, has the potential of reducing the risk and severity of the syndrome in susceptible cases [3]. Moreover, while withholding the ovulation-inducing trigger of hCG may eliminate severe early OHSS, it denotes patients’ frustration and is associated with time and money consuming.
9.3 Patients at Risk to Develop Severe OHSS
Controlled ovarian hyperstimulation which combines GnRH antagonist co-treatment and GnRH agonist (GnRHa) trigger has recently become a common tool aiming to eliminate severe early OHSS and to support the concept of an OHSS-free clinic [4, 5] (Figs. 9.7 and 9.8). However, due to the reported significantly reduced clinical pregnancy and increased first trimester pregnancy loss [6, 7], efforts have been made to improve reproductive outcome. While discussing the recent developments in GnRHa trigger, Kol and Humaidan [8] presented three optional strategies aiming to improve outcome: freeze-all policy; fresh transfer and intensive luteal support; and fresh transfer and low-dose HCG supplementation.
Fig. 9.8
Evaluation of OHSS with vaginal transducer
Fig. 9.9
GnRH agonist vs. hCG: 11 RCT—1055 women
9.3.1 Freeze-All Policy
Freeze-all policy is offered in extreme cases [5] in an attempt to ensure OHSS risk-free and maintain a reasonable cumulative pregnancy rate [9]. However, despite the recent improvement in live birth rates after replacement of frozen-thawed vitrified oocytes/embryos, it should be emphasized that in most centers, there is still a gap in live birth rates between fresh and frozen/thawed cycles (in favor of fresh cycle).
Following the FIGO REI Committee (2015–2018), the good practice for freeze-all policy is:
≥20 oocytes are collected
E2 above 15,000 pmol/L
Patient unwell
Ascites
9.3.2 Intensive Luteal Support
Intense luteal support with estradiol and progesterone (E2) and progesterone, as described by Engmann et al. [10]. The data regarding the efficacy of luteal phase rescue after GnRHa trigger followed by intensive luteal phase support are intriguingly conflicting. We compared our experience with GnRHa trigger before [7] and after modifying our luteal-phase support to the intensive support with E2 and progesterone similar to the one reported by Engmann et al. [10]. We could not demonstrate any differences in peak E2 levels, fertilization rate, number of embryos transferred, or implantation and pregnancy rates, between the two luteal support regimens [11]. Of notice, that in both groups of luteal support following GnRH-a trigger, implantation and pregnancy rates were lower compared to HCG trigger [7] (Fig. 9.9).
Fig. 9.10
Intensive luteal support
9.3.3 One Bolus of 1500 IU hCG
One bolus of 1500 IU hCG 35 h after the triggering bolus of GnRHa, i.e., 1 h after oocyte retrieval [12, 13], was demonstrated to rescue the luteal phase, resulting in a reproductive outcome comparable with that of HCG triggering, and with no increased risk of OHSS [14]. However, when applied to patients at high risk to develop severe OHSS, 26% developed severe early OHSS requiring ascites drainage and hospitalization [15]. A figure that is comparable to the acceptable 20% prevalence of severe OHSS in ostensibly high-risk patients [16] (Fig. 9.10).
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