Elagolix for ovulation suppression in in vitro fertilization: Is it time to switch from the painful costly injectables?

With our 6-year experience of using elagolix in IVF, we have noticed that a successful oocyte maturation trigger can be achieved with GnRH agonist alone (subcutaneous or nasal spray), human chorionic gonadotropin (hCG) trigger alone, or a combination of both GnRH agonist and hCG ( Fig. 1 ). A reassuring finding in the study by Soliman et al. ( 2 ) showed similar ongoing pregnancy, biochemical pregnancy, and miscarriage rates in “fresh” embryo transfer cycles because a fear of elagolix impacting uterine lining receptivity is a real concern. The GnRH receptors (GnRHRs) are expressed in the peripheral female reproductive tissues such as the uterus. In a normal endometrium, these receptors have been shown to regulate crucial processes such as trophoblast invasion and embryo implantation because the endometrium expresses higher levels of both GnRH and GnRHR during the luteal phase than during the follicular phase. Additionally, local GnRH and GnRHR have been proposed to be involved in the regulation of hCG synthesis and secretion. These findings support the concept that GnRH-related cross talk between the embryo and the endometrium is necessary for early pregnancy to maintain progesterone production from the trophoblast during the first trimester of gestation.

Zaher Merhi: Conceptualization, Writing–original draft, Writing–review & editing.

It has been shown that after hCG trigger injection, administration of a GnRH antagonist during the luteal phase could accelerate luteolysis, reduce ovarian vascular endothelial growth factor secretion, and promote regression of ovarian hyperstimulation syndrome symptoms. However, data are limited where many low-quality small studies showed conflicting results regarding the effectiveness of the injectable GnRH antagonist administration in the luteal phase to reduce ovarian hyperstimulation syndrome occurrence. Elagolix represents a potential candidate for this topic, and it is worthwhile for investigators to assess its possible benefit in future studies ( Fig. 1 ). The inhibition of ovulation and reduction of estradiol production are commonly achieved with the intramuscular long-acting GnRH agonist leuprolide acetate, which suppresses the hypothalamic-pituitary axis thus leading to better embryo implantation and pregnancy outcome in infertile women with endometriosis and adenomyosis undergoing IVF. Because many patients complain about intolerable menopausal symptoms on this 3-month regimen, elagolix comes to mind as a possible alternative ( Fig. 1 ). The good news is that we are impatiently waiting for the results of the PREGnant (Pre-IVF treatment with a GnRH antagonist in women with endometriosis) trial ( 5 ), a multicenter, prospective, randomized, double-blind, placebo-controlled trial that is studying the efficacy of elagolix pretreatment for 8 weeks in women with endometriosis before undergoing IVF.

Pituitary gonadotropin suppression during a controlled ovarian stimulation cycle using GnRH antagonists is one of the essential steps for IVF success. Although patients traditionally take daily injections of ganirelix or cetrotide (G/C) for 5–7 days on average, oral elagolix has emerged as a potential contender with studies showing its noninferiority to G/C. This study by Soliman et al. ( 2 ) is very unique because it is the first, to our knowledge, to assess pregnancy rates in women undergoing autologous IVF. The findings demonstrated that elagolix showed no significant difference in embryological and clinical outcomes when compared with G/C. However, and as noted by the investigators themselves, a major limitation was the lack of power analysis—an essential step that must have been performed in a study where no statistical significance was obtained.

The use of elagolix in assisted reproduction was first assessed by Boniface et al. ( 3 ) who evaluated its efficacy in donor oocyte cycles followed by Mouanness and Merhi ( 4 ) who evaluated it in autologous IVF cycles but did not assess the pregnancy rates in their studies. Comparing these 3 studies, one clear discrepancy is the use of different doses of elagolix where Soliman et al. ( 2 ) used 200 mg twice a day, Boniface et al. ( 3 ) used 200 mg once daily, and Mouanness and Merhi ( 4 ) used 50 mg once every other day ( Fig. 1 ). Conversely, they do have a commonality in that elagolix seemed to be more powerful in shutting down the hypothalamic-pituitary axis than the conventional GnRH antagonist injectable G/C. This was demonstrated by the fact that elagolix suppressed serum luteinizing hormone after administration by 42% (compared with that before administration) when compared with G/C (only a 24% decrease in the luteinizing hormone level between preadministration and postadministration) even at 50 mg every other day dose ( 4 ). Additionally, Soliman et al. ( 2 ) showed that the elagolix group at a dosage of 200 mg twice a day had significantly lower peak estradiol levels than the G/C group (11,352 vs. 7,505 pg/mL, respectively; P =.03) despite both groups having all other clinical parameters, such as ovarian reserve, age, and dose of gonadotropins, being similar ( 2 ). Figure 1 Schematic diagram of controlled ovarian stimulation (COS) with the use of elagolix at different doses for pituitary gonadotropin suppression and with few options for oocyte maturation triggers. GnRH = gonadotropin-releasing hormone; hCG = human chorionic gonadotropin; OHSS = ovarian hyperstimulation syndrome. Schematic diagram of controlled ovarian stimulation (COS) with the use of elagolix at different doses for pituitary gonadotropin suppression and with few options for oocyte maturation triggers. GnRH = gonadotropin-releasing hormone; hCG = human chorionic gonadotropin; OHSS = ovarian hyperstimulation syndrome.

It is time to challenge the status quo in the IVF field. We must look for more patient-friendly, less painful, and more cost-effective strategies to help women achieve their goal without suffering from the heavy innumerous injectable medications. The findings by Soliman et al. ( 2 ) provide further reassuring evidence for the use of elagolix in IVF for both fresh and frozen embryo transfer cycles.

Z.M. has nothing to disclose.