The role of elagolix in ovulation suppression during controlled ovarian stimulation: a retrospective cohort study

David Soliman: Writing – review & editing, Writing – original draft, Project administration, Investigation, Formal analysis, Data curation. Rita Naoom: Writing – original draft. Mohamed Zaied: Writing – original draft. Samuel Soliman: Supervision, Conceptualization.

A total of 194 cycles were included in this study: 71 cycles were included in the study group receiving E, and the control group comprised 123 patients receiving G. The G group had a significantly higher mean peak E2 level (11,352.3 vs. 7,505.6 pg/mL; P =.03) than the E group. Other than this, the baseline traits between groups were similar; there were no statistically significant differences in age or BMI between groups, with the mean age being approximately 35.4 years old in the E group and 36.1 years old in the control group ( P= .304). There were no significant differences between groups regarding the proportion of patients in each age group (40). ( Table 1 ) The mean BMI was 26.9 in the E group and 26.2 in the control group ( P= .368). The groups were similar regarding the mean levels of basal FSH (E: 7.00 vs. G: 7.60 IU/L; P= .186), AMH (E: 36.7 vs. G: 21.6 pmol/L; P= .456), or P4 at the time of trigger (E: 1.40 vs. G 1.20 ng/mL; P= .142). The groups were similar regarding the mean number of retrieved (E: 12.7 vs. G: 12.4; P= .879), mature (E: 10.2 vs. G: 10.1; P= .679), and fertilized oocytes (E: 8.6 vs. G: 8.2; P= .90). The mean number of blastocysts generated (E: 5.2 vs. G: 5.2; P= .569) and embryos frozen (E: 4.9 vs. G: 4.5; P= .467) were similar between groups ( Table 1 ). Table 1 Group demographics and cycle characteristics: fresh and frozen cycles combined. Characteristics Elagolix Ganirelix P value RR (95% CI) No. cycles 71 123 n/a n/a overall cancellation rate 5/71 (7.0%) 6/123 (4.9%) .499 a 1.4855 (0.4705–4.6898) Mean gonadotropin dose (IU) 3207.8 3422.0 .215 b n/a Mean FSH (IU/L) 7.60 7.00 .186 b n/a Mean P4 at hCG trigger (ng/mL) 1.40 1.20 .142 c n/a Mean AMH level (ng/mL) 5.138 3.024 .456 d n/a Mean peak E2 (pmol/L) (pg/mL) 1,050,784 1,589,322 .03 d n/a Mean peak LH (IU/L) 7.1 7.2 .281 d n/a Mean BMI (kg/m 2 ) 26.9 26.2 .368 b n/a Grav 0 41/71 (57.7%) 83/123 (67.5%) .192 e 0.856 (0.677–1.081) Para 0 57/71 (80.3%) 102/123 (82.9%) .651 e 0.968 (0.841–1.114) Mean age (y) 35.4 36.1 .304 b n/a 40 12/71 (16.9%) 19/123 (15.5%) .790 1.0941 (0.5649–2.1192) Note: AMH = antimüllerian hormone; BMI = body mass index; CI = confidence interval; E2 = estradiol; FSH = follicle-stimulating hormone; hCG = human chorionic gonadotropin; LH = luteinizing hormone; n/a = not applicable; RR = relative risk. a Fisher’s Exact Test b Student’s t -test c Welch’s t -test d Mann-Whitney U test e χ 2 test Group demographics and cycle characteristics: fresh and frozen cycles combined. Note: AMH = antimüllerian hormone; BMI = body mass index; CI = confidence interval; E2 = estradiol; FSH = follicle-stimulating hormone; hCG = human chorionic gonadotropin; LH = luteinizing hormone; n/a = not applicable; RR = relative risk. Fisher’s Exact Test Student’s t -test Welch’s t -test Mann-Whitney U test χ 2 test Regarding the primary cause of infertility, the E group showed a significantly higher incidence of polycystic ovarian syndrome (11.3% vs. 0.0%; P= .02; RR 29.28 [1.72, 499.81]) and tubal factor infertility (9.9% vs. 2.4%; P= .038; RR 4.042 [1.079, 15.141]) compared with the G group. The incidences of all other primary causes of infertility were similar between groups. ( Supplemental Table 1 , available online). The groups did not differ regarding the proportions of transfer types performed, including single ET, double ET, and >2 ET, with most of the cycles being single ETs. ( Supplemental Table 2 ). The gravidity and parity of each group were similar; most patients had no prior pregnancies (g0) and no prior deliveries (P0) ( Table 1 ). The intracytoplasmic sperm injection utilization rate was 75.8% and 76.1% for E and G, respectively ( P= .962). Out of 671 mature oocytes inseminated by either intracytoplasmic sperm injection or conventional IVF treatment in the E group, 566 oocytes were fertilized, achieving a fertilization rate of 84.4%. In the control group, 955 oocytes were fertilized out of 1,178 mature oocytes to obtain a fertilization rate of 81.1%, and the difference was not statistically significant ( P= .069; RR 1.041 [0.997, 1.086]). A total of 340 blastocysts were generated from fertilized oocytes of the E group, with a blastulation rate of 60.1%. In the control group, 610 blastocysts were generated, giving a blastulation rate of 63.9%. This difference was not significant ( P= .144; RR 0.941 [0.866, 1.021]). ( Table 2 ) Table 2 Embryology data. Characteristics Elagolix Ganirelix P value RR (95% CI) Mean oocytes retrieved 12.7 12.4 .879 a n/a Mean mature oocytes 10.2 10.1 .679 a n/a Mean oocytes fertilized 8.6 8.2 .9 a n/a Mean blasts generated 5.2 5.2 .569 a n/a Mean no. embryos frozen 4.90 4.50 .467 b n/a Fertilization rate 566/671 (84.4%) 955/1178 (81.1%) .069 c 1.041 (0.997–1.086) Blastulation rate 340/566 (60.1%) 610/955 (63.9%) .144 c 0.941 (0.866–1.021) No. cycles ICSI (%) 50/66 (75.8%) 89/117 (76.1%) .962 c 0.996 (0.840–1.181) No. cycles conventional IVF (%) 16/66 (24.2%) 28/117 (23.9%) n/a n/a Note: CI = confidence interval; ICSI = intracytoplasmic sperm injection; IVF = in vitro fertilization; n/a = not applicable; RR = relative risk. a Mann-Whitney U test b Student’s t -test c χ 2 test. Embryology data. Note: CI = confidence interval; ICSI = intracytoplasmic sperm injection; IVF = in vitro fertilization; n/a = not applicable; RR = relative risk. Mann-Whitney U test Student’s t -test χ 2 test. The number of canceled cycles in the E group was 5, 4 of which were canceled because of poor response to stimulation and one because of premature ovulation. The number of canceled cycles in the control group was six, including four because of poor response and two because of premature ovulation. The two groups’ overall cycle cancellation rates were similar (E: 7.0% vs. G: 4.9%; P= .499; RR 1.486 [0.471, 4.690]) ( Table 1 ). Overall, 51 patients underwent frozen embryo transfers (FETs) in the E group and 93 in the control group. In total, 13 (25.5%) patients in the E group and 30 (32.3%) in the G group underwent a transfer with preimplantation genetic testing for aneuploidy (PGT-A)-tested embryos ( P= .405). Among those in the E group, 11 (84.6%) were euploid, 1 (7.7%) was mosaic, and 1 (7.7%) was inconclusive. In the G group, 26 (86.7%) were euploid, 4 (13.3%) were mosaic, and 1 (4.7%) was inconclusive, and these proportions were statistically similar ( Supplemental Table 3 ). The biochemical pregnancy rate was significantly higher in the E group (E: 74.5% vs. G: 55.9%; P= .020; RR 1.333 [1.047, 1.697]) ( Table 3 ). Notably, the difference between the biochemical pregnancy rate of the FETs that did and those that did not have PGT-A-tested embryos transferred was not statistically significant (PGT-A: 58.1% vs. No PGT-A 64.4%; P= .496; RR 0.903 [0.675, 1.210]) and the differences still failed to reach significance after stratifying based on age (<35 and ≥ 35) years ( Supplemental Table 4 ). The sustained implantation rate was higher for the E group, but the difference was insignificant (51.0% vs. 39.8%; P= .186; RR 1.281 [0.888, 1.850]). The miscarriage rate was similar between groups (31.6% vs. 28.8%; P =.779; RR 1.095 [0.581, 2.063]). Table 3 Clinical outcomes: frozen cycles. Outcomes Elagolix (%) Ganirelix (%) P value RR (95% CI) Biochemical pregnancy rate/ET 38/51 (74.5) 52/93 (55.9) .020 a 1.333 (1.047–1.697) Sustained implantation rate/ET 26/51 (51.0) 37/93 (39.8) .186 a 1.281 (0.888–1.850) Miscarriage rate/biochemical pregnancy 12/38 (31.6) 15/52 (28.8) .779 a 1.095 (0.581–2.063) Note: CI = confidence interval; ET = embryo transfer; RR = relative risk. a χ 2 test. Clinical outcomes: frozen cycles. Note: CI = confidence interval; ET = embryo transfer; RR = relative risk. χ 2 test. In the E and G groups, 15 and 24 patients underwent a fresh ET, respectively. The biochemical pregnancy rates were similar (33.3% vs. 37.5%; P= .794; RR 0.889 [0.368, 2.149]) as were the sustained implantation rates (33.3% vs. 25.0%; P= .571; RR 1.333 [0.492, 3.611]). The miscarriage rate was lower in the E group, but this difference was non-significant (0 vs. 33.3%; P= .313; RR 0.238 [0.015, 3.857]) ( Table 4 ). For the fresh ET cycles, the proportion of patients with no prior delivery (Para 0) was significantly higher in the E group (E: 93.3% vs. G: 62.5%; P= .020; RR 1.492 [1.065, 2.094]). Besides this, the gravidity and parity of each group were similar ( Supplemental Table 5 ). Table 4 Clinical outcomes: fresh cycles. Outcomes Elagolix (%) Ganirelix (%) P value RR (95% CI) Biochemical pregnancy rate/ET 5/15 (33.3) 9/24 (37.5) .794 b 0.889 (0.368–2.149) Sustained implantation rate/ET 5/15 (33.3) 6/24 (25.0) .571 a 1.333 (0.492–3.611) Miscarriage rate/Biochemical pregnancy 0/5 (0.0) 3/9 (33.3) .313 a 0.238 (0.015–3.857) Note: CI = confidence interval; ET = embryo transfer; RR = relative risk. a Fisher’s exact test. b χ 2 test. Clinical outcomes: fresh cycles. Note: CI = confidence interval; ET = embryo transfer; RR = relative risk. Fisher’s exact test. χ 2 test.

This retrospective cohort study was conducted at a private IVF treatment center in Mississauga, Canada, and was approved by the local research ethics board. The data on clinical and embryological outcomes and usage of E were gathered from patients’ electronic medical records and the IVF treatment center dataset from January 4, 2022, until September 25, 2022. Included patients were those who had pituitary suppression achieved with E during the COS cycle and cases that used G as a comparator. Data on baseline demographic characteristics such as age, body mass index (BMI), number of embryos transferred, gonadotropin dose and stimulation duration, and infertility diagnosis were compared between the study and control groups. Clinical and embryological outcome data were analyzed retrospectively and compared between the study and control groups. The final sample comprised 194 patients with infertility aged 23–50 years with a BMI ranging from 15–42 kg/m 2 who had received E or G for pituitary suppression. The E group comprised 71 patients, whereas the G (control) group comprised 123 patients. • Inclusion criteria: patients with infertility, aged 23–50 years with a BMI ranging from 15–42 kg/m 2 having received either E alone or G alone for pituitary suppression during the COS cycle. • Exclusion criteria: patients outside the age range defined in the inclusion criteria. Patients who received neither or both E or G. Patients who were receiving either drug for a reason other than COS. Inclusion criteria: patients with infertility, aged 23–50 years with a BMI ranging from 15–42 kg/m 2 having received either E alone or G alone for pituitary suppression during the COS cycle. Exclusion criteria: patients outside the age range defined in the inclusion criteria. Patients who received neither or both E or G. Patients who were receiving either drug for a reason other than COS. On cycle day 3, patients began oral clomiphene citrate (Clomid. Ferring Inc., Toronto, Ontario, Canada; 100 mg orally) daily for 5 days as well as daily injections of recombinant FSH (Puregon; Organon Canada Inc., Kirkland, Quebec, Canada), with the initial dose ranging from 200–325 IU/d on the basis of age, FSH level, antimüllerian hormone (AMH) level, and antral follicular count. On day 7 and then at 3–4-day intervals, serum E2 level testing and ultrasound monitoring were performed to guide recombinant FSH dosing. When a lead follicle of 14 mm or greater was observed on ultrasound, pituitary suppression was initiated. The study group received E (Orilissa, AbbVie Inc., Saint-Laurent, Quebec, Canada; 200 mg orally, two times per day); the control group received G (Cetrotide, Merck Canada Inc., Kirkland, Quebec, Canada; 250 μg, subcutaneously [SC], every night at bedtime). Elagolix, or G, was discontinued 24 hours before the GnRH agonist and human chorionic gonadotropin (hCG) trigger. Once follicular maturity was reached, as indicated by the E2 levels and follicular number and size, a GnRH agonist (Decapeptyl, Ferring Inc., Toronto, Ontario, Canada; 0.2 mg, SC/Suprefact, Xediton Pharmaceuticals Inc., Oakville, Ontario, Canada; 0.5 mg SC) and an hCG trigger (Pregnyl, Organon Canada Inc., Kirkland, Quebec, Canada; 10,000 IU SC) was used to induce ovulation. Oocyte retrieval was performed 36 hours after the trigger injection. Hormone replacement therapy was adopted for endometrial preparation. The protocol was initiated with oral E2 (Estrace, Trimel Pharmaceuticals Inc., Mississauga, Ontario, Canada; 4 mg three times daily) beginning on cycle days 2–5 after the transvaginal ultrasound scan. After a second ultrasound scan was performed and serum E2 and P4 levels were checked, the dose of E2 was adjusted accordingly. Luteal support was initiated when endometrial thickness reached ≥8 mm, and serum E2 and P4 levels were optimal. Luteal phase support was achieved via oral P4 (Prometrium, Merck Canada Inc., Kirkland, Quebec, Canada; 200 mg three times) daily and intravaginal micronized P4 suppositories (200 mg, three times daily). Progestin supplementation continued until pregnancy was confirmed at 10 weeks. Embryo vitrification and thawing followed the Kitazato (Kitazato Corp., Fuji, Shizuoka, Japan) protocol. Embryos were thawed the morning of the transfer and moved into organ culture dishes containing 1 mL of culture media (Life GlobalTotal, Cooper Surgical Inc., Toronto, Ontario, Canada) to be cultured for 3–4 hours, awaiting the transfer. The embryo transfer (ET) procedure was performed as described previously ( 12 ). Embryos were hatched using a Reproductive Instruments Saturn diode laser (Cooper Surgical Inc., Toronto, Ontario, Canada) on day 3 of culture to allow trophectoderm herniation by day 5 or 6, after which biopsy was performed according to previously described methods ( 13 ). Biopsied samples were processed for deoxyribonucleic acid amplification, which was performed using a polymerase chain reaction. Chromosomal copy number analysis was performed using next-generation sequencing using the Illumina MiSeq platform (Illumina Canada Inc., Victoria, British Columbia, Canada) performed at the in-house genetic laboratory. A positive serum β-hCG level test confirmed biochemical pregnancy 2 weeks after the transfer. Sustained implantation was defined as the presence of a fetal heartbeat observed using ultrasonography 7–9 weeks post-ET. The sustained implantation rate per transfer was defined as the number of sustained implantations divided by the total number of ETs. Miscarriage was defined as a positive biochemical pregnancy test followed by the absence of a fetal heartbeat on the 7–9-week ultrasound. The miscarriage rate per biochemical pregnancy was defined as the proportion of patients who had a positive biochemical pregnancy test but did not show a fetal heartbeat on a 7–9-week ultrasound. The fertilization rate was defined as the number of fertilized oocytes divided by the total number of mature oocytes inseminated. The blastulation rate was defined as the number of blastocysts generated divided by the total number of fertilized oocytes. Continuous variables were presented as means. As appropriate, differences between groups were assessed using Student’s or Welch’s t -test and Mann-Whitney U tests. Categorical variables were expressed as frequencies and percentages within groups and were compared using Pearson’s χ 2 and Fisher’s exact tests as appropriate, with a P value of <.05 considered statistically significant. Relative risks (RRs) with 95% confidence intervals were calculated.

Elagolix is an oral GnRH antagonist that is US Food and Drug Administration-approved for the treatment of endometriosis-induced pain ( 4 , 5 ). Recently, studies have shown that it effectively suppresses ovulation during the COS cycle as efficiently as the injected antagonist, G ( 14 , 15 , 16 ). This retrospective cohort study examined the efficacy of E for ovulation suppression during COS relative to G. The study and control groups did not differ in their baseline characteristics and had similar numbers of oocytes retrieved and blastocysts frozen ( Tables 1 and 2 ). It should be noted that the E group had a significantly lower peak E2 level than the G group, and this was most likely because the dose of E for this group (200 mg twice daily) is higher than the dosage used in previous studies (200 mg once daily) ( 10 ). Importantly, the cycle cancellation rates were similar between the E and G groups ( Table 1 ), indicating that ovulation suppression is not compromised with the use of E. Regarding embryology outcomes, there were no differences in fertilization or blastocyst development rates between the study and control groups ( Table 2 ). Furthermore, the groups did not differ in the number of embryos transferred ( Supplemental Table 2 ). When examining FETs, the E group’s biochemical pregnancy rate was significantly higher (E: 74.5% vs. G: 55.9%; P= .02, RR 1.333 [1.047, 1.697]). However, this difference was not observed for patients undergoing fresh ETs ( Tables 3 and 4 ). Additionally, the E group displayed a decreased miscarriage rate within the fresh ET subgroup. Still, this difference did not reach statistical significance, and regarding FETs, the groups were similar in this respect. The sustained implantation rates per transfer were similar between the E and the control groups for fresh and frozen ETs ( Tables 3 and 4 ). Importantly, the utilization rate of PGT-A was similar in both groups, with a similar percentage of these patients having euploid embryos transferred ( Supplemental Table 4 ). Moreover, the biochemical pregnancy rate across all FETs seemed unaffected by the use of PGT-A, which was found for patients above and below 35 ( Supplemental Table 5 ). These data suggest that the apparent improvement in biochemical pregnancy in the E group undergoing FETs (E: 74.5% vs. G: 55.9%, P= .02, Table 3 ) is not because of greater utilization of euploid embryos. When analyzing FETs, the higher E2 levels in the G group were likely not the cause of the observed difference in biochemical pregnancy. This is because the endometrial disturbance caused by supraphysiologic E2 levels is removed in FET cycles by allowing time after the ovarian stimulation cycle for hormone level normalization. Additionally, no differences between the groups were observed in any clinical outcomes when analyzing fresh ET cycles, wherein a perturbed uterine environment caused by elevated E2 levels would normally pose an issue ( 17 ). One plausible explanation for the higher biochemical pregnancy rate in the E group is the higher incidence of patients with tubal factor infertility and polycystic ovary syndrome in this group. Patients with these etiologies can be considered to have a good prognosis and would be expected to have better outcomes. Thus, the higher proportion of these good prognosis patients in the E group could account for the observed improvement in biochemical pregnancy. These preliminary findings demonstrate the clinical utility of the oral GnRH antagonist E for ovulation suppression during the COS cycle. Our results agree with previous studies showing that E has similar efficacy to injectable antagonists for preventing premature ovulation. ( 10 , 11 ). To our knowledge, this is the first study to demonstrate that clinical outcomes do not differ significantly between patients using E and G for pituitary suppression. Herein, we observed a potential improvement in the biochemical pregnancy rate in the E group undergoing FETs, regardless of PGT-A utilization. This difference may suggest a potential benefit of E over G. However, the reason for this difference is currently unknown, and randomized clinical trials are needed to address this question. As the demand for IVF treatment grows, the potential arises to enhance patient care. Oral GnRH antagonists are less invasive, more efficient, and cost effective than the current antagonist and agonist protocols, which require multiple injections and more time for pituitary down-regulation and suppression ( 1 ). To expand on the financial benefit of the oral antagonist, patients in the elagolix group took two tablets daily for an average of 5 days, near the end of the stimulation cycle, until they were instructed to trigger. At an average cost of $8.40 Canadian Dollars (CAD) for each tablet of elagolix, patients paid approximately $84.00 for pituitary suppression during their cycles ( 18 ). Conversely, patients in the ganirelix group were administered one injection of ganirelix daily for an average of 7 days, near the end of the stimulation cycle. At an average cost of $103.30 CAD for one injection of ganirelix, patients would have paid approximately $723.10 CAD for pituitary suppression ( 19 ). Thus, the average savings accrued using elagolix instead of ganirelix amount to approximately $639.10 CAD per ovarian stimulation cycle. Therefore, elagolix could represent a promising alternative to injected antagonists for pituitary suppression in COS ( 1 ). Nonetheless, the current analysis is limited in its retrospective nature and because it was not powered to detect differences in the primary outcomes of biochemical pregnancy, sustained implantation, and cycle cancellation rates because of the small sample size (N = 194). The lack of follow-up to live births poses another limitation, as does the fact that some embryos were cryopreserved and not used for transfer within the study timeframe, meaning their input to the study cannot be considered. Additionally, these data were collected from a single center, thus limiting the generalizability of the findings. Therefore, these preliminary findings must be interpreted cautiously and validated with large, robust, randomized clinical trials.

The oral GnRH antagonist, elagolix, may be as effective as the injected antagonist, ganirelix, regarding embryological and clinical outcomes and could offer a less invasive, more cost effective, and “patient-friendly” approach to pituitary suppression for IVF treatment.

D.S. has nothing to disclose. R.N. has nothing to disclose. M.Z. has nothing to disclose. S.S. has nothing to disclose.