Evaluation of pregnancy outcomes using medroxyprogesterone acetate versus gonadotropin-releasing hormone antagonist in ovarian stimulation: A retrospective cohort study

Abstract Background Limited studies have compared pregnancy outcomes with medroxyprogesterone acetate (MPA) vs. gonadotropin-releasing hormone antagonist (GnRH antagonist) in ovarian stimulation protocols. The results show heterogeneity. Objective This study aims to assess pregnancy outcomes with the use of MPA instead of GnRH antagonist for ovarian stimulation in donor-recipient cycles. Materials and Methods This retrospective study was carried out from June 2016 to May 2019. The study included 250 donors receiving ovarian stimulation with 2 different protocols: group 1 (n = 109) receiving GnRH antagonist (0.25 mg/day) from the 5 th or 6 th day of menses and group 2 (n = 141) receiving MPA (10 mg/day) from the second day of menses. In 384 recipients, 2 good-quality blastocysts were transferred after endometrial preparation. The primary endpoint was live birth in recipients. Results The results showed that live birth was comparable in both recipient groups (59% vs. 60%, OR: 0.63, 95% CI: 0.13-2.99, p = 0.559). The number of live-born fetuses (adjusted OR: 0.57, 95% CI: 0.31-1.05, p > 0.01) showed no significant difference in both groups. However, the implantation rate with twin sacs was significantly lower in group 2 (adjusted OR: 0.57, 95% CI: 0.33-0.99, p = 0.05). The regression analysis for good-quality blastocyst proportion was comparable (OR: 0.63, 95% CI: -4.33-5.60, p = 0.802) in both donor groups. The mean stimulation cost in group 2 was less than in group 1. Conclusion MPA had a comparable live birth and embryological outcomes in both groups. Oral administration makes it convenient, acceptable, and patient-friendly. Its cost-effectiveness and convenience open new possibilities in ovarian stimulation protocols.


Introduction
Luteinizing hormone (LH) surges and, hence, ovulation can be blocked by progesterone. It has been shown that giving progestin from the start of the cycle blocks LH surge despite a rise in estradiol, as long as it is given.
It sharply decreases both follicle-stimulating hormone (FSH) and LH secretion. This inhibition is completely reversible after discontinuation of progestin (1,2). It has been shown that progestin blocks LH surges due to consistent LH suppression during ovarian stimulation (OS) (3)(4)(5).  Transvaginal ultrasound-guided oocyte retrieval was carried out 35-36 hr after the trigger.

Study design
Oocytes were denuded of cumulus cells and M2 were allocated to recipients in both groups.
Oocytes were inseminated by intracytoplasmic sperm injection (ICSI) after selecting sperms.
Embryos were cultured in 1-step media until the blastocyst stage. Gardner's grading system was used for grading blastocysts. Embryos of the 3AA stage and above were labeled as good-quality blastocysts. FET of 2 good-quality blastocysts was performed in recipients. The recipient's endometrium was prepared using an artificial hormonal replacement cycle.

Hormone replacement therapy (recipients)
Endometrial preparation was started in all recipient patients from day 2 of menses.

Outcome measures
The primary outcome was the live birth rate in recipients. Secondary outcomes related to donors included M2 oocyte proportion percent at oocyte retrieval, duration of stimulation, total consumption of gonadotropins, blastulation rate, and good-quality blastocyst proportion.
Secondary outcomes related to recipients were biochemical pregnancy, implantation rate, and clinical pregnancy rate.

Ethical considerations
The study protocols were approved by Sharda Narayan Ethics Committee, Mau, India

Discussion
The use of GnRH antagonist vs. MPA had a comparable live birth in both groups. In this study, the authors found embryological characteristics to be comparable in both groups. Although live birth was comparable, with 2 embryos transferred in both the groups, twin sac implantations were significantly less in group 2. Comparative studies of progestin for prevention of LH surge, and its subsequent embryological and pregnancy outcomes in OS of patients followed by FET in the next cycle have shown similar results and comparable outcomes (2,8). In a previous report of Beguería and colleagues, the duration of stimulation, as well as the total gonadotropin dose up to trigger, was similar in GnRH antagonist and MPA-treated patients (9).
As per the definition of premature LH surge, no premature LH surge was observed in other studies International Journal of Reproductive BioMedicine MPA vs. GnRH antagonist with the use of progestin to inhibit spontaneous ovulation during OS (10) or with the use of GnRH antagonists (11). In our study, MPA was started from day 2 of the menses along with rFSH injection. As a result, there was consistent LH suppression with no incidence of premature LH surge. In previous studies, there was no case of premature LH surge reported in PCOS patients receiving 10 mg of MPA daily as well as in normal responders co-administered with either 4 mg or 10 mg of MPA per day during OS (12,13). We observed that embryological characteristics were similar in both groups. The M2 oocyte proportion showed slightly higher retrieval in group 2 but this was not statistically significant when multivariable regression analysis was performed, unlike the finding of significantly higher yield of M2 oocyte as stated in a retrospective study of donor oocyte cycles (14). It was a small study on 13 oocyte donors. Our finding is in accordance with the earlier comparative study where MPA was comparable to GnRH antagonist in terms of the number of mature oocytes retrieved at ovum pick up in oocyte donation cycles and was non-inferior to GnRH antagonist. This study comparing both drugs in the oocyte-donation cycle had comparable M2 retrieval but showed negative pregnancy outcomes in recipients (9); however, the intention-to-treat multilevel analyses had a p-value = 0.05 for live birth rate. In our study, live births were not significantly different in the groups. The effectiveness of MPA on the clinical pregnancy rates, implantation rates, and live-birth rates was previously studied and was found to be comparable (2,13).
For proper interpretations of the results of pregnancy outcomes, one should keep in mind that, in most studies, a comparison of MPA was done with GnRH agonist or other progestins in short GnRH agonist protocols, rather than a GnRH antagonist protocol (2,13). The current study, however, analyzed the results of the use of MPA in a GnRH antagonist protocol. The use of this protocol is recommended in oocyte donation cycles to reduce the incidence of ovarian hyperstimulation syndrome (15,16). In addition, we administered rFSH to all patients and donors; in previous studies (15,9), a few authors used hMG, having a small amount of urinary human chorionic gonadotropin (HCG) (13,2). Moreover, we used the GnRH agonist trigger for donors to minimize the risk of ovarian hyperstimulation syndrome, as used in some studies (17,18), while in other studies the trigger was performed with HCG (2) or by HCG and triptorelin (14).

Conclusion
Based on the findings of this study, the authors conclude that MPA may be as effective as GnRH antagonists to achieve positive reproductive and pregnancy outcomes in the oocyte donation cycle.