Progestin primed ovarian stimulation using corifollitropin alfa in PCOS women effectively prevents LH surge and reduces injection burden compared to GnRH antagonist protocol

Utilizing corifollitropin alfa in GnRH antagonist (GnRHant) protocol in conjunction with GnRH agonist trigger/freeze-all strategy (corifollitropin alfa/GnRHant protocol) was reported to have satisfactory outcomes in women with polycystic ovary syndrome (PCOS). Although lessening in gonadotropin injections, GnRHant were still needed. In addition to using corifollitropin alfa, GnRHant was replaced with an oral progestin as in progestin primed ovarian stimulation (PPOS) to further reduce the injection burden in this study. We try to investigate whether this regimen (corifollitropin alfa/PPOS protocol) could effectively reduce GnRHant injections and prevent premature LH surge in PCOS patients undergoing IVF/ICSI cycles. This is a retrospective cohort study recruiting 333 women with PCOS, with body weight between 50 and 70 kg, undergoing first IVF/ICSI cycle between August 2015 and July 2018. We used corifollitropin alfa/GnRHant protocol prior to Jan 2017 (n = 160), then changed to corifollitropin alfa/PPOS protocol (n = 173). All patients received corifollitropin alfa 100 μg on menstruation day 2/3 (S1). Additional rFSH was administered daily from S8. In corifollitropin alfa/GnRHant group, cetrorelix 0.25 mg/day was administered from S5 till the trigger day. In corifollitropin alfa/PPOS group, dydrogesterone 20 mg/day was given from S1 till the trigger day. GnRH agonist was used to trigger maturation of oocyte. All good quality day 5/6 embryos were frozen, and frozen-thawed embryo transfer (FET) was performed on subsequent cycle. A comparison of clinical outcomes was made between the two protocols. The primary endpoint was the incidence of premature LH surge and none of the patients occurred. Dydrogesterone successfully replace GnRHant to block LH surge while an average of 6.8 days of GnRHant injections were needed in the corifollitropin alfa/GnRHant group. No patients suffered from ovarian hyperstimulation syndrome (OHSS). The other clinical outcomes including additional duration/dose of daily gonadotropin administration, number of oocytes retrieved, and fertilization rate were similar between the two groups. The implantation rate, clinical pregnancy rate, and live birth rate in the first FET cycle were also similar between the two groups. In women with PCOS undergoing IVF/ICSI treatment, corifollitropin alfa/PPOS protocol could minimize the injections burden with comparable outcomes to corifollitropin alfa/GnRHant protocol.

Using Letrozole Cotreatment With Progestin-Primed Ovarian Stimulation In Women With Polycystic Ovary Syndrome Treated For IVF

Background: Women with polycystic ovary syndrome (PCOS) often experience poor oocyte quality and a high risk of ovarian hyperstimulation syndrome (OHSS) when treated with controlled ovarian stimulation (COS) in vitro fertilization (IVF). Progestin-primed ovarian stimulation (PPOS) shows good potential to compete with conventional protocols in women with PCOS. However, it always accompanied by increased pituitary suppression and gonadotropin consumption. Letrozole (LE) has the ability to increase luteinizing hormone (LH) levels and appears to have the potential to alleviate pituitary inhibition during COS in women with PCOS. A retrospective cohort trial was performed to evaluate the efficacy of PPOS with or without letrozole in infertile women with PCOS.Methods: This retrospective cohort study included 448 women with PCOS who underwent COS with human menopausal gonadotropin (hMG) and medroxyprogesterone acetate (MPA) (n=224) or hMG and MPA cotreatment with LE (n=224) from January 2018 to March 2021. Baseline characteristics of the two groups were balanced with propensity score matching using the nearest neighbour random matching algorithm at a ratio of 1:1. The primary outcome measure was the implantation rate. The secondary outcomes were the endocrinological profiles, gonadotropin dose and duration, number of oocytes retrieved and viable embryos, clinical pregnancy rate, miscarriage rate and ectopic pregnancy rates.Result(s): The implantation rate was significantly higher in the study group than that in the control group (42.22% vs. 34.69%, P < 0.05). Compared with the control group，the study group had a higher LH concentration on the trigger day (3.85±3.6 mIU/ml vs. 2.44±1.71 mIU/ml, P < 0.01), but there was no case of premature LH surge or OHSS in both groups. The consumption of gonadotropin, the number of oocytes retrieved and viable embryos were similar between the two groups. Additionally, no difference was found in the clinical pregnancy rate, miscarriage rate or ectopic pregnancy rate.Conclusion(s): This study shows that LE administration in the PPOS protocol was feasible to improve the implantation rate and alleviate profound pituitary suppression from progestin administration without interfering with its premature LH surge blockade effect but with a non-significant reduction in gonadotropin consumption in women with PCOS undergoing IVF treatment.

Comparison of Progestin-Primed Ovarian Stimulation Regimen and Antagonist Regimen in Diminished Ovarian Reserve Patients Over 35 Years of Age

Background the aim of this study was to compare the efficacy of progestin-primed ovarian stimulation (PPOS) regimen and GnRH antagonist regimen in infertile patients older than 35 years with diminished ovarian reserve (DOR). Methods a retrospective cross-sectional study of 196 in vitro fertilization (IVF) cycles between January 2016 and January 2020 was performed. The measured outcomes included the number of retrieved oocytes, incidence of premature LH surge, laboratory indicators and frozen embryo transfer (FET) outcome. Results the number of oocytes retrieved in the antagonist group was higher than those in the PPOS group (p < 0.05). Incidence of premature LH surge in two groups showed no difference (p > 0.05). E2 and P on HCG administration day of antagonist group were higher than those of PPOS group (p < 0.05). And there was no significant difference between two groups of FET outcome indicators (p > 0.05). Conclusions for DOR patients over 35 years of age, antagonist regimen would retrieve more oocytes than PPOS regimen. Therefore, from the perspective of oocyte retrieving, the antagonist regimen might be more suitable for DOR patients over 35 years old.

P–685 Luteinization after final oocyte maturation induction is not compromised in women that receive double dose of Gonadotrophin-releasing hormone antagonists during controlled ovarian hyperstimulation

Study question Does the use of double dose of GnRH antagonists during COH in women with risk of premature LH surge alter luteinization after final oocyte maturation induction? Summary answer The use of double dose of GnRH antagonist in women with risk of premature luteinizing hormone surge dosent affect luteinization after final oocyte maturation induction. What is known already GnRH antagonists are used to prevent a premature LH surge during controlled ovarian hyperstimulation. The antagonists directly inhibit gonadotrophin release within several hours through competitive binding to pituitary GnRH receptors, producing a rapid suppression of LH and FSH, with no initial flare effect. In women with diminished ovarian reserve (DOR) it is not uncommon that premature luteinization cannot be completely prevented using a daily dose GnRH antagonist. To date, no study has evaluated the effects of using a daily double dose of GnRH antagonists to prevent a premature LH surge and its effect on luteinization after final oocyte maturation induction. Study design, size, duration This monocentric retrospective analysis evaluated the effect on luteinization after final oocyte maturation induction in twenty women during COH who received a daily double dose of GnRH antagonists (Cetrotide 0.25 mg/mL, Merck) from January 2020 to December 2020. Participants/materials, setting, methods Women with severe DOR and history of premature luteinization during COH received a double dose of GnRH antagonist when the leading follicle reached 12–14 mm (am and pm). When two follicles reached ≥18 mm in diameter, final oocyte maturation was induced with dual trigger using Leuprolide acetate and hCG. Progesterone, estradiol, bHCG, and LH levels were measured the day after final oocyte maturation induction to assure adequate luteinization. Main results and the role of chance In total twenty women were included in the analysis. Mean age 36.8± 4.2, AMH 0.65± 0.32 ng/ml, baseline antral follicle count 4± 2.3, serum hormone levels the day of ovulation induction trigger: progesterone 0.89± 0.34 ng/ml, LH 1.6± 2.1 ng/ml, estradiol 1235 ± 1420 pg/ml. Post-surge serum hormone levels average reached adequate levels: estradiol 1645 ± 1116 pg/ml, progesterone 20.4 ±2.2 ng/ml, LH 62.66± 10.5 IU/ml and, bHCG 247±115 IU/ml. A total of 76 oocytes were retrieved (3.8± 0.8 oocytes per patient), 63.1% (48/76) MII, 22% (17/76) MI, 14% (11/76) GV. Limitations, reasons for caution The retrospective nature of the study, small sample size, and potential variability in the study center’s laboratory protocol(s) compared to other reproductive treatment centers may limit the external validity of our findings. Wider implications of the findings: The daily use of double dose of GnRH antagonists during COH offers the possibility of preventing a premature LH surge in women with DOR with high risk of early ovulation, without compromising luteinization after final oocyte maturation induction. Trial registration number NA

Comparison of the effects of Duphaston and Cetrotide on oocyte and embryo quality in women undergoing ICSI: A cross-sectional study

Background: Premature luteinizing hormone (LH) surge is one of the causes for assisted reproductive technology cycle cancellation, and it is needed to find novel approaches with improved efficacy and safety profile. Objective: To compare the effects of Duphaston and Cetrotide on the prevention of premature LH surge and characteristics of retrieved follicles and embryos in women undergoing intracytoplasmic sperm injection. Materials and Methods: In this retrospective cross-sectional study, 200 patients who were administrated recombinant follicle-stimulating hormone from the third day of menstruation cycle were included. When the follicular diameter reached above 13-14 mm, Cetrotide was prescribed in the control group, while in the case group, Duphaston was taken orally from the third day of cycle. The retrieved oocytes were fertilized in vitro by intracytoplasmic sperm. The level of hormones on the third day of menstruation and the characteristic of follicles, oocytes, and embryos were compared between the two groups. Results: Duphaston successfully inhibits premature LH surge. There was no significant difference in the level of follicle-stimulating hormone, estradiol, and LH between the case and control groups (p > 0.05). However, results also showed that Duphaston causes more oocyte retrieval in comparison with Cetrotide (p = 0.04). Although, the number of follicles above 14 mm, mature oocyte, and the total number of viable embryos in the case group was slightly higher, it did not reach a significant difference compared with the control group (p > 0.05). Conclusion: Duphaston could be used as an appropriate medication instead of gonadotropin-releasing hormone antagonists in women undergoing controlled ovarian hyperstimulation. Duphaston prescription not only prevents premature LH surge but also improves the number of retrieved oocytes. Key words: Duphaston, Cetrorelix, Dydrogesterone, COH, GnRh antagonis.

Comparison of Dydrogesterone and GnRH Antagonists for Prevention of Premature LH Surge in IVF/ICSI Cycles: A Randomized Controlled Trial

Objective: To compare the effect of dydrogesterone and GnRH antagonists on prevention of premature luteinizing hormone (LH) surge and pregnancy outcomes in infertile women undergoing IVF/ICSI. Materials and methods: In a Randomized controlled trial (RCT), two-hundred eligible women undergoing in vitro fertilization (IVF) /intracytoplasmic sperm injection (ICSI) treatment were randomly assigned into two groups. Human menopausal gonadotropin (HMG) was administered for controlled ovarian stimulation (COS) in both groups. Intervention group (group 1) received 20 mg dydrogesterone from day 2 of menstrual cycle till trigger day and control group (group2) received GnRH antagonist from the day that leading follicle reached 13 mm in diameter till trigger day. Serum levels of LH, estradiol and progesterone were measured on the trigger day. The primary outcome measure was the incidence of a premature LH surge, and the secondary outcomes investigated were the chemical and clinical pregnancy rates in the first FET cycles. Results: There were no significant differences in patients' age, BMI, AMH levels, previous IVF cycle, and cause of infertility between the two groups. None of the patients in two groups experienced a premature luteinizing hormone surge. The numbers of retrieved oocytes, the MII oocytes and good quality embryos, were significantly higher in the intervention group than antagonist group (p < 0.05). The overall chemical pregnancy rate in intervention group (43/91: 46.2%) and control group (45/91: 49.5%) (p = 0.820) was similar. Meanwhile, the clinical pregnancy rate was similar between groups too. Conclusion: Regarding the cost, efficacy and easy usage of dydrogestrone, it may be reasonable to use it as an alternative to GnRH antagonist for the prevention of premature LH surge.

Dose-Dependent Chlormadinone Acetate Can Suppress Premature LH Surge in Parallel with LH Value Reduction

Background: Progestin-primed ovarian stimulation (PPOS) protocol is reported as an alternative method of premature luteinizing hormone (LH) surge suppression. How much dosage of chlormadinone acetate (CMA), a synthetic progestin, is appropriate treatment for this phenomenon? Methods: Retrospective case control study was performed at private assisted reproductive technology (ART) clinic in Japan. Collected data was 231 cycles in patients who underwent either PPOS protocol using 12, 6, 4, or 2 mg of CMA, groups 6C, 3C, 2C, and 1C, respectively (total, 113 cycles), or gonadotropin-releasing hormone (GnRH) antagonist protocol, groups 6A, 3A, 2A, and 1A, respectively (total, 118 cycles). In the CMA group, CMA and human menopausal gonadotropin (hMG) or follicle-stimulating hormone (FSH) were administered simultaneously beginning on menstrual cycle day 3. Serum P, E2, and LH were determined on the day of human chorionic gonadotropin (hCG) administration. Occurrence of premature LH surge was compared between two groups. Pregnancy outcomes were also calculated. Results: Premature LH surge was completely suppressed in CMA groups 6C, 3C, and 2C. On the other hand, this phenomenon was detected in antagonist method groups (5.9%, 7/118). But spontaneous ovulation was not observed in any group, and clinical outcomes are equal to those of GnRH antagonist treatment. Conclusions: Controlled ovarian stimulation (COS) using CMA can be an appropriate alternative progestin for PPOS protocol. Since CMA is an oral medication, this method can be easy to conduct and cost-effective compared with the antagonist method. From our observation, we suggest 4 mg/day of CMA can control the egg retrieval cycle without LH surge occurrence as in other PPOS methods.

Effect of Nimodipine on Premature Luteinizing Hormone Surge in Women Undergoing Intrauterine Insemination

Objectives: To determine the effect of nimodipine on premature luteinizing hormone (LH) surge in women undergoing intrauterine insemination (IUI). Patients and Methods: Fifty-six infertile women participated in this randomized clinical trial after referring to Mahdiyeh hospital, Tehran, Iran and undergoing IUI treatment in 2017. Participants were randomly divided into nimodipine (n=34) and placebo (n=22) groups. The demographic and clinical profile of women were collected using a predesigned checklist. In the nimodipine group, 30 mg tablets were given to patients three times daily for 2 days. Finally, the serum levels of LH and estradiol were measured before and after the intervention. Results: Based on the results, the LH surge was observed in 8 (34.8%) women in the placebo group (P=0.04) while it was not detected in 29 (78.4%) women in the nimodipine group. There were no statistical differences in the serum levels of estradiol and LH between the 2 groups before the intervention. The serum levels of estradiol in both groups increased after intervention although this increase was not significant. Eventually, no statistical difference was found between the 2 groups in terms of fertility rate. Conclusions: In general, nimodipine can significantly reduce premature LH surge in patients undergoing IUI compared to the placebo group.