Progesterone Primed Ovarian Stimulation Versus GnRH Antagonist Protocols in Women with Polycystic Ovarian Syndrome

Completed

• Conditions: Controlled Ovarian Hyperstimulation; Polycystic Ovarian Syndrome
• Interventions: Drug: Progesterone; Drug: GnRH antagonist (Cetrorelix)

• Registration Number: NCT06812559
• Lead Sponsor: El Shatby University Hospital for Obstetrics and Gynecology

Brief Summary

The purpose of this study is to compare the use of the progesterone-primed ovarian stimulation protocol versus GnRH antagonist protocol in women with polycystic ovarian syndrome (PCOS) regarding the number of oocytes retrieved, percentage of MII oocytes, and the rate of good quality blastocysts available for cryopreservation.

Detailed Description

The syndrome of polycystic ovary (PCOS) is a common endocrine disease. It accounts for about 80% of women with anovulatory infertility. In vitro fertilization (IVF) is a commonly used infertility treatment for PCOS patients who fail to conceive with ovulation induction or if there are concomitant infertility factors such as tubal damage or male subfertility.

Patients with polycystic ovary syndrome (PCOS) are at high risk of ovarian hyperstimulation syndrome (OHSS) during in vitro fertilization (IVF) / intracytoplasmic sperm injection (ICSI) treatment which may lead to cycle cancellation to prevent their high morbidity or death rates. Increasing evidence has confirmed that frozen embryo transfer (FET) is related to a lower risk of OHSS. The 'freeze-all' strategy is recommended for PCOS patients to reduce the potential of moderate/severe OHSS.

Controlled ovarian stimulation (COS) is a key step in assisted reproductive technology (ART). In addition to the use of gonadotropins to recruit multiple follicles, it is mandatory to use a drug to prevent luteinizing hormone (LH) surge and premature ovulation.

Early LH surge is a main cause of cycle cancellation during controlled ovarian stimulation (COH) for women receiving IVF/ICSI therapy. The release of LH causes ovulation in response to rapidly increasing levels of E2 in the normal cycle, and a premature LH increase may impair IVF/ICSI egg production.

Gonadotropin-releasing hormone (GnRH) antagonist protocol has emerged as a routine ovulation stimulation protocol in recent decades due to its comparable convenience, safety, and efficacy compared to GnRH agonists. GnRH antagonist protocol is now the most commonly used COS protocol in PCOS patients due to the significantly reduced risk of OHSS especially when gonadotropin-releasing hormone agonist (GnRHa) was used for ovulation trigger. The GnRH antagonists were used primarily to reduce the incidence of the early LH surge. However, GnRH antagonists are expensive and sometimes difficult to manage with high rates of cycle cancellation and premature LH surges.

In past decades, when IVF relied on fresh embryo transfer, progesterone could not be considered during COS as early exposure to progesterone could lead to embryo-endometrium asynchrony. Advances in vitrification have made cryopreservation and thawing of embryos in a reliable manner, which has eliminated concerns about the deleterious effects of progesterone exposure on endometrial receptivity. Although controversies remain regarding the selection of when to choose FET, the ''freeze-all'' strategy could make the use of P formulations for the suppression of premature LH surge during COH feasible regardless of the effects of P on endometrial receptivity. Therefore, the PPOS protocol may be a suitable option when fresh embryo transfer is not required.

Progesterone-primed ovarian stimulation is a recent stimulation protocol, which was first suggested in 2015 by Dr. Yanping Kuang of China, it is a novel ovarian stimulation system utilizing progestin coupled with exogenous gonadotrophin, and ovulation triggered by a GnRH agonist, via 'freeze-all' methods. Oral progestin are used as an alternative to GnRH antagonist to prevent premature LH surges during ovarian stimulation. This novel ovarian stimulation regimen has shown successful prevention of a premature LH surge in cycles followed by embryo cryopreservation. In addition, oral progestin has the advantage of being convenient, given orally, cheap, and available readily.

The mechanism of LH suppression using GnRH-ant or progestin is distinct. GnRH-ant administration could lead to rapid suppression of pituitary LH secretion by competitively blocking the GnRH receptor, with an obvious dose-dependent suppression effect. In contrast, the inhibition of LH levels with progestin is indirect by regulating the hypothalamus GnRH secretion and requires sufficient duration before estrogen priming.

Study Timeline

• Study Start: 2023-12-01
• Status Verified: 2025-02
• Primary Completion: 2025-02-01
• Study Completion: 2025-02-01
• Study First Submitted: 2025-02-02
• Study First Submitted QC: 2025-02-02
• Study First Posted: 2025-02-06
• Last Update Submitted: 2025-02-21
• Last Update Posted: 2025-02-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 100

Inclusion Criteria

1. Female age <37 years.
2. Body mass index (BMI) between (≥18 kg/m2 and ≤35 kg/m2).
3. Polycystic ovarian syndrome patients (according to Rotterdam criteria).
4. Patients suffering from primary or secondary infertility who are candidates for ICSI.

Exclusion Criteria

1. Uncorrected Uterine factor of infertility: intrauterine adhesions, submucosal fibroids, and septate uterus.
2. Severe male factor infertility

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Progesterone-primed ovarian stimulation Group	Progesterone	• A daily dose of 20 mg dydrogesterone (2 Duphastone 10 mg tablets) will be added from day 1 or 2 of the menstrual cycle and will be continued till the day of the GnRH agonist trigger.
Antagonist protocol	GnRH antagonist (Cetrorelix)	• GnRH antagonist (Cetrotide 0.25 mg) subcutaneous injection will be added daily from the 6th day of ovarian stimulation and will be continued till the day of the GnRH agonist trigger.

Primary Outcome Measures

Name	Time	Method
Number of oocytes retrieved (ovarian response).	Baseline	Total number of oocytes retrieved (in both groups)
Percentage of MII oocytes.	Baseline	Number of MII oocytes to the total number of oocytes retrieved (in both groups)
Rate of good-quality blastocysts available for cryopreservation	Baseline	percentage of the number of good-quality blastocysts to the number of 2PN fertilized oocytes cultured

Secondary Outcome Measures

Name	Time	Method
Fertilization rate	Baseline	Percentage of the number of MII oocytes microinjected which transform into 2PN
Rate of blastocyst formation	Baseline	percentage of the number of blastocysts formed to the number of 2PN fertilized oocytes cultured
Clinical pregnancy rate after 1st FET	Baseline	defined as elevated serum β-HCG (+) the presence of gestational sac(s) or fetal heartbeats (fetal pole) by ultrasonography

Trial Locations

Locations (1)

ELShatby University Hospital; 🇪🇬 Alexandria, Egypt