Comparison of flexible progestin-primed ovarian stimulation protocol (PPOS) with flexible GnRH antagonist protocol in polycystic ovary syndrome (PCOS) women undergoing IVF/ICSI cycles: A pilot randomized controlled trial

TITLE: Comparison of flexible progestin-primed ovarian stimulation protocol (PPOS) with flexible GnRH antagonist protocol in polycystic ovary syndrome (PCOS) women undergoing IVF/ICSI cycles: A pilot randomized controlled trial

AIM: To compare the efficacy and safety of flexible progestin-primed ovarian stimulation protocol (PPOS) with flexible GnRH antagonist protocol in polycystic ovary syndrome (PCOS) women undergoing IVF/ICSI cycles.

OBJECTIVES OF THE STUDY

Primary Objectives: To compare the efficacy and safety of the flexible progestin-primed ovarian stimulation protocol (PPOS) with the flexible GnRH antagonist protocol in PCOS women undergoing IVF/ICSI cycles in terms of 1. Premature LH surge  2. Oocyte yield.

Secondary Objectives: To compare the efficacy and safety of the flexible progestin-primed ovarian stimulation protocol (PPOS) with the flexible GnRH antagonist protocol in PCOS women undergoing IVF/ICSI cycles in terms of -

1.Total dose of gonadotropins required

2.Duration of controlled ovarian stimulation

3.Peak serum estradiol (E2), progesterone (P4) and luteinizing hormone level (LH) on the day of trigger

4.Number of total and MII oocytes retrieved

5.FORT (Follicular output rate)

6.FOI (Follicular oocyte index)

7.Fertilization rate

8.Cleavage rate

9.Clinical pregnancy rate

10.Incidence of OHSS

MATERIALS AND METHODS

Study design: Randomized, open label pilot study

Duration of study: From date of ethical clearance to July 2026

Place of study: Assisted Reproductive Technology (ART) Unit, Department of Obstetrics and Gynaecology, AIIMS, New Delhi.

Method of Randomization: Block Randomization

Study population: PCOS women recruited for IVF/ICSI cycles

Study group: PCOS patients undergoing flexible progestin primed ovarian stimulation (fPPOS)

Control group: PCOS patients undergoing flexible GnRH antagonist based ovarian stimulation (GnRHant.)

Sample size: 60 patients (30 patients in each group)

Inclusion criteria:

1.Women aged 21-38 years of age

2.BMI < 35kg/m2

3.PCOS diagnosis is made as per International guideline criteria  if  after excluding other causes of irregular menstrual cycle and hyperandrogenism , any two of the following is present: (i) Irregular menstrual cycles-oligomenorrhoea/amenorrhoea ; (ii) Clinical/biochemical hyperandrogenism; (iii) Polycystic ovarian morphology –Defined on TVS as (FNPO) Follicle number per ovary ≥20 in atleast one ovary

Exclusion Criteria:

1.Grade 3 or higher endometriosis

2.Uterine anomalies, fibroid or adenomyoma distorting the endometrial cavity

3.Uncontrolled thyroid and/or prolactin disorders

4.Not willing to participate in the study.

METHODOLOGY

Eligible candidates will be randomized into study and control groups.

Study group:

Baseline hormonal profile (E2/LH/P4) and TVS will be done on day 1-2 of menstrual cycle to ensure no follicle ≥10mm or ovarian pathology that would debar ovarian stimulation is present.

Ovarian stimulation will be started with recombinant FSH given subcutaneously daily from day 2 of menstrual cycle.

Monitoring of ovarian response will be done by TVS and hormonal profile (E2/ P4/ LH) starting from day 5 of stimulation and thereafter will be done every 2-3 days as deemed necessary. Gonadotropin (rFSH) dose will be adjusted as per ovarian response to stimulation.

Medroxyprogesterone acetate 10 mg orally daily (given as 5mg tablet in BD dose) will be added once the leading follicle is ≥ 12 mm size and continued until the day of trigger.

Final oocyte maturation will be triggered with injection leuprolide2 mg subcutaneously when ≥3 follicles have reached ≥17mm size.

Oocyte retrieval will be performed 34-36 hours after the trigger under transvaginal USG guidance.

Control group:

Baseline hormonal profile (E2/LH/P4) and TVS will be done on day 1-2 of menstrual cycle to ensure no follicle ≥10mm or ovarian pathology that would debar ovarian stimulation is present.

Ovarian stimulation will be started with recombinant FSH given subcutaneously daily from day 2 of menstrual cycle.

Monitoring of ovarian response will be done by TVS and hormonal profile (E2/ P4/ LH) starting from day 5 of stimulation and thereafter will be done every 2-3 days as deemed necessary.Gonadotropin (rFSH) dose will be adjusted as per ovarian response to stimulation.

GnRH antagonist (Inj. Cetrorelix 0.25 mg subcutaneous) will be administered daily once the leading follicle is ≥ 12 mm size and continued until the day of trigger.

Final oocyte maturation will be triggered with injection leuprolide 2 mg subcutaneously when ≥3 follicles have reached ≥17mm size.

Oocyte retrieval will be performed 34-36 hours after the trigger under transvaginal USG guidance.

Routine IVF or ICSI will be performed, as appropriate. Fertilization will be assessed 16-18 hours after insemination and the number/ percentage of oocytes fertilized will be noted. Further embryos will be evaluated on day 2 and day 3 for cleavage and will be graded. All embryos from the study group as well as control group will be cryopreserved (vitrified). Frozen embryo transfer will be performed under transabdominal ultrasound guidance . Luteal phase support will be given in the form of injection micronized progesterone 25mg subcutaneously given alternatively with micronized progesterone vaginal pessary 400mg twice daily. Luteal phase support is maintained until 12 weeks of gestation or until the day of pregnancy test if negative.

FOLLOW UP

Beta hCG and urine pregnancy test will be performed on day 16 after FET.

PRIMARY OUTCOME

**1.**Premature LH surge

2.Oocyte yield

SECONDARY OUTCOME

1.Total dose of gonadotropins required

2.Duration of controlled ovarian stimulation

3.Peak serum estradiol (E2), progesterone (P4) and luteinizing hormone (LH) level on the day of trigger

4.Number of total/MII oocytes retrieved

5.FORT (Follicular output rate)

6.FOI (follicular oocyte index)

7.Fertilization rate

8.Cleavage rate

9.Clinical pregnancy rate

10.Incidence of OHSS