Clinical trial NCT05112692: Progestin-primed Ovarian Stimulation Protocol Versus GnRH Antagonist Protocol in Polycystic Ovary Syndrome Patients Undergoing IVF/ICSI Cycles
Official title: Progestin-primed Ovarian Stimulation Protocol Versus GnRH Antagonist Protocol in Polycystic Ovary Syndrome Patients Undergoing IVF/ICSI Cycles
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: PCOS (Polycystic Ovary Syndrome) of Bilateral Ovaries
Keywords: Progestin
ICSI
antagonist
Lead sponsor: Mansoura University
Sponsor class: OTHER
First posted: 2021-11-09
Enrollment: 200
Sex: FEMALE
Minimum age (years): 20
Maximum age (years): 35
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this trial is to compare the efficacy and safety of the PPOS protocol to the GnRH antagonist protocol in patients with PCOS who are undergoing IVF/ICSI cycles.

Detailed description: Polycystic ovary syndrome (PCOS) is a common metabolic dysfunction and heterogeneous endocrine disorder. It is the most common cause of anovulatory infertility, affecting approximately 10%-18% of reproductive age women worldwide.

It is usually characterized by a clustering of hyperandrogenism, hypersecretion of luteinizing hormone (LH) and hyperinsulinaemia, which could result in the arrest of ovarian follicular growth, oligo-ovulation or anovulation, menstrual dysfunction, hirsutism, infertility, pregnancy and/or neonatal complications.

Women with PCOS undergoing IVF or Intracytoplasmic sperm injection (ICSI) treatment because of infertility are increasing in number, and these patients have been well described, typically characterized by producing an increased number of oocytes but are often of poor quality leading to lower fertilization, implantation, and pregnancy rates and a higher miscarriage rate and incidence of ovarian hyperstimulation syndrome.

Increasing evidence raises the issue that impaired oocyte maturation and developmental competence in women with PCOS are possibly linked to abnormal endocrine/ paracrine factors, metabolic dysfunction and alterations in the intrafollicular microenvironment during folliculogenesis and follicle maturation.

Several clinical ovarian stimulation protocols have been used so far in women with PCOS undergoing IVF treatment to prevent a premature LH surge during controlled ovarian stimulation (COS); these primarily include gonadotropin-releasing hormone (GnRH) agonist or antagonist protocols.

GnRH antagonists can competitively inhibit endogenous GnRH and produce an immediate and rapid decline in LH and Follicle-stimulating hormone (FSH) levels without the flare effect of a GnRH agonist, and their administration by subcutaneous injection in the late follicular phase prevents an LH surge.

With progress in embryo vitrification techniques, many studies have suggested that pregnancies that arise from the transfer of frozen-thawed IVF embryos appear to have better perinatal and pregnancy outcomes. Thus, GnRH antagonist regimens combined with a freeze-all strategy for women with PCOS are currently accepted as the most routine IVF procedures.

The progesterone's pituitary suppression was recently used in controlled ovarian stimulation and approved its efficacy in terms of low incidence of premature LH surge and comparable pregnancy outcomes to short protocols in infertile women of normal ovarian reserve and polycystic ovarian syndrome.

These data indicated that progestin treatment might improve oocyte quality compared with a GnRH antagonist during COS in these patients, plus there were the advantages of an oral administration route instead of repeated injections of GnRH antagonist, a lower drug price and more control over LH levels, which can reduce the patients' discomfort and costs.

Furthermore, to avoid a low response of the hypothalamic pituitary ovarian axis, a double trigger with GnRHa and a low dose of Human chorionic gonadotropin (hCG)(1000IU) was used to induce final oocyte maturation without increasing the risk of moderate or severe Ovarian hyperstimulation syndrome (OHSS).

Choosing the appropriate progestin is crucial to the success of the Progestin-primed ovarian stimulation protocol (PPOS). Previous studies have shown that both Medroxyprogesterone acetate (MPA) and Utrogestan are effective oral alternatives for the PPOS protocol.

MPA is preferred over Utrogestan because the administration of a natural exogenous progesterone, such as Utrogestan, can interfere with serum progesterone measurement and lead to the neglect of possible premature luteinization. However, the use of MPA during ovarian stimulation may lead to stronger pituitary suppression and thus may require a higher dosage of gonadotrophin and a longer ovarian stimulation duration than that of the conventional ovarian stimulation protocol. Therefore, the investigators need to test more synthetic progestins to find the most suitable option for PPOS.

Dydrogesterone (DYG), which has a molecular structure similar to that of natural progesterone, is widely used for hormone replacement therapy, endometriosis treatment, menstrual disorders and luteal support in pregnancy and threatened miscarriage. However, unlike MPA, the use of DYG under the recommended dosage (10-20 mg) does not inhibit ovulation, and thus, the use of DYG as an alternative to MPA and as an appropriate progestin in the PPOS regimen has yet to be explored.

In this study, the investigators hypothesize that DYG can be used as an alternative progestin in the PPOS protocol. A randomized controlled trial (RCT) is designed to investigate cycle characteristics and endocrinological profiles of patients taking gonadotrophin while using DYG co-treatment, and to compare pregnancy outcomes in first frozen embryo transfer (FET) cycles with GNRH antagonist protocol as a control.

Eligibility criteria: Inclusion Criteria:

* Women who have a history of infertility ≥1year.
* Ages between 20 and 35 years.
* Patients diagnosed with PCOS according to the revised 2003 Rotterdam consensus and met 2 out of 3 criteria as follows (Rotterdam, 2004):

  * Oligo- and/or anovulation.
  * Biochemical and/or clinical evidence of hyperandrogenism.
  * Polycystic ovarian morphology on ultrasound (the presence of ≥12 antral follicles (≤9mm) and/or ovarian volume \>10mL on transvaginal ultrasonographic scanning).

Other etiologies of hyperandrogenism and ovulatory dysfunction will be excluded, including androgen-secreting tumors, congenital adrenal hyperplasia, hyperprolactinemia and thyroid disease.

Exclusion Criteria:

* Endometriosis grade 3 or higher.
* Documented ovarian failure, including basal FSH above 10IU/L.
* Clinically significant systemic disease, or other endocrine disorders, including 21-hydroxylase deficiency, uncorrected thyroid disease or suspected Cushing's syndrome.
* Patients who in the previous 3 months received hormonal treatments or other medications known to affect reproductive function, including oral contraceptives and GnRH agonists.
* Documented history of ovarian surgery including laparoscopic ovarian drilling, ovarian endometrioma stripping and unilateral oophorectomy
* Previous diagnosis of congenital (septate uterus, duplex uterus, uterus bicornis and uterus unicornis) or acquired (intrauterine adhesion, submucosal myomas and adenomyosis) uterine anomalies
* History of recurrent spontaneous abortion, defined as three or more previous spontaneous pregnancy losses
* Abnormal chromosomal karyotype in either of the partners.
* Inability to comply with the study procedures.

Primary outcomes:
measure: clinical pregnancy rate
timeFrame: 6 weeks after embryo transfer
Secondary outcomes:
measure: the incidence of premature LH surges
timeFrame: trigger day
measure: fertilization rate
timeFrame: baseline
measure: implantation rate
timeFrame: baseline
measure: ongoing pregnancy rate
timeFrame: baseline
measure: live birth rate
timeFrame: baseline
Other outcomes:
Locations:
Study officials:
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