New Application of Sequential in Vitro Muturation System for Infertility Patients With Polycystic Ovary Syndrome

Sun Yat-sen University

Status and phase: Unknown; Phase 3

Conditions: Infertility; Polycystic Ovary Syndrome

Treatments: Drug: traditional IVM system; Procedure: Thawed embryo transfer (TET); Procedure: intracytoplasmic sperm injection (ICSI); Drug: sequential IVM system

Study type: Interventional

Funder types: Other

Identifiers

NCT03773263

newivf20181206

Details and patient eligibility

About

Oocyte in vitro maturation (IVM) is an artificial reproductive technologies (ART) in which cumulus-oocyte complex (COC) are collected at the immature germinal vesicle (GV) stage from unstimulated or FSH-primed ovaries and matured in vitro before fertilization. IVM has been proposed as a more patient-friendly ART alternative to conventional IVF. Contrary to IVF, IVM is the only ART method with no cases of OHSS reported. Hence, patients with PCOS represent the major target population for IVM treatment.

In clinical practice of standard IVM, COCs are aspirated from unstimulated or mildly stimulated ovaries and rapidly removed from the meiotic-inhibiting influence of the follicle and the follicular fluid. Regardless of in vitro gonadotrophin treatment, oocytes mature spontaneously in vitro, hence undergoing meiotic resumption in the absence of the usual elaborate cascade of endocrine and paracrine molecular signals that induce maturation in vivo. As such, the maturation of oocytes by standard IVM techniques is an artefact that compromises subsequent oocyte developmental competence. Numbers of studies have been proposed to improve the efficiency of IVM system. Synchronization of meiotic and cytoplasmic maturation in antral oocytes arrested at the immature GV-stage remains a major challenge and is of fundamental importance for successful fertilization. High intra-oocyte levels of cyclic adenosine monophosphate (cAMP), is crucial to maintain the nearly fully-grown oocytes under meiotic arrest and to induce oocyte maturation. Research in animal models has indicated that a non-physiological drop of cAMP levels in the oocyte results in asynchronous nuclear and cytoplasmic maturation.

Investigators have reported the development of a novel in vitro simulated sequential oocyte maturation system. Critical to success of the approach is a pre-IVM phase that generates a rapid increase in COC cAMP levels. Secondly, the system utilizes an extended IVM phase containing sufficient FSH to drive meiotic induction in the presence of a type-3 PDE inhibitor. The high levels of cAMP in the oocyte and the induced nature of oocyte maturation mimics some of the key, newly characterized molecular signals that occur during oocyte maturation in vivo. Technical and conceptual elements were first developed using mouse, bovine and human COCs. Investigators propose a randomized clinical trial to compare a novel sequential culture system with the traditional standard oocyte IVM system for PCOS patients.

Full description

A multi-center, prospective, randomized clinical trial will be conducted, of comparing sequential oocyte IVM system with traditional oocyte IVM system for high OHSS risk PCOS patients (AMH>5.6ng/ml). The inclusion criteria will be infertile patients diagnosed by the Chinese PCOS criteria, aged below 35 years, and without other known factors interfere reproductive or metabolic functions. 300 PCOS patients will be included and randomized into either of two groups: group A will administrate sequential oocyte IVM system and group B will administrate traditional standard oocyte IVM system. The comparison will be made between groups, and both groups are conducted with the HMG administration and embryo vitrification freezing. The primary outcome of the study is live birth rate. The embryo development and pregnancy outcomes will be followed up and compared between groups.

Enrollment: 300 estimated patients

Sex: Female

Ages: Under 35 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Women age ≤35 years;
2. AMH level ≥5.6ng/ml;
3. Women diagnosed as PCOS according to Chinese PCOS diagnosis criteria;
4. Written informed consent.

Exclusion criteria

• Women who diagnosed as uterus abnormality, adenomyosis, submucous myoma, intrauterine adhesion;
• Women who diagnosed as untreated hydrosalpinx;
• Women who had underwent unilateral ovariectomy;
• Women with medical condition that represent contraindication to assisted reproductive technology or pregnancy;
• Women or their partner with abnormal chromosome karyotype;
• Male partner with oligoasthenozoospermia or obstructive azoospermia;
• Male partner whose sperm is collected by surgery;
• Subjects are found breach the inclusion criteria, or in accordance with exclusion criteria during the test, excluded;
• Patients request withdrawal and exit the trial because adverse events occur during the trial.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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300 participants in 2 patient groups

sequential oocyte IVM group

Experimental group

Description:

From day 7\~9 of the menstrual cycle, 225 IU HMG (Menotrophins for Injection) per day will be administrated for 3 days. COCs were removed from aspirated follicular fluid and transferred into HEPES-buffered collection medium. The immature oocytes will be cultured in sequential IVM medium 1 for 6 hours (37℃, 5% CO2), and removed into sequential IVM medium 2 for further cultivation. After 24 and 40 hours cultivation, the mature oocytes will be fertilized by intracytoplasmic sperm injection (ICSI). Two of the D3 embryos (if available) which graded as top-quality embryo will be vitrified and the rest of embryos will be cultivated extendedly. Thawed embryo transfer (TET) will give preference to D3 embryos and carried out with a hormone replacement cycle.

Treatment:

Procedure: intracytoplasmic sperm injection (ICSI)

Drug: sequential IVM system

Procedure: Thawed embryo transfer (TET)

traditional oocyte IVM group

Active Comparator group

Description:

From day 7\~9 of the menstrual cycle, 225 IU HMG (Menotrophins for Injection) per day will be administrated for 3 days. On the day of ovulation, COCs were aspirated and the immature oocytes will be cultured in traditional standard oocyte IVM system (Sage). 30 and 44 hours after cultivation, the maturity of oocytes will be assessed and the mature oocytes will be fertilized by intracytoplasmic sperm injection (ICSI). Two of the D3 embryos (if available) which graded as top-quality embryo will be vitrified and the rest of embryos will be cultivated extendedly. Thawed embryo transfer (TET) will give preference to D3 embryos and carried out with a hormone replacement cycle. If biochemical pregnancy is not achieved, thawed blastocysts transfer will be performed.

Treatment:

Drug: traditional IVM system

Procedure: intracytoplasmic sperm injection (ICSI)

Procedure: Thawed embryo transfer (TET)