The Effectiveness of the Two Different Endometrial Preparation Regimes for Frozen Embryo Transfer in Patients With Adenomyosis
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 222
- 试验地点
- 1
- 主要终点
- Live birth rate after one frozen embryo transfer cycle
研究概览
简要总结
This randomized clinical trial aims to assess the comparative effectiveness of two distinct endometrial preparation protocols for frozen embryo transfer (FET) among women with adenomyosis undergoing IVF/ICSI. Specifically, it seeks to address the following key questions:
- Does the protocol involving the combination of GnRH agonist and letrozole for down regulation with exogenous steroids (GnRHa+AI - AC) result in a higher live birth rate compared to the use of exogenous steroids alone (AC) in women with adenomyosis undergoing frozen embryo transfer?
- What are the common side effects of the GnRHa+AI - AC regimen?
Eligible participants will undergo screening before endometrial preparation for FET, following which they will be randomly assigned to one of two groups: GnRHa+AI - AC or AC. In the GnRHa+AI - AC group, participants will be pre-treated with GnRH agonist and letrozole two months before endometrial preparation. After this period, participants will return for endometrial preparation, and any side effects resulting from the down regulation will be evaluated. In contrast, the AC group will receive standard treatment.
详细描述
- Adenomyosis is a benign gynecological disease in which the endometrial stroma invades the uterine myometrium. Adenomyosis affects approximately 10% of women of reproductive age. There are several hypothetical mechanisms in adenomyosis-associated infertility, including dysregulations of the myometrial architecture and function, chronic inflammation, presence of local oxygen, and altered endometrial function, which can cause implantation failure. The abnormal presence of endometrial tissue composed of glands and stroma impacts uterine smooth muscle's regular contractile function and peristalsis, resulting in menometrorrhagia, infertility, and adverse obstetric consequences. There is currently no consensus on the optimal protocol for endometrial preparation in this population, and a lack of data on this issue. Current protocols include routine protocols with or without the pre-treatment of GnRH agonist. However, it is still controversial whether GnRH agonist down-regulation can help patients with adenomyosis have better reproductive outcomes. To our knowledge, there have not been any randomized controlled trials to investigate the effectiveness of the protocols used for endometrial preparation in women with adenomyosis undergoing frozen embryo transfer.
- This will be a superiority-designed randomized clinical trial.
- This trial will be conducted at My Duc Hospital, Ho Chi Minh City, Vietnam. Potentially eligible women will be provided information about the trial as long as their stimulation cycles are initiated.
- Screening for eligibility will be performed by treating physicians on days 2nd - 4th of the menstrual cycle in the subsequent frozen embryo transfer cycles. Patients will be provided a copy of the informed consent documents. Written informed consent will be obtained from all women by the investigator before enrollment.
- Women will be randomized (1:1) to either AC (artificial cycle) or GnRHa+AI - AC (Down-Regulation with GnRH agonist and Letrozole combined with artificial cycle) protocols using block randomization with a variable block size of 4, 6, using HOPE Epi with a computer-generated random list.
- Artificial cycle (AC): the endometrium will be prepared using oral estradiol valerate (Valiera; Abbott) 6 mg/day starting from the second or fourth day of the menstrual cycle (5). The endometrial thickness will be monitored from the tenth day of estradiol-priming onwards, and vaginal progesterone (Cyclogest®; Actavis) 400 mg twice times a day will be initiated when endometrial thickness reaches 7 mm or more and received oestradiol valerate for at least nine days.
Embryo transfer will be scheduled by the time of the initiation of progesterone and embryo stages. Hormonal support will consist of oral estradiol valerate 4 mg/day and vaginal progesterone (Cyclogest®; Actavis) 400 mg twice times a day until the 7th week of gestation. Subsequently, progesterone alone (Cyclogest®; Actavis) at 400 mg twice times a day will be continued for luteal phase support until the 12th week of gestation.
- GnRH agonist + Letrozole - Artificial cycle protocol (GnRHa+AI - AC):
- Pre-treatment with GnRH agonist: GnRHa (Triptorelin - Diphereline®, Ipsen, France) will be injected at a dose of 3.75 mg on days 2nd - 4th of menstruation. In addition to GnRHa administration duration, the patients will be indicated letrozole 2.5 mg daily (Femara®, Novartis, Switzerland) to prevent the estradiol flare-up effect from the day of GnRH agonist injection. Repeat the same regimen for the second time 28 days after the first injection of GnRH agonist.
- After 55 days of Down Regulation with GnRH agonist, before starting the artificial cycle protocol for endometrial preparation, estradiol serum level will be tested before endometrial preparation.
- Endometrial preparation with AC protocol will be started 28 days after the second injection of GnRH agonist, as described previously
Frozen embryo transfer:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 42 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Confirm diagnosis with adenomyosis by using transvaginal ultrasonography (MUSA consensus) and/or pelvic magnetic resonance imaging.
- •Age between 18 - 42
- •Undergo less or equal to three previous IVF cycles
- •Indicate for frozen embryo transfer
- •Agree to have not more than two day-3 embryo or one blastocyst (day-5 and day-6) transferred
- •Not participating in any other study
排除标准
- •Embryos from IVM cycle
- •Having uterine or adnexal abnormalities (e.g., intrauterine adhesions, unicornuate/ bicornuate/ arcuate uterus; unremoved hydrosalpinx, endometrial polyp, submucosal leiomyoma, or leiomyoma with endometrial cavity distortion)
- •Having contraindications for exogenous hormones administration: breast cancer, risks of venous thromboembolism
- •Embryos from the oocyte donation cycle.
- •Patients with a history of GnRH injection within three months, measured from the last GnRHa injection to the study screening date.
研究组 & 干预措施
GnRH agonist + Letrzole - Artificial Cycle
Pre-treatment includes two doses of 3.75 mg GnRH agonist (Diphereline®, Ipsen, France) on days 2-4 of the menstrual cycle and 28 days later, along with daily 2.5 mg Letrozole (Femara®, Novartis, Switzerland) starting from the first agonist injection.
Endometrial preparation in an artificial cycle begins 28 days after the second agonist injection. Patients will take 6 mg/day of oral estradiol valerate (Valiera; Abbott) at least 9 days before initiating progesterone. Endometrial thickness is monitored starting on the 10th day. When it reaches ≥7 mm, 400 mg twice times a day of vaginal progesterone (Cyclogest®, Actavis, UK) is initiated. Embryo transfer aligns with progesterone initiation, taking the embryo's stage into account. Luteal phase support comprises oral estradiol valerate 4 mg/day and vaginal progesterone 400 mg twice times a day until the 7th week of gestational age (GA), followed by progesterone alone at 400 mg twice times a day up to the 12th week of GA.
干预措施: GnRHa+AI - AC (Procedure)
Artificial Cycle
The endometrium will be prepared using oral estradiol valerate (Valiera; Abbott) 6 mg/day starting from the 2nd to the 4th day of the menstrual cycle. The endometrial thickness will be monitored from day 10th onwards, and vaginal progesterone (Cyclogest®; Actavis) 400 mg twice times a day will be initiated when endometrial thickness reaches ≥7 mm. Estradiol exposure must last for at least 9 days before progesterone administration. Embryo transfer will be scheduled by the time of the initiation of progesterone and embryo stages. Luteal phase support comprises oral estradiol valerate 4 mg/day and vaginal progesterone 400 mg twice times a day until the 7th week of gestational age (GA), followed by progesterone alone at 400 mg twice times a day up to the 12th week of GA.
干预措施: Artificial cycle (Procedure)
结局指标
主要结局
Live birth rate after one frozen embryo transfer cycle
时间窗: At 22 weeks of gestation
Live birth is defined as the complete expulsion or extraction from a woman of a product of fertilization, after 22 completed weeks of gestational age; which, after such separation, breathes or shows any other evidence of life, such as heart beat, umbilical cord pulsation or definite movement of voluntary muscles, irrespective of whether the umbilical cord has been cut or the placenta is attached. A birth weight of 500 grams or more can be used if gestational age is unknown
次要结局
- Hypoestrogenic side effects(At 8 weeks from the start of the first dose of 3.75 mg GnRH agonist)
- Implantation rate(At 3 weeks after embryo placement)
- Cancellation rate(At 3 weeks from the start of artificial cycle)
- Positive pregnancy test(At 2 weeks after embryo placement)
- Clinical pregnancy(At 5 weeks after embryo placement)
- High birth weight(At the time of delivery)
- Venous thromboembolism relating to medication(From the start of treatment up to 10 weeks of gestation)
- Birth weight(At the time of delivery)
- Very low birth weight(At the time of delivery)
- Multiple delivery(At 22 weeks' gestation)
- Neonatal mortality(within 28 days of birth)
- Classification of adenomyosis(during ultrasound procedure)
- Differentiation of adenomyosis(during ultrasound procedure)
- Ectopic pregnancy(At 7 weeks of gestation)
- Miscarriage(before 22 completed weeks of gestational age)
- Ongoing pregnancy(At 10 weeks after embryo placement)
- Preterm delivery(At 22, 28, 32 weeks and 37 weeks of gestation)
- Gestational diabetes mellitus(At 24 to 28 weeks of gestation)
- Hypertension in pregnancy(after 20 weeks of gestation or beyond)
- Major congenital abnormalities(At birth)
- Very high birth weight(At the time of delivery)
- Multiple pregnancy(At 6 to 8 weeks' gestation)
- Low birth weight(At the time of delivery)
- Admission to NICU(At birth)
- Still birth(At 20 weeks' gestation)
- Direct costs to live birth(At the time of delivery)