Luteal Phase Support During Frozen Embryo Transfer Cycle

Duration of Estrogen for Luteal Phase in Pregnant Women Undergone Frozen Embryo Transfer Cycles- Randomized Controlled Trials Phase III

We aimed to decrease quantity of exogenous estrogen and evaluated the success rate of ongoing pregnancy in women undergone artificial FET who have a surplus embryos at previous fertility treatment cycles.

In this study, endometrial prepared with standard long GnRH protocol and for luteal phase support patients received 6 mg oral E2 and intramuscularly P 100 mg/d and embryos on day 2-3 were transferred. Control group continued E2 until 12 week of pregnancy, while for cases after identify gestational sac with heart beat (the 6 week of pregnancy) by vaginal ultrasonography, E2 will discontinued.

Study Overview

• Status: Completed
• Conditions: Infertility, Female; Frozen Embryo Transfer
• Intervention / Treatment: Drug: Strogen; Drug: Strogen

Detailed Description

Approval Status: Confirmed Approval reference Number: IR.ACECR.ROYAN.REC.1395.70 Board Name: Ethics committee of Royan infertility institute Board Affiliation: Reza Samani Phone: +982122305236 Email: samani@royaninstitute.org

Yes Health, Treatment and Medical Education Ministry: Iran

Hormones replace therapy (Artificial) is a method for endometrium preparation and embryo transfer. In this protocol for decrease of spontaneous ovulation, exogenous estrogen began in 2-3 days on follicular phase of the menstrual cycle which continue about 10 to 14 days. In the following luteal phase support by progesterone begins on 14 to 16 days of cycles. The luteal phase is supported with different dose and duration of estradiol (E2) and progesterone (P) until 8-12 week of pregnancy. Studied reported a higher risk of thromboembolism in pregnant women that using exogenous estrogen. Also, excess estrogen might be resulted fetus congenital anomalies, low birth weight and increased susceptibility to breast cancer in female fetuses. On the other hands, it seems placenta in early pregnancy duration synthesize estrogen and this time estrogen sufficient as a product of progesterone metabolism. We aimed to decrease quantity of exogenous estrogen and evaluated the success rate of ongoing pregnancy in women undergone artificial FET who have a surplus embryos at previous fertility treatment cycles.

In this study, endometrial prepared with standard long GnRH protocol and for luteal phase support patients received 6 mg oral E2 and intramuscularly P 100 mg/d and embryos on day 2-3 were transferred. Control group continued E2 until 12 week of pregnancy, while for cases after identify gestational sac with heart beat (the 6 week of pregnancy) by vaginal ultrasonography, E2 will discontinued.

The level of maternal estrogen and progesterone measured at progesterone days (day 15), the day of embryo transfer, 6 and 12 weeks of pregnancy.

This study is a randomized clinical trial to investigate the duration of estrogen for luteal phase in pregnant women undergone frozen embryo transfer cycles- Randomized controlled trials phase III. The study protocol is approved by the Ethics Committee (Institutional Review Board) of Royan institute and all participants provide informed consent.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 3

Contacts and Locations

Study Locations

• Iran, Islamic Republic of
  • Tehran, Iran, Islamic Republic of
    • Royan Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 37 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Patients with surplus embryos undergone infertility treatment cycles (e.g. OHSS, inadequate endometrium, surplus frozen embryo from any cause)
2. Age 21-37 years
3. Normal BMI (18.5 <BMI <30)
4. IVF / ICSI or IVF or ICSI cycles with antagonists or agonists protocols
5. Frozen embryos on 2-3 days

Exclusion Criteria:

1. Endometrial thickness ≤7mm
2. Egg Donors
3. Surrogacy
4. Male factor infertility with azoospermia
5. Age <37 years old
6. Hydrosalpinx
7. Uterine anomalies
8. Myoma with a compression effect or submocusa myoma
9. PGD
10. Blastocyst embryo transfer, ZIFT and GIFT

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: FET cycle, discontinue estradiol after 6 gestational weeks; In patients 35 days after embryo transfer and observation of gestational sac with heart beat (6 weeks of pregnancy) by ultrasound, exogenous estrogen will discontinued while progesterone will remain daily use until twelfth week of pregnancy.	Drug: Strogen; The OCP-LD begins in 2 to 3 days of the last menstrual cycle and then 500 μgr/d GnRH-a will received on day 17 for fourteen days. Then in 2-3 days of the next menstrual cycle, GnRH-a reduced to 200 μgr/d dose. the patients will receive 6 mg oral that will be continued for 14 days and during this time endometrium thickness evaluated by vaginal ultrasonography. If endometrial thickness is estimated ≥7mm, intramuscularly progesterone 100 mg/d will be started. After the onset of progesterone (days 17 to 18 cycles) frozen embryos transferred. Control group receive 6 mg oral estrogen and 100 mg intramuscularly progesterone until 12 week of pregnancy. The levels of maternal estrogen and progesterone was measured at the time of the starting day of progesterone (day 15), the day of embryo transfer, 6 and 12 weeks of pregnancy.; Other Names: estradiol till 12 gestational weeks; Drug: Strogen; The OCP-LD begins in 2 to 3 days of the last menstrual cycle and then 500 μgr/d GnRH-a will received on day 17 for fourteen days. Then in 2-3 days of the next menstrual cycle, GnRH-a reduced to 200 μgr/d dose. the patients will receive 6 mg oral that will be continued for 14 days and during this time endometrium thickness evaluated by vaginal ultrasonography. If endometrial thickness is estimated ≥7mm, intramuscularly progesterone 100 mg/d will be started. After the onset of progesterone (days 17 to 18 cycles) frozen embryos transferred. In patients 35 days after embryo transfer and observation of gestational sac with heart beat (6 weeks of pregnancy) by ultrasound, exogenous estrogen will discontinued while progesterone will remain daily use until twelfth week of pregnancy. The levels of maternal estrogen and progesterone was measured at the time of the starting day of progesterone (day 15), the day of embryo transfer, 6 and 12 weeks of pregnancy.; Other Names: estradiol till 6 gestational weeks
ACTIVE_COMPARATOR: FET cycle, continue estradiol till 12 gestational weeks; Control group receive 6 mg oral estrogen and 100 mg intramuscularly progesterone until 12 week of pregnancy.	Drug: Strogen; The OCP-LD begins in 2 to 3 days of the last menstrual cycle and then 500 μgr/d GnRH-a will received on day 17 for fourteen days. Then in 2-3 days of the next menstrual cycle, GnRH-a reduced to 200 μgr/d dose. the patients will receive 6 mg oral that will be continued for 14 days and during this time endometrium thickness evaluated by vaginal ultrasonography. If endometrial thickness is estimated ≥7mm, intramuscularly progesterone 100 mg/d will be started. After the onset of progesterone (days 17 to 18 cycles) frozen embryos transferred. Control group receive 6 mg oral estrogen and 100 mg intramuscularly progesterone until 12 week of pregnancy. The levels of maternal estrogen and progesterone was measured at the time of the starting day of progesterone (day 15), the day of embryo transfer, 6 and 12 weeks of pregnancy.; Other Names: estradiol till 12 gestational weeks; Drug: Strogen; The OCP-LD begins in 2 to 3 days of the last menstrual cycle and then 500 μgr/d GnRH-a will received on day 17 for fourteen days. Then in 2-3 days of the next menstrual cycle, GnRH-a reduced to 200 μgr/d dose. the patients will receive 6 mg oral that will be continued for 14 days and during this time endometrium thickness evaluated by vaginal ultrasonography. If endometrial thickness is estimated ≥7mm, intramuscularly progesterone 100 mg/d will be started. After the onset of progesterone (days 17 to 18 cycles) frozen embryos transferred. In patients 35 days after embryo transfer and observation of gestational sac with heart beat (6 weeks of pregnancy) by ultrasound, exogenous estrogen will discontinued while progesterone will remain daily use until twelfth week of pregnancy. The levels of maternal estrogen and progesterone was measured at the time of the starting day of progesterone (day 15), the day of embryo transfer, 6 and 12 weeks of pregnancy.; Other Names: estradiol till 6 gestational weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ongoing pregnancy rate after frozen embryo transfer	Ongoing pregnancy was defined when the pregnancy had completed ≥20 weeks of gestation.	≥20 weeks of gestational age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal serum estrogen level	Maternal serum estrogen level	The start day of using progesterone for luteal support in FET cycle (day 15 after onset estradiol), the day of embryo transfer (approximately 17-18 days after onset estradiol), 6 and 12 weeks of gestational age
Maternal serum progesterone level	Maternal serum progesterone level	The start day of using progesterone for luteal support in FET cycle (day 15 after onset estradiol), the day of embryo transfer (approximately 17-18 days after onset estradiol), 6 and 12 weeks of gestational age

Collaborators and Investigators

• Sponsor: Royan Institute

Publications and helpful links

General Publications

• Ghaffari F, Chekini Z, Vesali S. Duration of estradiol supplementation in luteal phase support for frozen embryo transfer in hormone replacement treatment cycles: a randomized, controlled phase III trial. Arch Gynecol Obstet. 2022 Mar;305(3):767-775. doi: 10.1007/s00404-021-06173-w. Epub 2021 Sep 24.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 1, 2017
• Primary Completion (ACTUAL): January 1, 2019
• Study Completion (ACTUAL): April 30, 2019

Study Registration Dates

• First Submitted: May 28, 2019
• First Submitted That Met QC Criteria: July 6, 2019
• First Posted (ACTUAL): July 9, 2019

Study Record Updates

• Last Update Posted (ACTUAL): July 9, 2019
• Last Update Submitted That Met QC Criteria: July 6, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: Frozen embryo transfer; Estrogen; Ongoing pregnancy rate; Luteal phase support
• Additional Relevant MeSH Terms: Infertility; Infertility, Female; Physiological Effects of Drugs; Urological Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Estradiol; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Polyestradiol phosphate; Saw palmetto extract
• Other Study ID Numbers: Royan, Female Infertility,LPS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No