Estradiol 8 vs 12 mg for Endometrial Preparation in HRT-FET

Oral Estradiol Dose for Endometrial Preparation in Hormone Replacement Frozen Embryo Transfer Cycles: A Randomized Comparative Clinical Trial Comparing 8 mg and 12 mg on Clinical Pregnancy Rate

The goal of this clinical trial is to learn whether 12 mg or 8 mg of oral estradiol valerate is better for preparing the endometrium in women undergoing hormone replacement frozen embryo transfer (HRT-FET) cycles. It also aims to assess how these two doses affect pregnancy outcomes and cycle success.

The main questions it aims to answer are:

Does oral estradiol 12 mg/day improve the clinical pregnancy rate compared with 8 mg/day? Do the two doses differ in endometrial thickness, cycle cancellation, miscarriage, and embryo transfer outcomes?

Researchers will compare oral estradiol valerate 12 mg/day with oral estradiol valerate 8 mg/day to see whether the higher dose leads to better endometrial preparation and higher clinical pregnancy rates.

Participants will:

Be randomly assigned to receive either oral estradiol 8 mg/day or 12 mg/day Undergo endometrial preparation before frozen embryo transfer Have endometrial thickness assessed before starting progesterone Undergo embryo transfer and follow-up to assess clinical pregnancy and other outcomes

Study Overview

• Status: Completed
• Conditions: Infertility (IVF Patients); Clinical Pregnancy Rates; Endometrial Preparation; Infertility Assisted Reproductive Technology; Frozen Embryo Transfer (FET)
• Intervention / Treatment: Drug: Progynova®; Drug: Progynova®

Detailed Description

Frozen embryo transfer (FET) in programmed hormone replacement therapy (HRT) cycles is widely used in assisted reproduction because it allows scheduling of endometrial preparation and embryo transfer independent of spontaneous ovulation. Although oral estradiol is commonly prescribed for proliferative endometrial priming in these cycles, the optimal daily dose remains uncertain. This trial was designed to evaluate whether increasing oral estradiol valerate from 8 mg/day to 12 mg/day during programmed HRT-FET cycles improves endometrial development and reproductive outcomes in women undergoing autologous frozen blastocyst transfer after a previous IVF/ICSI cycle.

This was a prospective, parallel-group, randomized controlled trial conducted at the Department of Obstetrics and Gynecology, Kasr Al-Ainy Teaching Hospital, Faculty of Medicine, Cairo University, during the period from [month year] to [month year]. Women undergoing their first programmed frozen embryo transfer cycle were randomized in a 1:1 ratio to receive oral estradiol valerate at a total daily dose of either 8 mg or 12 mg. Treatment was initiated early in the menstrual cycle after baseline clinical and ultrasound assessment. Endometrial reassessment was performed after 10 days of estrogen treatment. If adequate endometrial development was achieved, luteal phase support was started, and embryo transfer was scheduled according to the developmental stage of the vitrified-warmed day-5 blastocyst(s). If the endometrium remained below the protocol threshold, estradiol was continued for an additional short interval with repeat ultrasound assessment; cycles that failed to meet continuation criteria were cancelled according to protocol.

To reduce treatment variability, all transfers were performed in programmed HRT cycles using oral estradiol only for endometrial preparation, followed by a standardized progesterone regimen for luteal support. All embryos were derived from previous autologous IVF/ICSI cycles and were cryopreserved by vitrification. Embryo warming, grading, and transfer procedures were performed according to the unit's standard laboratory and clinical protocols. Pregnancy follow-up included serum beta-hCG testing after embryo transfer and subsequent transvaginal ultrasonographic confirmation of intrauterine gestation.

The study used concealed random allocation and a double-blind design. Participants, treating clinicians, sonographers, embryologists, and outcome assessors were masked to treatment assignment. The trial was designed to provide comparative evidence on whether a higher oral estradiol dose offers measurable benefit over a commonly used standard-dose regimen for endometrial preparation in programmed HRT-FET cycles while maintaining a uniform clinical pathway for embryo transfer and follow-up.

• Study Type: Interventional
• Enrollment (Actual): 850
• Phase: Phase 4

Contacts and Locations

Study Locations

• Egypt
  • Al-Manial
    • Cairo, Al-Manial, Egypt, 11956
      • Cairo University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

• Inclusion Criteria

  • Women aged 18 to 40 years
  • Body mass index (BMI) less than 30 kg/m²
  • Undergoing assisted reproduction treatment at the IVF Unit of Kasr Al-Ainy Teaching Hospital
  • Scheduled for an autologous programmed hormone replacement frozen embryo transfer (HRT-FET) cycle
  • Endometrial preparation planned using oral estradiol valerate only
  • Embryos obtained from a previous IVF or ICSI cycle
  • Planned transfer of vitrified-warmed day-5 blastocyst embryo(s)
  • First frozen embryo transfer cycle
  • Normal uterine cavity confirmed within the previous 12 months
  • Baseline transvaginal ultrasound showing no ovarian cyst, dominant follicle, or uterine cavity abnormality
  • Willing and able to provide informed consent

• Exclusion Criteria

  • Contraindication to estrogen treatment
  • History of breast cancer or endometrial cancer
  • History of deep venous thrombosis, pulmonary embolism, or stroke
  • Allergy to the study medication
  • Irregular vaginal bleeding
  • Thyroid disorder
  • Hyperprolactinemia
  • Uncontrolled diabetes mellitus
  • Uncontrolled hypertension
  • Significant liver disease
  • Significant kidney disease
  • Severe systemic illness
  • Uterine abnormality
  • Untreated hydrosalpinx
  • Untreated pathology inside the uterine cavity
  • Donor-oocyte cycle
  • Donor-embryo cycle
  • Gestational-carrier cycle
  • Preimplantation genetic testing for aneuploidy (PGT-A) cycle
  • Natural cycle or modified natural cycle for endometrial preparation
  • Use of transdermal, vaginal, or mixed estrogen regimens
  • Use of letrozole, gonadotropins, or GnRH agonists for endometrial preparation
  • Polycystic ovary syndrome (PCOS)
  • Premature ovarian insufficiency
  • Stage III or IV endometriosis
  • Recurrent implantation failure
  • Recurrent miscarriage
  • Abnormal parental karyotype
  • Active smoking
  • Difficult embryo transfer
  • Refusal to participate

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group A: received 8 mg daily oral estradiol valerate daily.; Women in the 8 mg group received four active 2 mg estradiol valerate tablets plus two matched placebo tablets.	Drug: Progynova®; Oral estradiol valerate 8 mg/day Oral estradiol valerate administered as 2 mg tablets for a total daily dose of 8 mg (four active tablets daily), starting on cycle day 2 for endometrial preparation in programmed HRT frozen embryo transfer cycles. Endometrial thickness was reassessed after 10 days; if the endometrium remained <7 mm, treatment could be continued for an additional 3 to 5 days. After adequate endometrial preparation, progesterone was initiated, and estradiol was continued through embryo transfer and until 12 completed weeks of gestation if pregnancy was confirmed.; Drug: Progynova®; Oral estradiol valerate 12 mg/day Oral estradiol valerate administered as 2 mg tablets for a total daily dose of 12 mg (six active tablets daily), starting on cycle day 2 for endometrial preparation in programmed HRT frozen embryo transfer cycles. Endometrial thickness was reassessed after 10 days; if the endometrium remained <7 mm, treatment could be continued for an additional 3 to 5 days. After adequate endometrial preparation, progesterone was initiated, and estradiol was continued through embryo transfer and until 12 completed weeks of gestation if pregnancy was confirmed.
Active Comparator: Group B: received 12 mg daily oral estradiol valerate daily.; women in the 12 mg group received six active 2 mg estradiol valerate tablets	Drug: Progynova®; Oral estradiol valerate 8 mg/day Oral estradiol valerate administered as 2 mg tablets for a total daily dose of 8 mg (four active tablets daily), starting on cycle day 2 for endometrial preparation in programmed HRT frozen embryo transfer cycles. Endometrial thickness was reassessed after 10 days; if the endometrium remained <7 mm, treatment could be continued for an additional 3 to 5 days. After adequate endometrial preparation, progesterone was initiated, and estradiol was continued through embryo transfer and until 12 completed weeks of gestation if pregnancy was confirmed.; Drug: Progynova®; Oral estradiol valerate 12 mg/day Oral estradiol valerate administered as 2 mg tablets for a total daily dose of 12 mg (six active tablets daily), starting on cycle day 2 for endometrial preparation in programmed HRT frozen embryo transfer cycles. Endometrial thickness was reassessed after 10 days; if the endometrium remained <7 mm, treatment could be continued for an additional 3 to 5 days. After adequate endometrial preparation, progesterone was initiated, and estradiol was continued through embryo transfer and until 12 completed weeks of gestation if pregnancy was confirmed.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
clinical pregnancy rate	Clinical pregnancy rate is defined as the proportion of participants with one or more gestational sacs detected by transvaginal ultrasound after frozen embryo transfer.	6 to 8 weeks after embryo transfer

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cycle cancellation rate	Proportion of treatment cycles cancelled before embryo transfer, including cancellation due to inadequate endometrial development or failure to meet continuation criteria	From treatment initiation until cycle cancellation before embryo transfer or embryo transfer if the cycle continued, assessed up to 8 weeks per treatment cycle.
Live birth rate	Proportion of participants who delivered at least one live-born infant after 24 completed weeks of gestation.	At delivery after 24 completed weeks of gestation

Collaborators and Investigators

• Sponsor: Cairo University

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2022
• Primary Completion (Actual): March 1, 2026
• Study Completion (Actual): April 1, 2026

Study Registration Dates

• First Submitted: April 2, 2026
• First Submitted That Met QC Criteria: April 10, 2026
• First Posted (Actual): April 13, 2026

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: randomized trial; endometrial preparation; hormone replacement therapy; frozen embryo transfer; assisted reproductive technology; clinical pregnancy; estradiol valerate
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Infertility; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Estrenes; Estranes; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Estradiol
• Other Study ID Numbers: Cairo-MD-42-2022

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The datasets generated and/or analyzed during the current study are included within the published article and its supplementary files. Additional data may be available from the corresponding author on reasonable request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No