FET-LET-2x2: Clinical Pregnancy Rates After Frozen Embryo Transfer in Natural and Modified Natural Cycles (FET-LET-2x2)

FET-LET-2x2: A Randomized Open-Label 2×2 Factorial Trial Comparing Clinical Pregnancy Rates After Frozen Embryo Transfer in True and Modified Natural Cycles With and Without Aromatase Inhibitors

The goal of this clinical trial is to learn whether different natural approaches to preparing the uterus for frozen embryo transfer (FET) can improve pregnancy success in women undergoing in vitro fertilization (IVF) treatment.

The main questions it aims to answer are:

1. Is a completely natural menstrual cycle more successful than a natural cycle in which ovulation is triggered with medication when preparing for frozen embryo transfer?
2. Does taking a medication called letrozole at the beginning of the cycle improve pregnancy success compared to not taking it?

Researchers will compare four different approaches to see which one results in the highest chance of achieving a clinical pregnancy, confirmed by ultrasound.

Participants will:

• Be randomly assigned to one of four groups
• Undergo monitoring with ultrasound and blood hormone tests during their menstrual cycle
• In some groups, take letrozole tablets for a few days early in the cycle
• In some groups, receive a hormone injection to help control the timing of ovulation
• Undergo frozen embryo transfer at the appropriate time
• Receive standard hormonal support after embryo transfer
• Researchers will compare four different approaches to see which one results in the highest chance of achieving a clinical pregnancy, confirmed by ultrasound.

Study Overview

• Status: Not yet recruiting
• Conditions: Infertility Female; Frozen Embryo Transfer (FET)
• Intervention / Treatment: Drug: Progesterone; Drug: Letrozole (Aromatase Inhibitors); Drug: Choriogonadotropin alpha (r-hCG)

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jelena Vukovic, MD; Phone Number: +381643070647; Email: jel.zor@gmail.com

Study Locations

• Serbia
  • Novi Sad, Serbia, 21000
    • Specialized Gynecological Hospital "Ferona" Novi Sad
    • Contact: Stevan Milatović, Associate Professor; Phone Number: +38121 3000220; Email: office@ferona.rs

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Women aged 18 to 40 years
• Regular menstrual cycles (26-35 days)
• Scheduled for frozen embryo transfer (FET) in a natural menstrual cycle
• Normal gynecological ultrasound findings without clinically significant uterine abnormalities
• Ability to provide written informed consent

Exclusion Criteria:

• Use of preimplantation genetic testing (PGT) for the transferred embryo
• Use of donor oocytes
• Inadequate embryo survival after thawing, defined as loss of viability in more than 50% of blastomeres
• Irregular menstrual cycles
• Presence of clinically significant uterine abnormalities detected by ultrasound
• Inability or unwillingness to provide written informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: True Natural Cycle Without Letrozole; Participants undergo frozen embryo transfer in a true natural menstrual cycle without the use of either an aromatase inhibitor or ovulation trigger medication. Ovulation is monitored by ultrasound and serum hormone levels. Luteal phase support (vaginal progesterone 200 mg twice daily or subcutaneous progesterone 25 mg once daily) is initiated on the day of ultrasound-confirmed ovulation and continued until 12 weeks of gestation if pregnancy occurs.	Drug: Progesterone; Luteal phase support with either vaginal progesterone 200 mg twice daily or subcutaneous progesterone 25 mg once daily, initiated after ovulation (or 2 days after hCG trigger) and continued until 12 weeks of gestation if pregnancy occurs.
Experimental: True Natural Cycle With Letrozole; Participants undergo frozen embryo transfer (FET) in a true natural menstrual cycle with administration of the aromatase inhibitor letrozole (2.5 mg twice daily) from cycle days 3-7. Ovulation is monitored by ultrasound and serum hormone levels. Luteal phase support (vaginal progesterone 200 mg twice daily or subcutaneous progesterone 25 mg once daily) is initiated on the day of ultrasound-confirmed ovulation and continued until 12 weeks of gestation if pregnancy occurs.	Drug: Progesterone; Luteal phase support with either vaginal progesterone 200 mg twice daily or subcutaneous progesterone 25 mg once daily, initiated after ovulation (or 2 days after hCG trigger) and continued until 12 weeks of gestation if pregnancy occurs.; Drug: Letrozole (Aromatase Inhibitors); Letrozole 2.5 mg administered orally twice daily from cycle days 3-7 during the early follicular phase.
Experimental: Modified Natural Cycle Without Letrozole; Participants undergo frozen embryo transfer in a modified natural menstrual cycle without the use of an aromatase inhibitor. When the dominant follicle reaches ≥17 mm and endometrial thickness is ≥7 mm, and after exclusion of a spontaneous LH surge by serum measurement, ovulation is triggered with recombinant human chorionic gonadotropin (hCG) 250 mcg. Luteal phase support (vaginal progesterone 200 mg twice daily or subcutaneous progesterone 25 mg once daily) is initiated 2 days after ovulation trigger and continued until 12 weeks of gestation if pregnancy occurs.	Drug: Progesterone; Luteal phase support with either vaginal progesterone 200 mg twice daily or subcutaneous progesterone 25 mg once daily, initiated after ovulation (or 2 days after hCG trigger) and continued until 12 weeks of gestation if pregnancy occurs.; Drug: Choriogonadotropin alpha (r-hCG); Recombinant human chorionic gonadotropin (hCG) 250 mcg administered subcutaneously to trigger ovulation when follicular and endometrial criteria are met.
Experimental: Modified Natural Cycle With Letrozole; Participants undergo frozen embryo transfer (FET) in a modified natural menstrual cycle with administration of letrozole (2.5 mg twice daily) from cycle days 3-7. Ultrasound monitoring begins between cycle days 8-10. When the dominant follicle reaches ≥17 mm and endometrial thickness is ≥7 mm, and after exclusion of a spontaneous LH surge by serum LH measurement, ovulation is triggered with recombinant human chorionic gonadotropin (hCG) 250 mcg. Luteal phase support (vaginal progesterone 200 mg twice daily or subcutaneous progesterone 25 mg once daily) is initiated 2 days after ovulation trigger and continued until 12 weeks of gestation if pregnancy occurs.	Drug: Progesterone; Luteal phase support with either vaginal progesterone 200 mg twice daily or subcutaneous progesterone 25 mg once daily, initiated after ovulation (or 2 days after hCG trigger) and continued until 12 weeks of gestation if pregnancy occurs.; Drug: Letrozole (Aromatase Inhibitors); Letrozole 2.5 mg administered orally twice daily from cycle days 3-7 during the early follicular phase.; Drug: Choriogonadotropin alpha (r-hCG); Recombinant human chorionic gonadotropin (hCG) 250 mcg administered subcutaneously to trigger ovulation when follicular and endometrial criteria are met.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Pregnancy Rate	Number of pregnancies with an ultrasound-confirmed gestational sac per embryo transfer.	Approximately 4-6 weeks after embryo transfer.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biochemical Pregnancy Rate	Number of pregnancies with elevated serum beta-human chorionic gonadotropin (β-hCG) levels measured two weeks after embryo transfer, per embryo transfer.	Two weeks after embryo transfer.
Implantation Rate	Number of ultrasound-confirmed gestational sacs divided by the number of embryos transferred.	Approximately 4-6 weeks after embryo transfer.
Miscarriage Rate	Pregnancy loss before 23 completed weeks of gestation, expressed per embryo transfer.	Up to 23 weeks of gestation.

Collaborators and Investigators

• Sponsor: University of Novi Sad

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2026
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: February 16, 2026
• First Submitted That Met QC Criteria: February 16, 2026
• First Posted (Actual): February 23, 2026

Study Record Updates

• Last Update Posted (Actual): February 23, 2026
• Last Update Submitted That Met QC Criteria: February 16, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Natural cycle FET
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Diseases, Female; Infertility; Infertility, Female; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Enzyme Inhibitors; Steroid Synthesis Inhibitors; Hormone Antagonists; Estrogen Antagonists; Peptide Hormones; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Pharmacologic Actions; Chemical Actions and Uses; Polycyclic Compounds; Pregnanes; Steroids; Fused-Ring Compounds; Nitriles; Gonadal Steroid Hormones; Gonadal Hormones; Pregnenediones; Pregnenes; Triazoles; Gonadotropins; Placental Hormones; Pregnancy Proteins; Corpus Luteum Hormones; Progesterone Congeners; Letrozole; Aromatase Inhibitors; Progesterone; Chorionic Gonadotropin
• Other Study ID Numbers: Ethics Approval No 01-39/8/1

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