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

NCT07425990 | Not Yet Recruiting

• 1 other identifier: Ethics Approval No 01-39/8/1
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

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:

• 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.

Conditions

Infertility Female; Frozen Embryo Transfer (FET)

Keywords

Natural cycle FET

Outcome Measures

Primary Outcomes (1)

• Clinical Pregnancy Rate

  Number of pregnancies with an ultrasound-confirmed gestational sac per embryo transfer.

  Approximately 4-6 weeks after embryo transfer.

Secondary Outcomes (3)

• Biochemical Pregnancy Rate

  Two weeks after embryo transfer.

• Implantation Rate

  Approximately 4-6 weeks after embryo transfer.

• Miscarriage Rate

  Up to 23 weeks of gestation.

Study Arms (4)

True Natural Cycle Without Letrozole

EXPERIMENTAL

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

True Natural Cycle With Letrozole

EXPERIMENTAL

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: Letrozole (Aromatase Inhibitors); Drug: Progesterone

Modified Natural Cycle Without Letrozole

EXPERIMENTAL

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: Choriogonadotropin alpha (r-hCG); Drug: Progesterone

Modified Natural Cycle With Letrozole

EXPERIMENTAL

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: Letrozole (Aromatase Inhibitors); Drug: Choriogonadotropin alpha (r-hCG); Drug: Progesterone

Interventions

Letrozole (Aromatase Inhibitors) DRUG

Letrozole 2.5 mg administered orally twice daily from cycle days 3-7 during the early follicular phase.

Modified Natural Cycle With Letrozole; True Natural Cycle With Letrozole

Progesterone DRUG

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.

Modified Natural Cycle With Letrozole; Modified Natural Cycle Without Letrozole; True Natural Cycle With Letrozole; True Natural Cycle Without Letrozole

Choriogonadotropin alpha (r-hCG) DRUG

Recombinant human chorionic gonadotropin (hCG) 250 mcg administered subcutaneously to trigger ovulation when follicular and endometrial criteria are met.

Modified Natural Cycle With Letrozole; Modified Natural Cycle Without Letrozole

Eligibility Criteria

• Age: 18 Years - 40 Years
• Gender Eligibility Details: Cisgender
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Novi Sad: lead

Study Sites (1)

Specialized Gynecological Hospital "Ferona" Novi Sad

Novi Sad, 21000, Serbia

Location

MeSH Terms

Conditions

Infertility, Female

Interventions

Letrozole; Aromatase Inhibitors; Chorionic Gonadotropin; Progesterone

Condition Hierarchy (Ancestors)

Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Infertility

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Gonadotropins; Peptide Hormones; Hormones; Placental Hormones; Peptides; Amino Acids, Peptides, and Proteins; Pregnancy Proteins; Proteins; Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Corpus Luteum Hormones; Gonadal Hormones; Progesterone Congeners; Gonadal Steroid Hormones

Central Study Contacts

Jelena Vukovic, MD

CONTACT

+381643070647; jel.zor@gmail.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: teaching assistant

Study Record Dates

• First Submitted: February 16, 2026
• First Posted: February 23, 2026
• Study Start: February 1, 2026
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): March 1, 2027
• Last Updated: February 23, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

SE (1)