Infertility FemaleFET-LET-2x2NCT07425990
FET-LET-2x2: Clinical Pregnancy Rates After Frozen Embryo Transfer in Natural and Modified Natural Cycles
A study testing Letrozole (Aromatase Inhibitors), Choriogonadotropin alpha (r-hCG) and Progesterone in people with Infertility Female and Frozen Embryo Transfer (FET), run by University of Novi Sad at 1 site in Serbia.
Trial 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: 1. Read more about this study
- Who is it for?
- Ages 18 to 40 years, women only
- Conditions the study is for
- Infertility Female, Frozen Embryo Transfer (FET)
- What is being tested?
- Letrozole (Aromatase Inhibitors), Choriogonadotropin alpha (r-hCG) and Progesterone
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 120 participants
- Where
- 1 siteSerbia
- Study dates
- 13 Mar 2026to Mar 2027
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Serbia1 site, 1 recruiting
- Recruiting
Specialized Gynecological Hospital "Ferona" Novi Sad
Novi Sad, 21000
Stevan Milatović, Associate Professor, +38121 3000220, office@ferona.rs
About this study
Official title: 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:
Read more
- 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?
- 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.
- Conditions
- Infertility Female, Frozen Embryo Transfer (FET)
- Being tested
- Letrozole (Aromatase Inhibitors), Choriogonadotropin alpha (r-hCG), Progesterone
- Keywords
- Natural cycle FET
- Medical subject headings
- Infertility, Female
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Letrozole (Aromatase Inhibitors)Drug
Letrozole 2.5 mg administered orally twice daily from cycle days 3-7 during the early follicular phase.
Choriogonadotropin alpha (r-hCG)Drug
Recombinant human chorionic gonadotropin (hCG) 250 mcg administered subcutaneously to trigger ovulation when follicular and endometrial criteria are met.
ProgesteroneDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: Letrozole (Aromatase Inhibitors); Drug: Choriogonadotropin alpha (r-hCG); Drug: Progesterone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Clinical Pregnancy Rate
Number of pregnancies with an ultrasound-confirmed gestational sac per embryo transfer.
Measured: Approximately 4-6 weeks after embryo transfer.
Secondary outcomes (3)
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.
Measured: Two weeks after embryo transfer.
Implantation Rate
Number of ultrasound-confirmed gestational sacs divided by the number of embryos transferred.
Measured: Approximately 4-6 weeks after embryo transfer.
Miscarriage Rate
Pregnancy loss before 23 completed weeks of gestation, expressed per embryo transfer.
Measured: Up to 23 weeks of gestation.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Feb 2026
- Study start13 Mar 2026
- Primary completionFeb 2027 (estimated)
- Study completionMar 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Infertility FemaleStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Enrolment
- 120 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Novi Sad
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Jelena Vuković, University of Novi Sad
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07425990
- Sponsor's protocol ID
- Ethics Approval No 01-39/8/1
- Acronym
- FET-LET-2x2
- Status last verified
- Feb 2026
- First submitted
- 16 Feb 2026
- Last updated
- 29 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 Sep 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT07425990
- Acronym / sponsor ID
- FET-LET-2x2 / Ethics Approval No 01-39/8/1
- Conditions
- Infertility Female, Frozen Embryo Transfer (FET)
- Keywords
- Natural cycle FET
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 120 participants (estimated)
- Lead sponsor
- University of Novi SadUniversity, hospital or other
- Study start
- 13 Mar 2026 (actual)
- Primary completion
- Feb 2027 (estimated)
- Study completion
- Mar 2027 (estimated)
- First posted
- 23 Feb 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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?
- 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| True Natural Cycle Without Letrozole | Experimental | Drug: ProgesteroneParticipants 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. |
| True Natural Cycle With Letrozole | Experimental | Drug: Letrozole (Aromatase Inhibitors), Drug: ProgesteroneParticipants 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. |
| Modified Natural Cycle Without Letrozole | Experimental | Drug: Choriogonadotropin alpha (r-hCG), Drug: ProgesteroneParticipants 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. |
| Modified Natural Cycle With Letrozole | Experimental | Drug: Letrozole (Aromatase Inhibitors), Drug: Choriogonadotropin alpha (r-hCG), Drug: ProgesteroneParticipants 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. |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (6 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Letrozole (Aromatase Inhibitors)Letrozole 2.5 mg administered orally twice daily from cycle days 3-7 during the early follicular phase. | Drug | Modified Natural Cycle With Letrozole, True Natural Cycle With Letrozole |
| Choriogonadotropin alpha (r-hCG)Recombinant human chorionic gonadotropin (hCG) 250 mcg administered subcutaneously to trigger ovulation when follicular and endometrial criteria are met. | Drug | Modified Natural Cycle With Letrozole, Modified Natural Cycle Without Letrozole |
| ProgesteroneLuteal 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 | Modified Natural Cycle With Letrozole, Modified Natural Cycle Without Letrozole, True Natural Cycle With Letrozole, True Natural Cycle Without Letrozole |
Primary outcome
Clinical Pregnancy Rate
Time frame: Approximately 4-6 weeks after embryo transfer.
Number of pregnancies with an ultrasound-confirmed gestational sac per embryo transfer.
3 secondary outcomes
Biochemical Pregnancy Rate
Time frame: Two weeks after embryo transfer.
Implantation Rate
Time frame: Approximately 4-6 weeks after embryo transfer.
Miscarriage Rate
Time frame: Up to 23 weeks of gestation.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Sep 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Letrozole (Aromatase Inhibitors), Choriogonadotropin alpha (r-hCG) and Progesterone in people with Infertility Female and Frozen Embryo Transfer (FET), run by University of Novi Sad at 1 site in Serbia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 29 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Serbia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Jelena Vukovic, MD (+381643070647, jel.zor@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Clinical Pregnancy Rate (time frame: Approximately 4-6 weeks after embryo transfer.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Sep 2026.