Embryo TransferNCT06372119
Letrozole-stimulated Cycle Strategy Versus Artificial Cycle Strategy (LETSACT)
A study testing Letrozole-stimulated cycle strategy and Artificial cycle strategy in people with Embryo Transfer and Irregular Menstruation, run by Mỹ Đức Hospital at 2 sites in Vietnam.
Trial summary
The goal of this randomized clinical trial is to evaluate the effectiveness of the letrozole-stimulated cycle strategy versus the artificial cycle strategy for endometrial preparation in women with irregular menstrual cycles after one cycle of endometrial preparation. Read more about this study
- Who is it for?
- Ages 18 to 42 years, women onlyHealthy volunteers can take part
- Conditions the study is for
- Embryo Transfer, Irregular Menstruation, Letrozole
- What is being tested?
- Letrozole-stimulated cycle strategy and Artificial cycle strategy
- Type of treatment
- Pill or oral medicine, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 790 participants
- Where
- 2 sitesVietnam
- Study dates
- 22 Apr 2024to Apr 2026
- 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 42 years
- Women only
- Healthy volunteers accepted
- Adult
Who may be able to join
- Aged between 18 - 42.
- Irregular menstrual cycle (< 21 days or > 35 days or < 8 cycles/years).
- Indicated for endometrial preparation.
- Transfer of only one blastocyst.
- Not participating in any other trials.
Who cannot join
- Allergy to letrozole or Ovitrelle or oral estradiol valerate or micronized progesterone
- Having embryos from either oocyte donation or PGT (pre-implantation genetics testings) cycles.
- Ovarian cysts that are unrelated to the oocyte pick-up.
- Confirmed diagnosis with recurrent pregnancy loss (RPL) according to ESHRE guideline 2023, recurrent implantation failure (RIF) according to ESHRE 2023 good practice recommendations.
- Endometrial abnormalities include endometrial hyperplasia, intrauterine adhesions, endometrial polyp, and chronic endometritis.
- Uterine abnormalities include leiomyomas L0, L1, or L2 (according to FIGO 2011); adenomyosis (according to MUSA 2022); congenital uterine abnormalities, include didelphus, arcuate, unicornuate, bicornuate, septate (according to ASRM 2021).
- Untreated hydrosalpinx.
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Vietnam2 sites, 2 recruiting
- Recruiting
My Duc Hospital
Ho Chi Minh City, Ho Chi Minh City, 70000
Vu NA Ho, MD, +84935843336, bsvu.hna@myduchospital.vn
Nam T Nguyen, MD, +84354120209, bsnam.nt@myduchospital.vn
- Recruiting
My Duc Phu Nhuan Hospital
Ho Chi Minh City, Ho Chi Minh City, 70000
Ho L Le, MD, +84356177147, bsho.ll@myduchospital.vn
Tien K Le, MD, +84962803875, bstien.lk@myduchospital.vn
About this study
Official title: Letrozole-stimulated Cycle Strategy Versus Artificial Cycle Strategy for Endometrial Preparation in Women With Irregular Menstrual Cycles: A Randomized Controlled Trial
The goal of this randomized clinical trial is to evaluate the effectiveness of the letrozole-stimulated cycle strategy versus the artificial cycle strategy for endometrial preparation in women with irregular menstrual cycles after one cycle of endometrial preparation. The primary question it aims to answer is:
- Does the letrozole-stimulated cycle strategy for endometrial preparation result in a higher live birth rate compared to the artificial cycle strategy in women with irregular menstrual cycles after one cycle of endometrial preparation?
Participants will undergo screening before endometrial preparation for frozen embryo transfer, following which they will be randomly assigned to one of two groups: LETS or AC. In the LETS group, investigators will prescribe letrozole 5 milligrams/day for 5 days to stimulate follicular development and micronized progesterone 800 milligrams/day for luteal phase support. In contrast, the AC group will receive oral estradiol valerate 6-12 milligrams/day and micronized progesterone 800 milligrams/day. Researchers will compare the LETS and AC groups to determine if there are differences in live birth rates.
Read the detailed description
Freeze-all and later frozen embryo transfer (FET) to reduce the risk of ovarian hyperstimulation syndrome (OHSS) is a common strategy in modern assisted reproduction technology (ART). Preparing the endometrium for FET in women with irregular menstrual cycles poses a challenge due to limited protocol options. There are two basic endometrial preparation regimens before FET: artificial cycle (AC) or natural cycle (NC). NC is often only considered if the woman has regular ovulation. In women with irregular menstrual cycles, the most popular conventional technique of endometrial preparation is AC. The advantages of AC include its convenience (meaning that the window of implantation can be determined actively and correctly) and its adaptability (meaning that the duration and the dose of exposure to estradiol and progesterone hormones can be flexibly scheduled). On the other hand, artificial exogenous estradiol levels may diminish endometrial receptivity, increase the risk of thrombosis and cancer, and negatively impact the baby's outcomes. Furthermore, the absence of the corpus luteum and its products in early pregnancy may be associated with an increased risk of placentation deficiency and an increased risk of (pre)eclampsia, which is already common in this population.
The current modern approach in endometrial preparation is to create the endometrial proliferative phase that mimics the NC's physiology and to attempt to produce the corpus luteum. Previous studies showed that in the general population, ovulation-based cycles resulted in considerably greater pregnancy rates than AC, regardless of whether ovulation was natural or inducted. Exogenous gonadotropins, clomiphene citrate (CC), and aromatase inhibitors (AI) are the three types of ovulation-inducing agents widely utilized for women with irregular menstrual periods. Gonadotropin is not patient-friendly due to the route of administration and increases the risk of OHSS. CC is well-known for its antagonistic effect on estrogen receptors and its negative impact on endometrial receptivity. Letrozole, a preferred drug in the AI group, has been explored for almost two decades to avoid the drawbacks of other methods. First, letrozole can stimulate mono-follicular growth and minimize the incidence of OHSS at a low cost and in a more patient-friendly manner. Second, letrozole decreases intraovarian and serum estrogen levels, thereby upregulating endometrial estrogen receptors, increasing endometrial sensitivity to estrogen increase, and preventing premature progesterone action, which results in increased endometrial proliferation. Thirdly, there was evidence that letrozole may improve endometrial receptivity by modulating the formation of αvβ3 and HOXA10 integrin, leukemia inhibitory factor (LIF), L-selectin, and pinopode formation.
The findings of some previous studies showed that the letrozole-stimulated cycle was superior to AC in terms of improving clinical pregnancy rate, live birth rate, and lower risk of miscarriage, preterm birth, pre-ecclampisa and also decreasing the risk of ectopic pregnancy. However, there was also evidence that shows no consistent advantage of letrozole as compared to AC. Notably, prior research on the effectiveness of letrozole in endometrial preparation for FET was predominantly retrospective. There were few randomized controlled trials (RCT) comparing the letrozole-stimulated cycle versus AC. However, these studies found similar treatment outcomes with two endometrial preparation methods. The sample size was also limited (N < 150), and letrozole was often used in combination with hMG concurrently.
This study will be undertaken at IVFMD, a reproductive center of My Duc Hospital in Ho Chi Minh City, Vietnam, to provide evidence on how effective letrozole is compared to conventional AC.
- Being tested
- Letrozole-stimulated cycle strategy, Artificial cycle strategy
- Keywords
- Blastocyst Transfer, Irregular Menstruation, Letrozole, Hormone Replacement Therapy
- Medical subject headings
- Menstruation Disturbances
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Letrozole-stimulated cycle strategyProcedure or surgery
Also called LETS
Letrozole (Femara® 2.5 milligrams, Novartis, Switzerland or Lezra® 2.5 milligrams, Actavis, Rumani) 5 milligrams/day for 5 days, starting on the second to fourth day of the menstrual cycle.
Post-letrozole, ultrasound checks follicle growth. If ≥18mm, Ovitrelle® 250 mcg (Merck, Kenilworth, New Jersey, USA) induces ovulation.
Luteal phase support with vaginal micronized progesterone (Cyclogest® 400 milligrams, Actavis, UK or Utrogestan® 200 milligrams, Besins, Belgium) 800 milligrams/day starting two days post-hCG.
Embryo transfer, 5 days post-progesterone. Ultrasounds use Samsung HS-30, vaginal probe, and ≥7.5MHz frequency. Hormonal support until the 12th gestational week with vaginal micronized progesterone 800 milligrams/day.
Cycle cancellation criteria: no follicle development on day 21 from the day of starting letrozole, spontaneous ovulation, letrozole intolerance, fluid retention. Cycle cancellation will be noted as a study's outcome.
Artificial cycle strategyProcedure or surgery
Also called AC
Oral estradiol valerate (Progynova® 2 milligrams, Bayer Pharma AG, Germany or Valiera® 2 milligrams, Laboratories Recalcine, Chile) 6 milligrams/day for 10 days, starting on the second to fourth day of the menstrual cycle.
Post-estradiol, ultrasound checks endometrial thickness. If ≥7mm, start vaginal micronized progesterone (Cyclogest® 400 milligrams, Actavis, UK or Utrogestan® 200 milligrams, Besins, Belgium) 800 milligrams/day. If <7mm, increase the dose of oral estradiol valerate to 8 milligrams/day (5-6 days) and 12 milligrams/day (5-6 days).
Embryo transfer, 5 days post-progesterone. Ultrasounds use Samsung HS-30, vaginal probe, and ≥7.5MHz frequency. Hormonal support until the 12th gestational week with vaginal micronized progesterone 800 milligrams/day.
Cycle cancellation criteria: endometrial thickness <7mm on day 21 of using estradiol, spontaneous ovulation, oral estradiol valerate intolerance, fluid retention. Cycle cancellation will be noted as a study's outcome.
| Study group | Role | What they receive |
|---|---|---|
| Letrozole-stimulated cycle strategy (LETS) | Active comparator | to fourth day of the menstrual cycle.
Post-letrozole, ultrasound checks follicle growth. If ≥18mm, Ovitrelle® 250 mcg (Merck, Kenilworth, New Jersey, USA) induces ovulation.
Luteal phase support with vaginal micronized progesterone (Cyclogest® 400 milligrams, Actavis, UK or Utrogestan® 200 milligrams, Besins, Belgium) 800 milligrams/day starting two days post-hCG.
Embryo transfer, 5 days post-progesterone. Ultrasounds use Samsung HS-30, vaginal probe, and ≥7.5MHz frequency. Hormonal support until the 12th gestational week with vaginal micronized progesterone 800 milligrams/day.
Cycle cancellation criteria: no follicle development on day 21 from the day of starting letrozole, spontaneous ovulation, letrozole intolerance, fluid retention. Cycle cancellation will be noted as a study's outcome. Receives: Procedure: Letrozole-stimulated cycle strategy |
| Artificial cycle strategy (AC) | Active comparator | Oral estradiol valerate (Progynova® 2 milligrams, Bayer Pharma AG, Germany or Valiera® 2 milligrams, Laboratories Recalcine, Chile) 6 milligrams/day for 10 days, starting on the second to fourth day of the menstrual cycle.
Post-estradiol, ultrasound checks endometrial thickness. If ≥7mm, start vaginal micronized progesterone (Cyclogest® 400 milligrams, Actavis, UK or Utrogestan® 200 milligrams, Besins, Belgium) 800 milligrams/day. If <7mm, increase the dose of oral estradiol valerate to 8 milligrams/day (5-6 days) and 12 milligrams/day (5-6 days).
Embryo transfer, 5 days post-progesterone. Ultrasounds use Samsung HS-30, vaginal probe, and ≥7.5MHz frequency. Hormonal support until the 12th gestational week with vaginal micronized progesterone 800 milligrams/day.
Cycle cancellation criteria: endometrial thickness <7mm on day 21 of using estradiol, spontaneous ovulation, oral estradiol valerate intolerance, fluid retention. Cycle cancellation will be noted as a study's outcome. Receives: Procedure: Artificial cycle strategy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Live birth rate after one cycle of endometrial preparation
Live birth will be defined as the complete expulsion or extraction from a woman of a product of fertilization, after 22 completed weeks of gestational age; which, after such separation, breathes or shows any other evidence of life, such as heart beat, umbilical cord pulsation or definite movement of voluntary muscles, irrespective of whether the umbilical cord has been cut or the placenta is atached. A birth weight of 500 grams or more can be used if gestational age is unknown. Twin and higher multiple births will be reported as a single live birth event.
Measured: After 22 completed weeks of gestational age.
Secondary outcomes (30)
Positive pregnancy test after one cycle of endometrial preparation
Defined as serum human chorionic gonadotropin level greater than 25 mIU/mL.
Measured: At 11 days after blastocyst transfer.
Clinical pregnancy after one cycle of endometrial preparation
Diagnosed by ultrasonographic visualization of one or more gestational sacs or definitive clinical signs of pregnancy at 6 weeks or more after the onset of last menstrual period. In addition to intra-uterine pregnancy, it includes a clinically documented ectopic pregnancy.
Measured: First ultrasound before 6 weeks of gestational age.
Ongoing pregnancy after one cycle of endometrial preparation
Defined as pregnancy with a detectable heart rate at 12 weeks gestation or beyond.
Measured: After 12 weeks of gestational age.
Multiple pregnancy after one cycle of endometrial preparation
Defined as the presence of more than one gestational sac at early pregnancy ultrasound (6-9 weeks gestation) (Hecher and Diehl, 2009).
Measured: Ultrasound at 6-9 weeks of gestational age.
Implantation rate after one cycle of endometrial preparation
A cycle in which monitoring has been initiated with the intention to treat but which did not proceed to embryo transfer (as defined above).
Measured: Ultrasound at 6-9 weeks of gestational age.
Cycle cancellation rate
A cycle in which monitoring has been initiated with the intention to treat but which did not proceed to embryo transfer due to the criteria defined above or protocol violation.
Measured: During the intervention (on day 21 from the day of starting to use letrozole or valiera).
Ectopic pregnancy rate after one cycle of endometrial preparation
A pregnancy outside the uterine cavity, diagnosed by ultrasound, surgical visualization or histopathology.
Measured: Ultrasound at 6-9 weeks of gestational age.
Threatened miscarriage rate before 12 weeks of gestation after one cycle of endometrial preparation
Vaginal bleeding before 12 weeks of gestation.
Measured: At 12 weeks of gestational age.
Early miscarriage rate after one cycle of endometrial preparation
Spontaneous loss of pregnancy up to 12 weeks of gestation (Oxford Textbook of Obstetrics and Gynaecology, 2020).
Measured: At 12 weeks of gestational age.
Late miscarriage rate after one cycle of endometrial preparation
Spontaneous loss of pregnancy between12 to 22 weeks of gestation (Oxford Textbook of Obstetrics and Gynaecology, 2020).
Measured: At 22 weeks of gestational age.
Gestational age at birth
Calculated by gestational age of all live births
Measured: On the day of delivery.
Onset of labor
Spontaneous, labor induction, elective C-section.
Measured: On the day of delivery.
Mode of delivery
Vaginal delivery, C-section (elective, suspected fetal distress, non-progressive labor).
Measured: On the day of delivery.
Very low birth weight
Birth weight less than 1500g.
Measured: On the day of delivery.
Low birth weight
Birth weight less than 2500g.
Measured: On the day of delivery.
High birth weight (macrosomia)
Implies growth beyond an absolute birth weight, historically 4000 g or 4500 g, regardless of the gestational age ("Macrosomia: ACOG Practice Bulletin, Number 216," 2020).
Measured: On the day of delivery.
Very high birth weight (macrosomia)
Birth weight over than 4500 g for women with diabetes, and a threshold of 5000 g for women without diabetes ("Macrosomia: ACOG Practice Bulletin, Number 216," 2020).
Measured: On the day of delivery.
Gestational diabetes (GDM)
Diagnosed according to the latest version of ADA guidelines: a 75-g OGTT, with plasma glucose measurement when patient is fasting and at 1 and 2 h, at 24-28 weeks of gestation in women not previously diagnosed with diabetes; fasting: 92 mg/dL (5.1 mmol/L); 1h: 180 mg/dL (10.0 mmol/L); 2h: 153 mg/dL (8.5 mmol/L).
Measured: At 24-28 weeks of gestational age.
Hypertensive disorders of pregnancy
Comprising pregnancy-induced hypertension (PIH), pre-eclampsia/eclampsia and Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. PIH diagnosed after 20 weeks' gestation; systolic blood pressure ≥140 mmHg or diastolic pressure ≥90 mmHg on two occasions, two hours apart, or severely elevated single blood pressure measurement requiring an hypertensive medication. Pre-eclampsia/eclampsia diagnosed according to ACOG practice bulletin (ACOG Committee on Obstetric Practice, 2002). Diagnosis and management of preeclampsia and eclampsia. HELLP syndrome is defined as a condition with the clinical presentation of hemolysis, elevated liver enzymes, and low platelet count; lactate dehydrogenase (LDH) elevated to 600 IU/L or more, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevated more than twice the upper limit of normal, and the platelets count less than 100000 × 10^9/L (ACOG Committee on Obstetric Practice, 2002).
Measured: On the day of delivery.
Preterm birth
Defined as delivery at <24, <28, <32, <37 completed weeks. A birth that takes place after 22 weeks and before 37 completed weeks of gestational age.
Measured: On the day of delivery.
Stillbirth
The death of a fetus prior to the complete expulsion or extraction from its mother after 28 completed weeks of gestational age. The death will be determined by the fact that, after such separation, the fetus does not breathe or show any other evidence of life, such as heartbeat, umbilical cord pulsation, or definite movement of voluntary muscles. Note: It includes deaths occurring during labor.
Measured: On the day of delivery.
Antepartum hemorrhage
Defined as bleeding from or into the genital tract, occurring from 24 weeks of pregnancy and prior to the birth of the baby (Royal College of Obstetricians and Gynaecologists, 2011).
Measured: On the day of delivery.
Postpartum hemorrhage
Defines as cumulative blood loss greater than or equal to 1,000 mL or blood loss accompanied by signs or symptoms of hypovolemia within 24 hours after the birth process (includes intrapartum loss) regardless of route of delivery (Committee on Practice Bulletins-Obstetrics, 2017).
Measured: On the day of delivery.
Small for gestational age (singleton/twins)
Small for gestational age was defined as a birth weight below the 10th percentile (de Onis and Habicht, 1996).
Measured: On the day of delivery.
Large for gestational age (singleton/twins)
Large for gestational age was defined as a birth weight above the 90th percentile.
Measured: On the day of delivery.
Birth weight
In grams; of singletons and twins.
Measured: On the day of delivery.
Congenital anomalies
Structural or functional disorders that occur during intra-uterine life and can be identified prenatally, at birth, or later in life. Congenital anomalies can be caused by single gene defects, chromosomal disorders, multifactorial inheritance, environmental teratogens, and micronutrient deficiencies. The time of identification should be reported.
Measured: Within 28 days of birth.
NICU admission
Counting number of babies admited to neonatal intensive care unit.
Measured: Within 28 days of birth.
Reason for NICU admission
Respiratory distress, intraventricular hemorrhagea, necrotizing enterocolitis, or sepsis.
Measured: Within 28 days of birth.
Neonatal mortality rate
Death of a live-born baby within 28 days of birth. This can be divided into early neonatal mortality, if death occurs in the first seven days after birth, and late neonatal if death occurs between eight and 28 days after delivery.
Measured: Within 28 days of birth.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Apr 2024
- Study start22 Apr 2024
- Primary completionApr 2026 (estimated)
- Study completionApr 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (53)Papers the sponsor has linked to this study.
- Other trials for Embryo TransferStudies 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
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 790 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Mỹ Đức Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Lan TN Vuong, Assoc. Prof., Principal investigator, University of Medicine and Pharmacy at Ho Chi Minh City
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06372119
- Sponsor's protocol ID
- 13/23/DD-BVMD
- Status last verified
- Sep 2025
- First submitted
- 27 Dec 2023
- Last updated
- 25 Sep 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
ACOG Committee on Obstetric Practice. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet. 2002 Apr;77(1):67-75.
PubMed 12094777Aleyasin A, Aghahosseini M, Safdarian L, Noorzadeh M, Fallahi P, Rezaeian Z, Hoseinimosa S. Can letrozole plus HMG protocol improve pregnancy outcomes in frozen-thawed embryo transfer? An RCT. Int J Reprod Biomed. 2017 Feb;15(2):83-86.
PubMed 28462399Aslih N, Dorzia D, Atzmon Y, Estrada D, Ellenbogen A, Bilgory A, Shalom-Paz E. Ovulatory-Based FET Cycles May Achieve Higher Pregnancy Rates in the General Population and among Anovulatory Women. J Clin Med. 2021 Feb 11;10(4):703. doi: 10.3390/jcm10040703.
PubMed 33670133Atkinson M, Crittenden J, Smith H, Sjoblom C. Retrospective cohort study on preparation regimens for frozen embryo transfer. Reprod Fertil. 2021 Nov 23;2(4):308-316. doi: 10.1530/RAF-21-0044. eCollection 2021 Dec.
PubMed 35118408Bocca-Tjeertes IF, Kerstjens JM, Reijneveld SA, Veldman K, Bos AF, de Winter AF. Growth patterns of large for gestational age children up to age 4 years. Pediatrics. 2014 Mar;133(3):e643-9. doi: 10.1542/peds.2013-0985. Epub 2014 Feb 24.
PubMed 24567020Braakhekke M, Kamphuis EI, Dancet EA, Mol F, van der Veen F, Mol BW. Ongoing pregnancy qualifies best as the primary outcome measure of choice in trials in reproductive medicine: an opinion paper. Fertil Steril. 2014 May;101(5):1203-4. doi: 10.1016/j.fertnstert.2014.03.047.
PubMed 24786739Casper RF, Mitwally MF. Use of the aromatase inhibitor letrozole for ovulation induction in women with polycystic ovarian syndrome. Clin Obstet Gynecol. 2011 Dec;54(4):685-95. doi: 10.1097/GRF.0b013e3182353d0f.
PubMed 22031258Chung TW, Park MJ, Kim HS, Choi HJ, Ha KT. Integrin alphaVbeta3 and alphaVbeta5 are required for leukemia inhibitory factor-mediated the adhesion of trophoblast cells to the endometrial cells. Biochem Biophys Res Commun. 2016 Jan 22;469(4):936-40. doi: 10.1016/j.bbrc.2015.12.103. Epub 2015 Dec 24.
PubMed 26723254Committee on Practice Bulletins-Obstetrics. Practice Bulletin No. 183: Postpartum Hemorrhage. Obstet Gynecol. 2017 Oct;130(4):e168-e186. doi: 10.1097/AOG.0000000000002351.
PubMed 28937571Donderwinkel PF, Schoot DC, Pache TD, de Jong FH, Hop WC, Fauser BC. Luteal function following ovulation induction in polycystic ovary syndrome patients using exogenous gonadotrophins in combination with a gonadotrophin-releasing hormone agonist. Hum Reprod. 1993 Dec;8(12):2027-32. doi: 10.1093/oxfordjournals.humrep.a137976.
PubMed 8150898Duffy JMN, Bhattacharya S, Bhattacharya S, Bofill M, Collura B, Curtis C, Evers JLH, Giudice LC, Farquharson RG, Franik S, Hickey M, Hull ML, Jordan V, Khalaf Y, Legro RS, Lensen S, Mavrelos D, Mol BW, Niederberger C, Ng EHY, Puscasiu L, Repping S, Sarris I, Showell M, Strandell A, Vail A, van Wely M, Vercoe M, Vuong NL, Wang AY, Wang R, Wilkinson J, Youssef MA, Farquhar CM; Core Outcome Measure for Infertility Trials (COMMIT) initiative. Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study. Fertil Steril. 2021 Jan;115(1):201-212. doi: 10.1016/j.fertnstert.2020.11.013. Epub 2020 Nov 30.
PubMed 33272619ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, Collins BS, Hilliard ME, Isaacs D, Johnson EL, Kahan S, Khunti K, Leon J, Lyons SK, Perry ML, Prahalad P, Pratley RE, Seley JJ, Stanton RC, Gabbay RA, on behalf of the American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Care in Diabetes-2023. Diabetes Care. 2023 Jan 1;46(Suppl 1):S19-S40. doi: 10.2337/dc23-S002.
PubMed 36507649ESHRE Working Group on Recurrent Implantation Failure; Cimadomo D, de Los Santos MJ, Griesinger G, Lainas G, Le Clef N, McLernon DJ, Montjean D, Toth B, Vermeulen N, Macklon N. ESHRE good practice recommendations on recurrent implantation failure. Hum Reprod Open. 2023 Jun 15;2023(3):hoad023. doi: 10.1093/hropen/hoad023. eCollection 2023.
PubMed 37332387Franik S, Eltrop SM, Kremer JA, Kiesel L, Farquhar C. Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2018 May 24;5(5):CD010287. doi: 10.1002/14651858.CD010287.pub3.
PubMed 29797697Ganesh A, Chauhan N, Das S, Chakravarty B, Chaudhury K. Endometrial receptivity markers in infertile women stimulated with letrozole compared with clomiphene citrate and natural cycles. Syst Biol Reprod Med. 2014 Apr;60(2):105-11. doi: 10.3109/19396368.2013.862316. Epub 2013 Dec 5.
PubMed 24304327
Study at a glance
From the registry record, last updated by the sponsor on 25 Sep 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Letrozole-stimulated Cycle Strategy Versus Artificial Cycle Strategy for Endometrial Preparation in Women With Irregular Menstrual Cycles: A Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT06372119
- Acronym / sponsor ID
- 13/23/DD-BVMD
- Keywords
- Blastocyst Transfer, Irregular Menstruation, Letrozole, Hormone Replacement Therapy
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 790 participants (estimated)
- Lead sponsor
- Mỹ Đức HospitalUniversity, hospital or other
- Study start
- 22 Apr 2024 (actual)
- Primary completion
- Apr 2026 (estimated)
- Study completion
- Apr 2026 (estimated)
- First posted
- 17 Apr 2024 (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 randomized clinical trial is to evaluate the effectiveness of the letrozole-stimulated cycle strategy versus the artificial cycle strategy for endometrial preparation in women with irregular menstrual cycles after one cycle of endometrial preparation. The primary question it aims to answer is:
- Does the letrozole-stimulated cycle strategy for endometrial preparation result in a higher live birth rate compared to the artificial cycle strategy in women with irregular menstrual cycles after one cycle of endometrial preparation?
Participants will undergo screening before endometrial preparation for frozen embryo transfer, following which they will be randomly assigned to one of two groups: LETS or AC. In the LETS group, investigators will prescribe letrozole 5 milligrams/day for 5 days to stimulate follicular development and micronized progesterone 800 milligrams/day for luteal phase support. In contrast, the AC group will receive oral estradiol valerate 6-12 milligrams/day and micronized progesterone 800 milligrams/day. Researchers will compare the LETS and AC groups to determine if there are differences in live birth rates.
Detailed description
Freeze-all and later frozen embryo transfer (FET) to reduce the risk of ovarian hyperstimulation syndrome (OHSS) is a common strategy in modern assisted reproduction technology (ART). Preparing the endometrium for FET in women with irregular menstrual cycles poses a challenge due to limited protocol options. There are two basic endometrial preparation regimens before FET: artificial cycle (AC) or natural cycle (NC). NC is often only considered if the woman has regular ovulation. In women with irregular menstrual cycles, the most popular conventional technique of endometrial preparation is AC. The advantages of AC include its convenience (meaning that the window of implantation can be determined actively and correctly) and its adaptability (meaning that the duration and the dose of exposure to estradiol and progesterone hormones can be flexibly scheduled). On the other hand, artificial exogenous estradiol levels may diminish endometrial receptivity, increase the risk of thrombosis and cancer, and negatively impact the baby's outcomes. Furthermore, the absence of the corpus luteum and its products in early pregnancy may be associated with an increased risk of placentation deficiency and an increased risk of (pre)eclampsia, which is already common in this population.
The current modern approach in endometrial preparation is to create the endometrial proliferative phase that mimics the NC's physiology and to attempt to produce the corpus luteum. Previous studies showed that in the general population, ovulation-based cycles resulted in considerably greater pregnancy rates than AC, regardless of whether ovulation was natural or inducted. Exogenous gonadotropins, clomiphene citrate (CC), and aromatase inhibitors (AI) are the three types of ovulation-inducing agents widely utilized for women with irregular menstrual periods. Gonadotropin is not patient-friendly due to the route of administration and increases the risk of OHSS. CC is well-known for its antagonistic effect on estrogen receptors and its negative impact on endometrial receptivity. Letrozole, a preferred drug in the AI group, has been explored for almost two decades to avoid the drawbacks of other methods. First, letrozole can stimulate mono-follicular growth and minimize the incidence of OHSS at a low cost and in a more patient-friendly manner. Second, letrozole decreases intraovarian and serum estrogen levels, thereby upregulating endometrial estrogen receptors, increasing endometrial sensitivity to estrogen increase, and preventing premature progesterone action, which results in increased endometrial proliferation. Thirdly, there was evidence that letrozole may improve endometrial receptivity by modulating the formation of αvβ3 and HOXA10 integrin, leukemia inhibitory factor (LIF), L-selectin, and pinopode formation.
The findings of some previous studies showed that the letrozole-stimulated cycle was superior to AC in terms of improving clinical pregnancy rate, live birth rate, and lower risk of miscarriage, preterm birth, pre-ecclampisa and also decreasing the risk of ectopic pregnancy. However, there was also evidence that shows no consistent advantage of letrozole as compared to AC. Notably, prior research on the effectiveness of letrozole in endometrial preparation for FET was predominantly retrospective. There were few randomized controlled trials (RCT) comparing the letrozole-stimulated cycle versus AC. However, these studies found similar treatment outcomes with two endometrial preparation methods. The sample size was also limited (N < 150), and letrozole was often used in combination with hMG concurrently.
This study will be undertaken at IVFMD, a reproductive center of My Duc Hospital in Ho Chi Minh City, Vietnam, to provide evidence on how effective letrozole is compared to conventional AC.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Letrozole-stimulated cycle strategy (LETS) | Active comparator | Procedure: Letrozole-stimulated cycle strategyto fourth day of the menstrual cycle. Post-letrozole, ultrasound checks follicle growth. If ≥18mm, Ovitrelle® 250 mcg (Merck, Kenilworth, New Jersey, USA) induces ovulation. Luteal phase support with vaginal micronized progesterone (Cyclogest® 400 milligrams, Actavis, UK or Utrogestan® 200 milligrams, Besins, Belgium) 800 milligrams/day starting two days post-hCG. Embryo transfer, 5 days post-progesterone. Ultrasounds use Samsung HS-30, vaginal probe, and ≥7.5MHz frequency. Hormonal support until the 12th gestational week with vaginal micronized progesterone 800 milligrams/day. Cycle cancellation criteria: no follicle development on day 21 from the day of starting letrozole, spontaneous ovulation, letrozole intolerance, fluid retention. Cycle cancellation will be noted as a study's outcome. |
| Artificial cycle strategy (AC) | Active comparator | Procedure: Artificial cycle strategyOral estradiol valerate (Progynova® 2 milligrams, Bayer Pharma AG, Germany or Valiera® 2 milligrams, Laboratories Recalcine, Chile) 6 milligrams/day for 10 days, starting on the second to fourth day of the menstrual cycle. Post-estradiol, ultrasound checks endometrial thickness. If ≥7mm, start vaginal micronized progesterone (Cyclogest® 400 milligrams, Actavis, UK or Utrogestan® 200 milligrams, Besins, Belgium) 800 milligrams/day. If <7mm, increase the dose of oral estradiol valerate to 8 milligrams/day (5-6 days) and 12 milligrams/day (5-6 days). Embryo transfer, 5 days post-progesterone. Ultrasounds use Samsung HS-30, vaginal probe, and ≥7.5MHz frequency. Hormonal support until the 12th gestational week with vaginal micronized progesterone 800 milligrams/day. Cycle cancellation criteria: endometrial thickness <7mm on day 21 of using estradiol, spontaneous ovulation, oral estradiol valerate intolerance, fluid retention. Cycle cancellation will be noted as a study's outcome. |
Who may qualify
- Ages
- 18 to 42 years
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- Aged between 18 - 42.
- Irregular menstrual cycle (< 21 days or > 35 days or < 8 cycles/years).
- Indicated for endometrial preparation.
- Transfer of only one blastocyst.
- Not participating in any other trials.
Key exclusion criteria (7 listed)
- Allergy to letrozole or Ovitrelle or oral estradiol valerate or micronized progesterone
- Having embryos from either oocyte donation or PGT (pre-implantation genetics testings) cycles.
- Ovarian cysts that are unrelated to the oocyte pick-up.
- Confirmed diagnosis with recurrent pregnancy loss (RPL) according to ESHRE guideline 2023, recurrent implantation failure (RIF) according to ESHRE 2023 good practice recommendations.
- Endometrial abnormalities include endometrial hyperplasia, intrauterine adhesions, endometrial polyp, and chronic endometritis.
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-stimulated cycle strategyAlso: LETSLetrozole (Femara® 2.5 milligrams, Novartis, Switzerland or Lezra® 2.5 milligrams, Actavis, Rumani) 5 milligrams/day for 5 days, starting on the second to fourth day of the menstrual cycle. Post-letrozole, ultrasound checks follicle growth. If ≥18mm, Ovitrelle® 250 mcg (Merck, Kenilworth, New Jersey, USA) induces ovulation. Luteal phase support with vaginal micronized progesterone (Cyclogest® 400 milligrams, Actavis, UK or Utrogestan® 200 milligrams, Besins, Belgium) 800 milligrams/day starting two days post-hCG. Embryo transfer, 5 days post-progesterone. Ultrasounds use Samsung HS-30, vaginal probe, and ≥7.5MHz frequency. Hormonal support until the 12th gestational week with vaginal micronized progesterone 800 milligrams/day. Cycle cancellation criteria: no follicle development on day 21 from the day of starting letrozole, spontaneous ovulation, letrozole intolerance, fluid retention. Cycle cancellation will be noted as a study's outcome. | Procedure or surgery | Letrozole-stimulated cycle strategy (LETS) |
| Artificial cycle strategyAlso: ACOral estradiol valerate (Progynova® 2 milligrams, Bayer Pharma AG, Germany or Valiera® 2 milligrams, Laboratories Recalcine, Chile) 6 milligrams/day for 10 days, starting on the second to fourth day of the menstrual cycle. Post-estradiol, ultrasound checks endometrial thickness. If ≥7mm, start vaginal micronized progesterone (Cyclogest® 400 milligrams, Actavis, UK or Utrogestan® 200 milligrams, Besins, Belgium) 800 milligrams/day. If <7mm, increase the dose of oral estradiol valerate to 8 milligrams/day (5-6 days) and 12 milligrams/day (5-6 days). Embryo transfer, 5 days post-progesterone. Ultrasounds use Samsung HS-30, vaginal probe, and ≥7.5MHz frequency. Hormonal support until the 12th gestational week with vaginal micronized progesterone 800 milligrams/day. Cycle cancellation criteria: endometrial thickness <7mm on day 21 of using estradiol, spontaneous ovulation, oral estradiol valerate intolerance, fluid retention. Cycle cancellation will be noted as a study's outcome. | Procedure or surgery | Artificial cycle strategy (AC) |
Primary outcome
Live birth rate after one cycle of endometrial preparation
Time frame: After 22 completed weeks of gestational age.
Live birth will be defined as the complete expulsion or extraction from a woman of a product of fertilization, after 22 completed weeks of gestational age; which, after such separation, breathes or shows any other evidence of life, such as heart beat, umbilical cord pulsation or definite movement of voluntary muscles, irrespective of whether the umbilical cord has been cut or the placenta is atached. A birth weight of 500 grams or more can be used if gestational age is unknown. Twin and higher multiple births will be reported as a single live birth event.
30 secondary outcomes
Positive pregnancy test after one cycle of endometrial preparation
Time frame: At 11 days after blastocyst transfer.
Clinical pregnancy after one cycle of endometrial preparation
Time frame: First ultrasound before 6 weeks of gestational age.
Ongoing pregnancy after one cycle of endometrial preparation
Time frame: After 12 weeks of gestational age.
Multiple pregnancy after one cycle of endometrial preparation
Time frame: Ultrasound at 6-9 weeks of gestational age.
Implantation rate after one cycle of endometrial preparation
Time frame: Ultrasound at 6-9 weeks of gestational age.
Cycle cancellation rate
Time frame: During the intervention (on day 21 from the day of starting to use letrozole or valiera).
Ectopic pregnancy rate after one cycle of endometrial preparation
Time frame: Ultrasound at 6-9 weeks of gestational age.
Threatened miscarriage rate before 12 weeks of gestation after one cycle of endometrial preparation
Time frame: At 12 weeks of gestational age.
Early miscarriage rate after one cycle of endometrial preparation
Time frame: At 12 weeks of gestational age.
Late miscarriage rate after one cycle of endometrial preparation
Time frame: At 22 weeks of gestational age.
Gestational age at birth
Time frame: On the day of delivery.
Onset of labor
Time frame: On the day of delivery.
Mode of delivery
Time frame: On the day of delivery.
Very low birth weight
Time frame: On the day of delivery.
Low birth weight
Time frame: On the day of delivery.
High birth weight (macrosomia)
Time frame: On the day of delivery.
Very high birth weight (macrosomia)
Time frame: On the day of delivery.
Gestational diabetes (GDM)
Time frame: At 24-28 weeks of gestational age.
Hypertensive disorders of pregnancy
Time frame: On the day of delivery.
Preterm birth
Time frame: On the day of delivery.
Stillbirth
Time frame: On the day of delivery.
Antepartum hemorrhage
Time frame: On the day of delivery.
Postpartum hemorrhage
Time frame: On the day of delivery.
Small for gestational age (singleton/twins)
Time frame: On the day of delivery.
Large for gestational age (singleton/twins)
Time frame: On the day of delivery.
Birth weight
Time frame: On the day of delivery.
Congenital anomalies
Time frame: Within 28 days of birth.
NICU admission
Time frame: Within 28 days of birth.
Reason for NICU admission
Time frame: Within 28 days of birth.
Neonatal mortality rate
Time frame: Within 28 days of birth.
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 25 Sep 2025.
- Background: PubMed 12094777ACOG Committee on Obstetric Practice. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet. 2002 Apr;77(1):67-75.
- Background: PubMed 28462399Aleyasin A, Aghahosseini M, Safdarian L, Noorzadeh M, Fallahi P, Rezaeian Z, Hoseinimosa S. Can letrozole plus HMG protocol improve pregnancy outcomes in frozen-thawed embryo transfer? An RCT. Int J Reprod Biomed. 2017 Feb;15(2):83-86.
- Background: PubMed 33670133Aslih N, Dorzia D, Atzmon Y, Estrada D, Ellenbogen A, Bilgory A, Shalom-Paz E. Ovulatory-Based FET Cycles May Achieve Higher Pregnancy Rates in the General Population and among Anovulatory Women. J Clin Med. 2021 Feb 11;10(4):703. doi: 10.3390/jcm10040703.
- Background: PubMed 35118408Atkinson M, Crittenden J, Smith H, Sjoblom C. Retrospective cohort study on preparation regimens for frozen embryo transfer. Reprod Fertil. 2021 Nov 23;2(4):308-316. doi: 10.1530/RAF-21-0044. eCollection 2021 Dec.
- Background: PubMed 24567020Bocca-Tjeertes IF, Kerstjens JM, Reijneveld SA, Veldman K, Bos AF, de Winter AF. Growth patterns of large for gestational age children up to age 4 years. Pediatrics. 2014 Mar;133(3):e643-9. doi: 10.1542/peds.2013-0985. Epub 2014 Feb 24.
- Background: PubMed 24786739Braakhekke M, Kamphuis EI, Dancet EA, Mol F, van der Veen F, Mol BW. Ongoing pregnancy qualifies best as the primary outcome measure of choice in trials in reproductive medicine: an opinion paper. Fertil Steril. 2014 May;101(5):1203-4. doi: 10.1016/j.fertnstert.2014.03.047.
- Background: PubMed 22031258Casper RF, Mitwally MF. Use of the aromatase inhibitor letrozole for ovulation induction in women with polycystic ovarian syndrome. Clin Obstet Gynecol. 2011 Dec;54(4):685-95. doi: 10.1097/GRF.0b013e3182353d0f.
- Background: PubMed 26723254Chung TW, Park MJ, Kim HS, Choi HJ, Ha KT. Integrin alphaVbeta3 and alphaVbeta5 are required for leukemia inhibitory factor-mediated the adhesion of trophoblast cells to the endometrial cells. Biochem Biophys Res Commun. 2016 Jan 22;469(4):936-40. doi: 10.1016/j.bbrc.2015.12.103. Epub 2015 Dec 24.
- Background: PubMed 28937571Committee on Practice Bulletins-Obstetrics. Practice Bulletin No. 183: Postpartum Hemorrhage. Obstet Gynecol. 2017 Oct;130(4):e168-e186. doi: 10.1097/AOG.0000000000002351.
- Background: PubMed 8150898Donderwinkel PF, Schoot DC, Pache TD, de Jong FH, Hop WC, Fauser BC. Luteal function following ovulation induction in polycystic ovary syndrome patients using exogenous gonadotrophins in combination with a gonadotrophin-releasing hormone agonist. Hum Reprod. 1993 Dec;8(12):2027-32. doi: 10.1093/oxfordjournals.humrep.a137976.
- Background: PubMed 33272619Duffy JMN, Bhattacharya S, Bhattacharya S, Bofill M, Collura B, Curtis C, Evers JLH, Giudice LC, Farquharson RG, Franik S, Hickey M, Hull ML, Jordan V, Khalaf Y, Legro RS, Lensen S, Mavrelos D, Mol BW, Niederberger C, Ng EHY, Puscasiu L, Repping S, Sarris I, Showell M, Strandell A, Vail A, van Wely M, Vercoe M, Vuong NL, Wang AY, Wang R, Wilkinson J, Youssef MA, Farquhar CM; Core Outcome Measure for Infertility Trials (COMMIT) initiative. Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study. Fertil Steril. 2021 Jan;115(1):201-212. doi: 10.1016/j.fertnstert.2020.11.013. Epub 2020 Nov 30.
- Background: PubMed 36507649ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, Collins BS, Hilliard ME, Isaacs D, Johnson EL, Kahan S, Khunti K, Leon J, Lyons SK, Perry ML, Prahalad P, Pratley RE, Seley JJ, Stanton RC, Gabbay RA, on behalf of the American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Care in Diabetes-2023. Diabetes Care. 2023 Jan 1;46(Suppl 1):S19-S40. doi: 10.2337/dc23-S002.
- Individual participant dataSharing planned: No
Related trials for Embryo Transfer
Not yet recruitingObservational study
Linzagolix in Adenomyosis and Recurrent Implantation Failure
Adenomyosis of Uterus, Implantation Failure
RecruitingPhase 2
Effect of FB301 on Vaginal Bacterial Profile in Women With Asymptomatic Vaginal Dysbiosis Undergoing a Mock Frozen Embryo Transfer Cycle
Vaginal Dysbiosis
RecruitingPhase 2/3
Thymosin-α1 for Recurrent Implantation Failure
Recurrent Implantation Faliure
Not yet recruitingObservational study
Association Between Serum Progesterone Levels on Embryo Transfer Day and Clinical Pregnancy in Frozen-thawed Embryo Transfer Cycles Using Hormone Replacement Therapy
Infertility Assisted Reproductive Technology
Not yet recruiting
Cryopreserved Pre-embryo Transfer in a Cytokine-rich Medium Versus Hyaluronic Acid
Frozen Embryo Transfer (FET)
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.
Lan TN Vuong, Assoc. Prof. principal investigator
University of Medicine and Pharmacy at Ho Chi Minh City
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Letrozole-stimulated cycle strategy and Artificial cycle strategy in people with Embryo Transfer and Irregular Menstruation, run by Mỹ Đức Hospital at 2 sites in Vietnam.
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 7 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 25 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Vietnam. 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 Nam T Nguyen, MD. (+84354120209, bsnam.nt@myduchospital.vn), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Live birth rate after one cycle of endometrial preparation (time frame: After 22 completed weeks of gestational age.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06372119, which also lists 53 linked publications.
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 25 Sep 2025.