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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Letrozole-stimulated cycle strategy | Procedure | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | After 22 completed weeks of gestational age. |
| Measure | Description | Time Frame |
|---|---|---|
| Positive pregnancy test after one cycle of endometrial preparation | Defined as serum human chorionic gonadotropin level greater than 25 mIU/mL. | At 11 days after blastocyst transfer. |
| Clinical pregnancy after one cycle of endometrial preparation |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Nam T Nguyen, MD. | Contact | +84354120209 | bsnam.nt@myduchospital.vn | |
| Vu NA Ho, MD. | Contact | +84935843336 | bsvu.hna@myduchospital.vn |
| Name | Affiliation | Role |
|---|---|---|
| Lan TN Vuong, Assoc. Prof. | University of Medicine and Pharmacy at Ho Chi Minh City | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| My Duc Hospital | Recruiting | Ho Chi Minh City | Ho Chi Minh City | 70000 | Vietnam |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 12094777 | Background | 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. | |
| 28462399 | Background | Aleyasin 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. |
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| ID | Term |
|---|---|
| D008599 | Menstruation Disturbances |
| ID | Term |
|---|---|
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C042667 | enkephalinamide-Leu, Tyr sulfate(1)- |
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|
| Artificial cycle strategy | Procedure | 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. |
|
|
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.
| 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. | 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). | 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). | 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. | 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. | 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. | 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). | 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). | At 22 weeks of gestational age. |
| Gestational age at birth | Calculated by gestational age of all live births | On the day of delivery. |
| Onset of labor | Spontaneous, labor induction, elective C-section. | On the day of delivery. |
| Mode of delivery | Vaginal delivery, C-section (elective, suspected fetal distress, non-progressive labor). | On the day of delivery. |
| Very low birth weight | Birth weight less than 1500g. | On the day of delivery. |
| Low birth weight | Birth weight less than 2500g. | 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). | 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). | 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). | 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). | 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. | 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. | 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). | 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). | 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). | 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. | On the day of delivery. |
| Birth weight | In grams; of singletons and twins. | 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. | Within 28 days of birth. |
| NICU admission | Counting number of babies admited to neonatal intensive care unit. | Within 28 days of birth. |
| Reason for NICU admission | Respiratory distress, intraventricular hemorrhagea, necrotizing enterocolitis, or sepsis. | 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. | Within 28 days of birth. |
| My Duc Phu Nhuan Hospital | Recruiting | Ho Chi Minh City | Ho Chi Minh City | 70000 | Vietnam |
|
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