Letrozole-stimulated Cycle Strategy Versus Artificial Cycle Strategy (LETSACT)

Официальное название

Letrozole-stimulated Cycle Strategy Versus Artificial Cycle Strategy for Endometrial Preparation in Women With Irregular Menstrual Cycles: A Randomized Controlled Trial

Обзор

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.

Подробное описание

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.

Вмешательства

• Процедура Letrozole-stimulated cycle strategy
  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 startin
• Процедура Artificial cycle strategy
  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 mill

Первичные конечные точки

• Live birth rate after one cycle of endometrial preparation [Срок оценки: After 22 completed weeks of gestational age.]

Вторичные конечные точки (12)

• Positive pregnancy test after one cycle of endometrial preparation [Срок оценки: At 11 days after blastocyst transfer.]
• Clinical pregnancy after one cycle of endometrial preparation [Срок оценки: First ultrasound before 6 weeks of gestational age.]
• Ongoing pregnancy after one cycle of endometrial preparation [Срок оценки: After 12 weeks of gestational age.]
• Multiple pregnancy after one cycle of endometrial preparation [Срок оценки: Ultrasound at 6-9 weeks of gestational age.]
• Implantation rate after one cycle of endometrial preparation [Срок оценки: Ultrasound at 6-9 weeks of gestational age.]
• Cycle cancellation rate [Срок оценки: 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 [Срок оценки: Ultrasound at 6-9 weeks of gestational age.]
• Threatened miscarriage rate before 12 weeks of gestation after one cycle of endometrial preparation [Срок оценки: At 12 weeks of gestational age.]
• Early miscarriage rate after one cycle of endometrial preparation [Срок оценки: At 12 weeks of gestational age.]
• Late miscarriage rate after one cycle of endometrial preparation [Срок оценки: At 22 weeks of gestational age.]
• Gestational age at birth [Срок оценки: On the day of delivery.]
• Onset of labor [Срок оценки: On the day of delivery.]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Вьетнам · 2 центра

• My Duc Hospital — Ho Chi Minh City
• My Duc Phu Nhuan Hospital — Ho Chi Minh City

Публикации

• 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. PMID 12094777
• 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. PMID 28462399
• Aslih 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. PMID 33670133
• Atkinson 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. PMID 35118408
• Bocca-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. PMID 24567020
• Braakhekke 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. PMID 24786739
• Casper 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. PMID 22031258
• Chung 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. PMID 26723254

Идентификаторы

NCT: NCT06372119 · 13/23/DD-BVMD

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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