Is There a Need for Luteal Support in Modified Natural Cycle Frozen Embryo Transfer Cycles

Summary

Without progesterone there is no pregnancy. Following ovulation, the endocrine function of the follicle changes and progesterone replacing estradiol becomes its main secretory product. In the follicular phase the increasing amount of estradiol secreted by the growing follicle builds up the endometrium, while in the luteal phase progesterone, the main product of the corpus luteum, prepares the endometrium for implantation. This process is called decidualization. If implantation occurs, human chorionic gonadotropin (hCG) secreted by the trophopblasts maintains the function of the corpus luteum. This continued activity is required to be maintained up to week 7-9 of gestation when the hormone secreting activity is taken over by the placenta (luteo-placental shift) and the corpus luteum regresses. During in vitro fertilization (IVF) gonadotropins are used to induce multifollicular development and therefore following the oocyte retrieval ("ovulation") multiple corpora lutea are formed. At the same time, partly due to the supraphysiologic steroid levels reached during stimulation and partly to the removal of the granulosa cell mass during the retrieval, the activity of these corpora lutea remains insufficient and luteal support, primarily in the form of progesterone, is needed to achieve success. Embryo cryopreservation has become available soon after the first successful IVF treatment. In some of the IVF treatments cryopreservation is electively planned, while in others surplus embryos are frozen. As a result of the currently available vitrification technology a close to 100% survival can be expected upon thawing. Frozen embryos can be transferred according to different protocols: 1. True natural cycle FET (tNC-FET): in these cases, spontaneous follicle growth is followed by spontaneous ovulation and the timing of the embryo transfer (ET) is timed according to the spontaneous luteinizing hormone (LH) surge 2. Modified natural cycle FET (mNC-FET): in these cases, follicle growth is spontaneous but ovulation is induced with hCG injection as soon as the follicle reaches maturity and the ET is timed to the trigger injection 3. Stimulated cycle FET (sNC-FET): in these cases, follicle growth is induced with oral agents or gonadotropins and once the lead follicle reaches maturity hCG injection is given to induce ovulation and the ET is timed to the trigger injection 4. Artificial, hormone replacement cycle (HRT-FET): in these cases, the ovaries are not active but estradiol is given to build up the endometrium and once proper thickness is reached progesterone is added to prepare to implantation According to the available evidence the different approaches are equally effective. The common theme in mNC, tNC and sNC FET cycles is that a corpus luteum is formed and its activity is not compromised by supraphysiologic steroid levels and the oocyte retrieval either. Despite this, in most clinics, similarly to the fresh IVF-ETs, luteal support is administered in FET cycles as well. The benefit of luteal support in NC-FET cycles is questionable, however. The available literature is inconclusive whether there is a need for luteal support in mNC-FET treatments? In order to answer this question, the investigators plan to perform a prospective, multicenter randomized pilot study. Eligible participants will be randomized to one of the following groups: 1. No luteal support 2. 2x200 mg vaginal progesterone luteal support (Utrogestan) starting on the day of ET 3. 2x200 mg vaginal progesterone luteal support (Utrogestan) starting on the day of ET + 125 mcg rHCG s.c. (1/2 amp Ovitrelle) on the day of ET and 62.5 mcg rHCG s.c. (1/4 amp Ovitrelle) 4 days later. Baseline demographic, FET treatment related, and clinical outcomes will be compared in the three different luteal phase management groups.

Timeline

Start

2025-04-12

Primary completion

2026-04-01

Completion

2026-12-01

Publications

• Results Stavridis K, Kastora SL, Triantafyllidou O, Mavrelos D, Vlahos N. Effectiveness of progesterone rescue in women presenting low circulating progesterone levels around the day of embryo transfer: a systematic review and meta-analysis. Fertil Steril. 2023 Jun;119(6):954-963. doi: 10.1016/j.fertnstert.2023.02.007. Epub 2023 Feb 11.
• Results Su S, Zeng M, Duan J. Luteal phase support for natural cycle frozen embryo transfer: a meta-analysis. Gynecol Endocrinol. 2022 Feb;38(2):116-123. doi: 10.1080/09513590.2021.1998438. Epub 2021 Nov 3.
• Results Jiang Y, Wang L, Shen H, Wang B, Wu J, Hu K, Wang Y, Ma B, Zhang X. The effect of progesterone supplementation for luteal phase support in natural cycle frozen embryo transfer: a systematic review and meta-analysis based on randomized controlled trials. Fertil Steril. 2023 Apr;119(4):597-605. doi: 10.1016/j.fertnstert.2022.12.035. Epub 2022 Dec 24.
• Results Mizrachi Y, Horowitz E, Ganer Herman H, Farhi J, Raziel A, Weissman A. Should women receive luteal support following natural cycle frozen embryo transfer? A systematic review and meta-analysis. Hum Reprod Update. 2021 Jun 22;27(4):643-650. doi: 10.1093/humupd/dmab011.
• Results Bjuresten K, Landgren BM, Hovatta O, Stavreus-Evers A. Luteal phase progesterone increases live birth rate after frozen embryo transfer. Fertil Steril. 2011 Feb;95(2):534-7. doi: 10.1016/j.fertnstert.2010.05.019. Epub 2010 Jun 26.
• Results Wanggren K, Dahlgren Granbom M, Iliadis SI, Gudmundsson J, Stavreus-Evers A. Progesterone supplementation in natural cycles improves live birth rates after embryo transfer of frozen-thawed embryos-a randomized controlled trial. Hum Reprod. 2022 Sep 30;37(10):2366-2374. doi: 10.1093/humrep/deac181.
• Results Horowitz E, Mizrachi Y, Finkelstein M, Farhi J, Shalev A, Gold E, Raziel A, Weissman A. A randomized controlled trial of vaginal progesterone for luteal phase support in modified natural cycle - frozen embryo transfer. Gynecol Endocrinol. 2021 Sep;37(9):792-797. doi: 10.1080/09513590.2020.1854717. Epub 2020 Dec 14.
• Results Saupstad M, Bergenheim SJ, Bogstad JW, Petersen MR, Klajnbard A, Praetorius L, Freiesleben NLC, Englund AL, Lokkegaard ECL, Knudsen UB, Husth M, Alsbjerg B, Moller JE, Dam TV, Forman JL, Pinborg A, Lossl K. Progesterone concentrations on blastocyst transfer day in modified natural cycle frozen embryo transfer cycles. Reprod Biomed Online. 2024 Jul;49(1):103862. doi: 10.1016/j.rbmo.2024.103862. Epub 2024 Feb 6.
• Results Melo P, Wood S, Petsas G, Chung Y, Easter C, Price MJ, Fishel S, Khairy M, Kingsland C, Lowe P, Rajkhowa M, Sephton V, Pandey S, Kazem R, Walker D, Gorodeckaja J, Wilcox M, Gallos I, Tozer A, Coomarasamy A. The effect of frozen embryo transfer regimen on the association between serum progesterone and live birth: a multicentre prospective cohort study (ProFET). Hum Reprod Open. 2022 Nov 28;2022(4):hoac054. doi: 10.1093/hropen/hoac054. eCollection 2022.
• Results Gaggiotti-Marre S, Alvarez M, Gonzalez-Foruria I, Parriego M, Garcia S, Martinez F, Barri PN, Polyzos NP, Coroleu B. Low progesterone levels on the day before natural cycle frozen embryo transfer are negatively associated with live birth rates. Hum Reprod. 2020 Jul 1;35(7):1623-1629. doi: 10.1093/humrep/deaa092.
• Results Bortoletto P, Prabhu M, Baker VL. Association between programmed frozen embryo transfer and hypertensive disorders of pregnancy. Fertil Steril. 2022 Nov;118(5):839-848. doi: 10.1016/j.fertnstert.2022.07.025. Epub 2022 Sep 25.
• Results Glujovsky D, Pesce R, Sueldo C, Quinteiro Retamar AM, Hart RJ, Ciapponi A. Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes. Cochrane Database Syst Rev. 2020 Oct 28;10(10):CD006359. doi: 10.1002/14651858.CD006359.pub3.
• Results Lawrenz B, Coughlan C, Melado L, Fatemi HM. The ART of frozen embryo transfer: back to nature! Gynecol Endocrinol. 2020 Jun;36(6):479-483. doi: 10.1080/09513590.2020.1740918. Epub 2020 Mar 18.
• Results Trounson A, Mohr L. Human pregnancy following cryopreservation, thawing and transfer of an eight-cell embryo. Nature. 1983 Oct 20-26;305(5936):707-9. doi: 10.1038/305707a0.
• Results Csapo AI, Pulkkinen MO, Wiest WG. Effects of luteectomy and progesterone replacement therapy in early pregnant patients. Am J Obstet Gynecol. 1973 Mar 15;115(6):759-65. doi: 10.1016/0002-9378(73)90517-6. No abstract available.

Drugs

Indications

No indication recorded.