Comparison of clinical pregnancy rates between hormone replacement therapy and modified natural cycle for endometrial preparation in frozen embryo transfer cycles: An RCT

Published date: Jul 29 2025

Journal Title: International Journal of Reproductive BioMedicine

Issue title: International Journal of Reproductive BioMedicine (IJRM): Volume 23, Issue No. 5

Pages: 409 – 424

DOI: 10.18502/ijrm.v23i5.19264

Farnaz SafarlooDepartment of Obstetrics and Gynecology, Faculty of Medicine, Imam Khomeini Hospital, IVF Ward, Mazandaran University of Medical Sciences, Sari

Marzieh ZamaniyanDepartment of Obstetrics and Gynecology, Faculty of Medicine, Sexual and Reproductive Health Research Center, Diabetes Research Center, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari

Eisa NazarOrthopedic Research Center, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari

Keshvar Samadaee GelehkolaeeDepartment Of Reproductive Health and Midwifery, Faculty of Nursing and Midwifery, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari

Mahboubeh OmidDepartment Of Reproductive Health and Midwifery, Faculty of Nursing and Midwifery, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari

Sepideh Peivandispeivandi@mazums.ac.irDepartment of Obstetrics and Gynecology, Faculty of Medicine, Sexual and Reproductive Health Research Center, Imam Khomeini Hospital, IVF Ward, Mazandaran University of Medical Sciences, Sari

Background: Frozen-thawed embryo transfer (FET) during the endometrial receptivity window is important for implantation.

Objective: This study aims to compare the clinical pregnancy rate in 2 methods of endometrial preparation in FET using the hormone replacement cycle (HRC) and the modified natural cycle (mNC).

Materials and Methods: In this randomized clinical trial, 128 infertile women who visited the Imam Khomeini hospital infertility clinic, Sari, Iran between April and October 2024 were randomly assigned to 2 groups (n = 64/each): the mNC frozen embryo transfer group and the HRC group. In the mNC frozen embryo transfer group, ovulation was induced using human chorionic gonadotropin, and the timing of frozen embryo transfer was scheduled based on ovulation. The HRC group received estradiol valerate until the endometrial thickness reached 8 mm, then daily injections of progesterone were added and FET were performed.

Results: The participants had no significant differences in demographic characteristics. The primary outcome was clinical pregnancy rate with no significant difference between two groups (p = 0.282). No significant differences were observed between the mNC and HRC groups regarding the secondary outcome, which included human chorionic gonadotropin positive rate, chemical pregnancy rate, implantation rate, ongoing pregnancy rate, early miscarriage, ectopic pregnancy, twin pregnancy, and cycle cancellation rate. Significant differences were observed in the number of monitoring visits between the mNC frozen embryo transfer and HRC groups (p = 0.001).

Conclusion: Although the results indicate that the impact of both methods is similar, the fact that fewer visits are required in a natural cycle and there is also less need for hormones could make it preferable.

Keywords: Embryo transfer, Pregnancy rate, Vitrification, Hormone replacement therapy, Ovulation induction

[1] Singh B, Reschke L, Segars J, Baker VL. Frozen-thawed embryo transfer: The potential importance of the corpus luteum in preventing obstetrical complications. Fertil Steril 2020; 113: 252–257.

[2] Gardner DK, Weissman A, Howles CM, Shoham Z. Textbook of assisted reproductive techniques: Volume 2: Clinical perspectives. 5th Ed. Boca Raton: CRC Press; 2018.

[3] Mackens S, Santos-Ribeiro S, van de Vijver A, Racca A, Van Landuyt L, Tournaye H, et al. Frozen embryo transfer: A review on the optimal endometrial preparation and timing. Hum Reprod 2017; 32: 2234–2242.

[4] Duzguner INB, Sahin Y, Ozer G, Gokturk U, Akca A, Kahraman S. P-542 How should we prepare the endometrium in euploid embryo transfer cycles? Modified natural or artificial endometrial preparation? Hum Reprod 2023; 38 (Suppl.): dead093.

[5] Cerrillo M, Herrero L, Guillén A, Mayoral M, García-Velasco JA. Impact of endometrial preparation protocols for frozen embryo transfer on live birth rates. Rambam Maimonides Med J 2017; 8: e0020.

[6] Wei D, Liu J-Y, Sun Y, Shi Y, Zhang B, Liu J-Q, et al. Frozen versus fresh single blastocyst transfer in ovulatory women: A multicentre, randomised controlled trial. Lancet 2019; 393: 1310–1318.

[7] Romanski PhA, Bortoletto P, Liu Y-L, Chung PH, Rosenwaks Z. Length of estradiol exposure > 100 pg/ml in the follicular phase affects pregnancy outcomes in natural frozen embryo transfer cycles. Hum Reprod 2021; 36: 1932–1940.

[8] Kalem Z, Cakir Z, Sahin B. Natural cycle versus hormone replacement therapy cycle in frozen-thawed embryo transfer. Saudi Med J 2018; 39: 1251–1256.

[9] Hsueh Y-W, Huang C-C, Hung S-W, Chang C-W, Hsu H-C, Yang T-C, et al. Finding of the optimal preparation and timing of endometrium in frozen-thawed embryo transfer: A literature review of clinical evidence. Front Endocrinol 2023; 14: 1250847.

[10] Groenewoud ER, Cohlen BJ, Macklon NS. Programming the endometrium for deferred transfer of cryopreserved embryos: Hormone replacement versus modified natural cycles. Fertil Steril 2018; 109: 768–774.

[11] Craciunas L, Tsampras N, Raine-Fenning N, Coomarasamy A. Intrauterine administration of human chorionic gonadotropin (hCG) for subfertile women undergoing assisted reproduction. Cochrane Database Syst Rev 2018; 10: CD011537.

[12] Le QV, Abhari S, Abuzeid OM, DeAnna J, Satti MA, Abozaid T, et al. Modified natural cycle for embryo transfer using frozen-thawed blastocysts: A satisfactory option. Eur J Obstet Gynecol Reprod Biol 2017; 213: 58–63.

[13] Pan Y, Li B, Wang Z, Wang Y, Gong X, Zhou W, et al. Hormone replacement versus natural cycle protocols of endometrial preparation for frozen embryo transfer. Front Endocrinol 2020; 11: 546532.

[14] Shuai J, Chen Q, Wan S, Chen X, Liu W, Ye H, et al. Impact of elevated serum estradiol levels before progesterone administration on pregnancy outcomes in frozen-thawed embryo transfer for hormone replacement therapy. Rprod Biol Endocrinol 2021; 19: 131.

[15] Agha-Hosseini M, Hashemi L, Aleyasin A, Ghasemi M, Sarvi F, Nashtaei MS, et al. Natural cycle versus artificial cycle in frozen-thawed embryo transfer: A randomized prospective trial. Turk J Obstet Gynecol 2018; 15: 12–17.

[16] Soliman N, Fakih M, Alhmoudi M, Nad RM, Sajjad Y. Personalized fertility strategies: Assessing the efficacy of HRT vs. natural cycle protocols in frozen embryo replacement. J IVF-Worldwide 2025; 15: 88–94.

[17] Mendes Godinho C, Soares SR, Nunes SG, Martínez JMM, Santos-Ribeiro S. Natural proliferative phase frozen embryo transfer: A new approach which may facilitate scheduling without hindering pregnancy outcomes. Hum Reprod 2024; 39: 1089–1097.

[18] Carosso AR, Brunod N, Filippini C, Revelli A, Evangelisti B, Cosma S, et al. Reproductive and obstetric outcomes following a natural cycle vs. artificial endometrial preparation for frozen-thawed embryo transfer: A retrospective cohort study. J Clin Med 2023; 12: 4032.

[19] Gale J, Shmorgun D, Bacal V, Leveille M-C. Evaluation of early frozen blastocyst transfer in A true natural cycle protocol in comparison to a hormone replacement protocol: A single-center cohort study. Int J Fertil Steril 2023; 17: 195–200.

[20] Rodrigues R, Setti A, Braga D, Guilherme P, Iaconelli Jr A, Borges Junior E. O-260 improved implantation and pregnancy rates in frozen-thawed embryo transfer using a modified-natural ovulatory regimen. Hum Reprod 2022; 37 (Suppl.): deac106.

[21] Moffa F, Garcia-Faura A, Novo S, Perez-Alzueta A, Acin L, Moreno A, et al. O-022 shall we go “natural” for endometrial preparation in egg donation programs? Live birth rates and obstetrical outcome from 797 frozen single-blastocyst transfers cycles. Hum Reprod 2023; 38 (Suppl.): dead093.

[22] Mensing L, Dahlberg ES, Bay B, Gabrielsen A, Knudsen UB. Endometrial preparation methods prior to frozen embryo transfer: A retrospective cohort study comparing true natural cycle, modified natural cycle and artificial cycle. Arch Gynecol Obstet 2022; 306: 1381–1388.

[23] Huang J, Jiao X, You Y, Wu Y, Lin H, Zhang Q. The effects of different endometrial preparation regimens on pregnancy outcomes in frozen-thawed embryo transfer cycles: A prospective randomized controlled study. Gynecol Endocrinol 2023; 39: 2269235.

[24] Zhang Y, Fu X, Gao S, Gao Sh, Gao Sh, Ma J, et al. Preparation of the endometrium for frozen embryo transfer: An update on clinical practices. Reprod Biol Endocrinol 2023; 21: 52.

[25] Wu H, Zhou P, Lin X, Wang S, Zhang S. Endometrial preparation for frozen-thawed embryo transfer cycles: A systematic review and network meta-analysis. J Assist Reprod Genet 2021; 38: 1913–1926.

[26] Vitagliano A, Paffoni A, Viganò P. Does maternal age affect assisted reproduction technology success rates after euploid embryo transfer? A systematic review and meta-analysis. Fertil Steril 2023; 120: 251–265.

[27] Yuksel B, Ozer G, Duzguner INB, Akca A, Kumtepe Y, Yelke H, et al. Are there associations between clinical and embryological factors with pregnancy loss following transfer of a single euploid embryo? Reprod Fertil 2024; 12: 121–134.

[28] Ghobara T, Gelbaya TA, Ayeleke RO. Cycle regimens for frozen-thawed embryo transfer. Cochrane Database Syst Rev 2017; 7: CD003414.