Progesterone-modified Natural Cycle for FET

NCT06644794 | Recruiting Phase 3 DMC

• 1 other identifier: P4mNC@SDUTCM
• Study Type: interventional
• Target: 336
• Locations: 1 country
• Sites: 1

Brief Summary

Hormone replacement therapy (HRT) cycles, despite the ease of synchronizing embryo thawing and embryo transfer timing, increase the risk of pregnancies and obstetric complications compared to natural cycles (NC). By ensuring the presence of the corpus luteum while reducing the number of monitoring sessions, the progesterone modified natural cycle (P4mNC) offers more convenience for the patient than the normal NC. This study is designed to compare the effects of P4mNC and HRT cycles on FET outcomes.

Conditions

Infertility, Female

Keywords

Progesterone-modified natural cycle; Hormone replacement therapy; Frozen-thawed embryo transfer

Outcome Measures

Primary Outcomes (1)

• Live birth

  A live birth is defined as the delivery of any surviving newborn at 28 weeks or more of gestation.

  Within 1 year after randomization

Secondary Outcomes (4)

• Biochemical pregnancy

  Two weeks after embryo transfer

• Clinical pregnancy

  Five weeks after embryo transfer

• Ongoing pregnancy

  Ten weeks after embryo transfer

• Miscarriage

  Within 28 weeks of pregnancy

Study Arms (2)

P4mNC group

EXPERIMENTAL

On days 8-12 of the menstrual cycle (MC), depending on the length of the patient's MC, transvaginal ultrasound is used to monitor follicular development and endometrial growth. Vaginal micronized progesterone (Utrogestan, Besins, Belgium) is started at 200 mg in the afternoon and 200 mg in the evening when the dominant follicle reached ≥16 mm and the endometrial thickness is at least 7 mm. A blastocyst is transferred on day 5 after the addition of progesterone. On day 14 after blastocyst transfer, serum β-hCG levels are measured. Upon positive serum pregnancy testing, progesterone support will continue until 8-10 weeks of gestation. However, afternoon progesterone use is eliminated for 30 days after embryo transfer.

Drug: Progesterone-modified natural cycle preparation for frozen embryo transfer

HRT group

ACTIVE COMPARATOR

Endometrial preparation will begin on the second day of the menstrual cycle with oral estradiol (E2) valerate at a dose of 2 mg twice daily. When the patient's endometrial thickness is ≥7 mm, vaginal progesterone administration will be initiated at a dose of 200 mg 3 times daily. On day 5 of the progesterone administration, blastocysts are thawed and transferred. For patients with endometrial thickness \<7 mm, patients continued oral E2 until the endometrium is ≥7 mm. On day 14 after blastocyst transfer, serum β-hCG levels are measured. Upon positive serum pregnancy testing, E2 and progesterone supplementation is continued for 8-10 weeks of gestation.

Drug: Hormone replacement therapy cycle preparation for frozen embryo transfer

Interventions

Progesterone-modified natural cycle preparation for frozen embryo transfer DRUG

A novel endometrial preparation protocol that optimizes the natural cycle, whereby as long as the thickness of the endometrium is suitable for embryo transfer, vaginal progesterone can be used to transform the endometrium before ovulation and subsequently FET.

P4mNC group

Hormone replacement therapy cycle preparation for frozen embryo transfer DRUG

A traditional endometrial preparation protocol is used for FET, which involves using fixed or flexible exogenous estradiol for artificial cycles. This protocol typically involves starting exogenous estradiol on day 3 or 4 of the cycle, continuing for 7-10 days, and then discontinuing. Upon determining that the endometrial thickness meets the standard, progesterone conversion of the endometrium can be performed.

HRT group

Eligibility Criteria

• Age: 21 Years - 44 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Patients aged 21 to 44 years undergoing FBT
• Body mass index (BMI) 18-35 kg/m2
• Having regular ovulatory cycles

You may not qualify if:

• Untreated uterine adhesions
• Medical contraindications to estrogen and progesterone therapy
• Illnesses contraindicating assisted reproductive technology or pregnancy
• History of recurrent implantation failures (\> 2 embryo transfer failures)

Sponsors & Collaborators

• Shandong University of Traditional Chinese Medicine: lead

Study Sites (1)

Affiliated Hospital of Shandong University of Traditional Chinese Medicine

Jinan, Shandong, 250014, China

RECRUITING

Related Publications (9)

• Inhorn MC, Patrizio P. Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century. Hum Reprod Update. 2015 Jul-Aug;21(4):411-26. doi: 10.1093/humupd/dmv016. Epub 2015 Mar 22.

  PMID: 25801630 BACKGROUND

• Mascarenhas MN, Cheung H, Mathers CD, Stevens GA. Measuring infertility in populations: constructing a standard definition for use with demographic and reproductive health surveys. Popul Health Metr. 2012 Aug 31;10(1):17. doi: 10.1186/1478-7954-10-17.

  PMID: 22938182 BACKGROUND

• Doody KJ. Cryopreservation and delayed embryo transfer-assisted reproductive technology registry and reporting implications. Fertil Steril. 2014 Jul;102(1):27-31. doi: 10.1016/j.fertnstert.2014.04.048. Epub 2014 Jun 4.

  PMID: 24907917 BACKGROUND

• Zhang Y, Fu X, Gao S, Gao S, Gao S, Ma J, Chen ZJ. Preparation of the endometrium for frozen embryo transfer: an update on clinical practices. Reprod Biol Endocrinol. 2023 Jun 8;21(1):52. doi: 10.1186/s12958-023-01106-5.

  PMID: 37291605 BACKGROUND

• Roelens C, Blockeel C. Impact of different endometrial preparation protocols before frozen embryo transfer on pregnancy outcomes: a review. Fertil Steril. 2022 Nov;118(5):820-827. doi: 10.1016/j.fertnstert.2022.09.003.

  PMID: 36273850 BACKGROUND

• Gu F, Wu Y, Tan M, Hu R, Chen Y, Li X, Lin B, Duan Y, Zhou C, Li P, Ma W, Xu Y. Programmed frozen embryo transfer cycle increased risk of hypertensive disorders of pregnancy: a multicenter cohort study in ovulatory women. Am J Obstet Gynecol MFM. 2023 Jan;5(1):100752. doi: 10.1016/j.ajogmf.2022.100752. Epub 2022 Sep 15.

  PMID: 36115572 BACKGROUND

• von Versen-Hoynck F, Schaub AM, Chi YY, Chiu KH, Liu J, Lingis M, Stan Williams R, Rhoton-Vlasak A, Nichols WW, Fleischmann RR, Zhang W, Winn VD, Segal MS, Conrad KP, Baker VL. Increased Preeclampsia Risk and Reduced Aortic Compliance With In Vitro Fertilization Cycles in the Absence of a Corpus Luteum. Hypertension. 2019 Mar;73(3):640-649. doi: 10.1161/HYPERTENSIONAHA.118.12043.

  PMID: 30636552 BACKGROUND

• Kornilov N, Polyakov A, Mungalova A, Yakovleva L, Yakovlev P. Progesterone-modified natural cycle preparation for frozen embryo transfer. Reprod Biomed Online. 2024 Nov;49(5):104350. doi: 10.1016/j.rbmo.2024.104350. Epub 2024 Jul 2.

  PMID: 39244908 BACKGROUND

• Yuan HN, Song JY, Sun ZG. Comparison of progesterone-modified natural cycle and hormone replacement therapy cycle for endometrial preparation in single frozen blastocyst transfer (COMPROSET): protocol for an open-label randomized controlled trial. Front Med (Lausanne). 2025 Apr 28;12:1522004. doi: 10.3389/fmed.2025.1522004. eCollection 2025.

  PMID: 40357273 DERIVED

MeSH Terms

Conditions

Infertility, Female

Condition Hierarchy (Ancestors)

Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Infertility

Study Officials

• Zhen-Gao Sun, MD

  Affiliated Hospital of Shandong University of Traditional Chinese Medicine

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Xian-Ling Cao, MD

CONTACT

0531-68901236; caoxianlingling@163.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof.

Study Record Dates

• First Submitted: October 12, 2024
• First Posted: October 16, 2024
• Study Start: March 5, 2025
• Primary Completion (Estimated): September 10, 2027
• Study Completion (Estimated): December 1, 2028
• Last Updated: April 29, 2026

Record last verified: 2026-04

Locations

CN (1)