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

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.

NCT Number	NCT06875752
Lead Sponsor	Dunamenti REK Istenhegyi IVF Center Collaborators: Medical University of Pecs, Dunamenti REK Gyor Clinic, Dunementi REK Pannon Clinic, Szeged University
Conditions	Luteal Support, Frozen Embryo Transfer (FET)
Enrollment	180 participants
Start Date	2025-04-12
Primary Completion	2026-04-01 (estimated)
Study Completion	2026-12-01 (estimated)
Updated on ClinicalTrials.gov	2025-07-25