Frozen Embryo Transfer (FET)

Endometrial peristalsis may influence embryo implantation and pregnancy outcomes, but its role during hormone replacement therapy (HRT)-prepared frozen embryo transfer (FET) cycles remains unclear. This prospective observational study will assess endometrial peristalsis at predefined time points during HRT-prepared FET cycles using transvaginal ultrasonography and evaluate its association with pregnancy outcomes. The study aims to clarify the clinical significance of endometrial peristalsis in HRT-prepared FET cycles and to provide evidence supporting endometrial assessment in assisted reproductive technology.

The uterus is a dynamic muscular organ that undergoes rhythmic, wave-like contractions known as endometrial peristalsis or endometrial waves. This muscular activity, which is an essential component of natural fertility, presents a nuanced and sometimes contradictory role in the context of assisted reproductive treatments. Endometrial peristalsis refers to the frequency, amplitude, and pattern of myometrial contractions occurring in different reproductive phases. These peristalsis play vital roles in sperm transport, embryo migration, and implantation. Clinical and imaging studies suggest that abnormal patterns or excessive contractility at the time of embryo transfer may disrupt endometrial-embryo synchrony, impair implantation, and increase miscarriage risk. However, most evidence on endometrial peristalsis pertains to fresh embryo transfer cycles, natural conceptions, or pathological contexts, such as adenomyosis or fibroids, with limited insights regarding its effects on different endometrial preparation protocols in frozen embryo transfer (FET). Understanding the dynamics of endometrial peristalsis in this context is clinically important, as inappropriate contractile activity could physically expel the embryo or create a non-receptive environment, ultimately reducing the chances of live birth. Despite its theoretical significance, there is a paucity of robust, prospective data correlating endometrial peristalsis patterns measured around the time of FET with different endometrial preparation protocols with subsequent pregnancy outcomes.

The goal of this observational study is to compare two commonly used vaginal progesterone formulations - soft capsules versus pessaries - in women undergoing frozen embryo transfer (FET). The main question it aims to answer is: \- Do soft vaginal progesterone capsules provide similar or better patient satisfaction, convenience, and tolerability compared with vaginal progesterone pessaries during preparation for frozen embryo transfer? Participants undergoing FET who are prescribed vaginal progesterone as part of their endometrial preparation and luteal phase support will use one of the two formulations and complete patient-reported assessments regarding satisfaction, convenience, and tolerability. The study will also measure serum progesterone levels on the day of embryo transfer and evaluate pregnancy outcomes, including clinical pregnancy and live birth rates.

The goal of this clinical trial is to learn whether different natural approaches to preparing the uterus for frozen embryo transfer (FET) can improve pregnancy success in women undergoing in vitro fertilization (IVF) treatment. The main questions it aims to answer are: 1. Is a completely natural menstrual cycle more successful than a natural cycle in which ovulation is triggered with medication when preparing for frozen embryo transfer? 2. Does taking a medication called letrozole at the beginning of the cycle improve pregnancy success compared to not taking it? Researchers will compare four different approaches to see which one results in the highest chance of achieving a clinical pregnancy, confirmed by ultrasound. Participants will: * Be randomly assigned to one of four groups * Undergo monitoring with ultrasound and blood hormone tests during their menstrual cycle * In some groups, take letrozole tablets for a few days early in the cycle * In some groups, receive a hormone injection to help control the timing of ovulation * Undergo frozen embryo transfer at the appropriate time * Receive standard hormonal support after embryo transfer * Researchers will compare four different approaches to see which one results in the highest chance of achieving a clinical pregnancy, confirmed by ultrasound.

Subclinical hypothyroidism (SCH) is defined by elevated thyroid-stimulating hormone (TSH) with normal free thyroxine (fT4) levels. It affects approximately 5-7% of women of reproductive age and may negatively influence outcomes of assisted reproductive technology (ART). During controlled ovarian stimulation, rising estradiol increases thyroxine-binding globulin and thyroid hormone requirements. These physiological changes, combined with increased metabolic demand in early pregnancy, may worsen SCH and contribute to adverse outcomes such as miscarriage, preterm birth, and hypertensive disorders of pregnancy. Although levothyroxine (LT4) is routinely used to treat overt hypothyroidism, evidence for its benefit in SCH, especially among infertile women undergoing In Vitro Fertilization (IVF) or Intra-Cytoplasmic Sperm Injection (ICSI) with frozen embryo transfer (FET), remains inconclusive. Some trials and meta-analyses have shown reductions in miscarriage and neonatal mortality, while others have found no improvement in ART or obstetric outcomes. This study aims to evaluate the effectiveness of levothyroxine therapy on IVF/FET outcomes and subsequent pregnancy results in women with subclinical hypothyroidism and infertility. This retrospective cohort study will emulate the target trial to evaluate whether LT4 treatment, titrated to achieve a pre-transfer TSH \< 2.5 mIU/L, improves implantation, live birth, and obstetric outcomes compared with expectant management.

The multi-step thawing protocol with a reduction of non-permeable cryoprotectant concentrations to reduce osmotic shock caused by the rapid influx of water. Recent studies have shown that a simplified warming protocol by only a thawing solution gave a comparable survival rate but increased pregnancy rate, reduced patients' waiting time, and decreased the workload of embryologists.

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.

This randomized clinical trial aims to assess the comparative effectiveness of different pre-treatment protocols prior to frozen embryo transfer (FET) among women with adenomyosis, providing evidence-based guidance for clinical decision-making. The main questions it aims to answer are: Does the protocol involving two doses of gonadotropin-releasing hormone agonist (GnRH-a) pretreatment result in a higher live birth rate compared to one dose of GnRH-a pretreatment in women with adenomyosis undergoing frozen embryo transfer? Does the protocol involving GnRH-a with letrozole supplementation result in a higher live birth rate compared to GnRH-a monotherapy in women with adenomyosis undergoing frozen embryo transfer? Eligible participants will undergo screening before endometrial preparation for FET, following which they will be randomly assigned to one of four groups: GnRH-a-1M, GnRH-a-2M, GnRH-a+LE-1M or GnRH-a+LE-2M. In the GnRH-a-1M group, participants will be pre-treated with one dose GnRH agonist before endometrial preparation. In the GnRH-a-2M group, participants will be pre-treated with two doses GnRH agonist before endometrial preparation. In the GnRH-a+LE-1M group, participants will be pre-treated with one dose GnRH agonist and letrozole 28 days before endometrial preparation. In the GnRH-a+LE-2M group, participants will be pre-treated with two doses GnRH agonist, along with daily 2.5 mg letrozole for 28 days since the first injection of GnRH agonist before endometrial preparation. After pre-treament, all participants will return for endometrial preparation in artificial cycles.

The goal of this clinical trial is to evaluate whether the direct warming method for frozen embryo transfers (FET) can improve live birth and pregnancy outcomes in women aged 18-45 undergoing IVF treatments. The main questions it aims to answer are: * Does the direct warming method achieve a similar or higher clinical success rate for FET compared to the conventional multi-step method? * Is the direct warming method more cost-effective than the conventional method? Researchers will compare the direct warming method to the conventional multi-step method to see if the former leads to better pregnancy outcomes and reduced procedural time. Participants will: * Undergo either the one-step or conventional embryo thawing procedure. * Complete standard clinical follow-ups for pregnancy, including ultrasound scans and pregnancy tests.

Background: The capability to transfer frozen embryos reduces embryo loss following in vitro fertilization (IVF) and results in higher pregnancy rates compared to a single IVF cycle. Endogenous progesterone from the corpus luteum, following frozen embryo transfer in natural or modified natural cycles, is expected to provide sufficient luteal support, as observed in spontaneous pregnancies. Nevertheless, research has demonstrated higher pregnancy success rates with additional luteal support. The current standard for luteal phase support involves vaginal progesterone administration. Several case reports have indicated that administering a gonadotropin-releasing hormone (GnRH) agonist during the luteal phase does not compromise pregnancy continuation achieved through IVF and may, in fact, enhance implantation success. Studies have shown that the luteal phase can be maintained with a GnRH agonist alone, without the need for progesterone supplementation. A recent prospective randomized controlled trial compared standard progesterone support with GnRH agonist support in fresh embryo transfers. The group receiving GnRH agonist support demonstrated a significantly higher pregnancy rate. Given the studies proving the positive impact of GnRH agonist, there is a need for a prospective randomized controlled trial to evaluate the use of GnRH agonist support in frozen embryo transfers. Aims and Significance: This study aims to compare pregnancy rates between women receiving GnRH agonist treatment and those receiving standard progesterone-based luteal support during frozen embryo transfers in natural cycles as part of IVF treatments. Conducting a prospective comparative study will enable us to assess the effectiveness of GnRH agonist treatment relative to standard luteal phase support. Based on the results, the investigators may consider treatment with intranasal GnRH agonist, which improves quality of life and may also enhance pregnancy and live birth rates. Methods: The study will be conducted on patients scheduled to undergo modified natural cycles. Participants will be randomly allocated into two groups: 1. Study Group: Luteal phase support will begin on the day of ovulation with Nafarelin nasal spray (200 mcg twice daily) for two weeks, until pregnancy blood test (hCG). 2. Control Group: Luteal phase support will be provided through vaginal progesterone. Endometrin 100 mg twice daily. If the hCG test is positive, the supportive treatment will continue until the 8th week of pregnancy, as per the attending physician's instructions. Clinical follow-up will include monitoring for clinical pregnancy outcomes, miscarriage rates, and live births.