A comparison of progesterone via vaginal oil capsules versus pessaries for luteal phase support in assisted reproduction treatment: a multicentre cohort study of 42 291 cycles

Does the addition of oral dydrogesterone to vaginal progesterone as luteal phase support improve pregnancy outcomes during frozen embryo transfer (FET) cycles compared with vaginal progesterone alone? Luteal phase support with oral dydrogesterone added to vaginal progesterone had a higher live birth rate and lower miscarriage rate compared with vaginal progesterone alone. Progesterone is an important hormone that triggers secretory transformation of the endometrium to allow implantation of the embryo. During IVF, exogenous progesterone is administered for luteal phase support. However, there is wide inter-individual variation in absorption of progesterone via the vaginal wall. Oral dydrogesterone is effective and well tolerated when used to provide luteal phase support after fresh embryo transfer. However, there are currently no data on the effectiveness of luteal phase support with the combination of dydrogesterone with vaginal micronized progesterone compared with vaginal micronized progesterone after FET. Prospective cohort study conducted at an academic infertility center in Vietnam from 26 June 2019 to 30 March 2020. We studied 1364 women undergoing IVF with FET. Luteal support was started when endometrial thickness reached ≥8 mm. The luteal support regimen was either vaginal micronized progesterone 400 mg twice daily plus oral dydrogesterone 10 mg twice daily (second part of the study) or vaginal micronized progesterone 400 mg twice daily (first 4 months of the study). In women with a positive pregnancy test, the appropriate luteal phase support regimen was continued until 7 weeks' gestation. The primary endpoint was live birth after the first FET of the started cycle, with miscarriage <12 weeks as one of the secondary endpoints. The vaginal progesterone + dydrogesterone group and vaginal progesterone groups included 732 and 632 participants, respectively. Live birth rates were 46.3% versus 41.3%, respectively (rate ratio [RR] 1.12, 95% CI 0.99-1.27, P = 0.06; multivariate analysis RR 1.30 (95% CI 1.01-1.68), P = 0.042), with a statistically significant lower rate of miscarriage at <12 weeks in the progesterone + dydrogesterone versus progesterone group (3.4% versus 6.6%; RR 0.51, 95% CI 0.32-0.83; P = 0.009). Birth weight of both singletons (2971.0 ± 628.4 versus 3118.8 ± 559.2 g; P = 0.004) and twins (2175.5 ± 494.8 versus 2494.2 ± 584.7; P = 0.002) was significantly lower in the progesterone plus dydrogesterone versus progesterone group. The main limitations of the study were the open-label design and the non-randomized nature of the sequential administration of study treatments. However, our systematic comparison of the two strategies was able to be performed much more rapidly than a conventional randomized controlled trial. In addition, the single ethnicity population limits external generalizability. Our findings study suggest a role for oral dydrogesterone in addition to vaginal progesterone as luteal phase support in FET cycles to reduce the miscarriage rate and improve the live birth rate. Carefully planned prospective cohort studies with limited bias could be used as an alternative to randomized controlled clinical trials to inform clinical practice. This study received no external funding. LNV has received speaker and conference fees from Merck, grant, speaker and conference fees from Merck Sharpe and Dohme, and speaker, conference and scientific board fees from Ferring; TMH has received speaker fees from Merck, Merck Sharp and Dohme, and Ferring; R.J.N. has received scientific board fees from Ferring and receives grant funding from the National Health and Medical Research Council (NHMRC) of Australia; BWM has acted as a paid consultant to Merck, ObsEva and Guerbet, and is the recipient of grant money from an NHMRC Investigator Grant. NCT0399876.

Endometrin as luteal phase support in assisted reproduction

Study question Are pregnancy rates in GnRH-antagonist cycles triggered with hCG and luteal phase support (LPS) with intranasal GnRH-agonist or vaginal progesterone comparable? Summary answer Nasal GnRH-agonist for LPS is associated with higher pregnancy rates compared with standard progesterone support in antagonist-based cycles triggered with hCG What is known already Regardless of its mechanism of action, the use of GnRH-a during the luteal phase in addition to progesterone, either in a single or multiple doses, has become a common practice as a part of ART protocols, based on its association with higher pregnancy and live birth rates . Its use as a sole agent for LPS has not gained the same popularity although studies supporting non-inferiority and even higher live birth rates with GnRH-a as a sole LPS agent have been published. Study design, size, duration A single-center, prospective, randomized study. A total of 150 patients underwent 164 GnRH-antagonist-based IVF cycles triggered with hCG and fresh embryo transfer. The study was conducted between June 9th, 2020, and May 5th, 2022. Participants/materials, setting, methods The study was conducted in the IVF clinic at University-affiliated tertiary medical center. Patients meeting the inclusion criteria who underwent antagonist-based IVF cycles and hCG triggering were enrolled. Computer-based randomization (1:1 ratio) was performed on the day of oocyte pickup (OPU). In both groups LPS was initiated on the evening of the OPU day with either GnRH-agonist nasal spray (Nafareline, nasal spray 200 mcg twice daily)or vaginal micronized progesterone (Utrogestan 300 mg, 3 times daily). Main results and the role of chance A total of 150 patients underwent 164 cycles, 127 cycles of which were included in the study cohort. Of them, 64 (50.4%) and 63 (49.6%) cycles were treated with GnRH-agonist or progesterone respectively as sole luteal phase support. A significantly higher pregnancy rate was found in the GnRH-a group compared with the progesterone group (43.8% versus 25.4% respectively; P = 0.030). After adjustment of several potential confounders such as age, body mass index (BMI), past obstetric history, number of IVF cycles, oocytes retrieved and embryos transferred, GnRH-agonist was still associated with a higher pregnancy rate (odds ratio 3.4, 95% confidence interval 1.4-8.3). Ovarian hyperstimulation syndrome (OHSS) rates were similar between the groups. Significantly higher progesterone levels were measured at β-hCG testing day in the GnRH-a group, both for the cleavage stage embryos (129.1±23.7 nmol/L vs. 97.7±48.9 nmol/L, P = 0.024) and for the blastocysts (127.2±0.1 nmol/L vs. 75.3±49.1 nmol/L, P = 0.034). Limitations, reasons for caution This study is not powered for analysis of clinical pregnancy rates, live birth rates and pregnancy outcomes. Larger studies are needed for research of these outcomes. All patients participating were at low risk for OHSS, therefore the study is underpowered to find significant differences in early or late OHSS.Wider implications of the findings Our findings suggest that intranasal GnRH-agonist administration as a sole luteal support in antagonist-based IVF cycles triggered with hCG results in higher pregnancy rates in comparison with traditional irritating vaginal preparations while not mandating additional support in the first weeks of pregnancy. Trial registration number Clinicaltrials.gov - NCT05484193

Study question Should women receive luteal phase support (LPS) following natural cycle frozen embryo transfer (NC-FET)? Summary answer Progesterone LPS following NC-FET increases the live birth rate. There is no evidence to support the administration of hCG for LPS in these cases. What is known already Whether or not women should receive LPS following NC-FET is highly controversial. Previous studies have shown conflicting results. Study design, size, duration We conducted a systematic search of the literature published in Medline/PubMed, Embase and the Cochrane Library, from January 2000 until December 2020. We included all original English, peer-reviewed articles, irrespective of study-design. The search strategy included keywords related to natural cycle frozen embryo transfer and luteal phase support. Studies reporting the results of artificial or stimulated FET cycles were excluded. Participants/materials, setting, methods Our systematic search generated 395 records. After screening, eight studies were included in the review and seven studies were included in the meta-analysis. Two studies (n = 858) used hCG, and 6 studies (n = 1507) used progesterone for luteal support. Four studies were randomized controlled trials (RCTs), whereas the other four were historic cohort studies. Main results and the role of chance In a meta-analysis using random effects model, hCG administration for LPS did not increase the clinical pregnancy rate (two studies, OR 0.85, 95% CI 0.64–1.14). On the other hand, progesterone LPS was associated with a higher clinical pregnancy rate (five studies, OR 1.48, 95% CI 1.14–1.94), and a higher live birth rate (three studies, OR 1.67, 95% CI 1.19–2.36). Limitations, reasons for caution There was large heterogeneity in progesterone dose and route of administration, as well as the methods used for ovulation detection and triggering. Moreover, only four studies were randomized. Finally, both studies examining the use of hCG for LPS were performed by the same group of researchers in a single center. Wider implications of the findings: The available evidence indicates that progesterone administration for LPS is beneficial following natural cycle frozen embryo transfer. There is no evidence to support the administration of hCG for LPS in these cases. Additional Large RCTs are necessary in order to improve the quality of evidence and validate our findings. Trial registration number PROSPERO ID: CRD42020199045

Dosage and delivery method of progesterone luteal support in overweight/obese women undergoing cryopreserved cycles

Spontaneous ovulation during a natural menstrual cycle is frequently used for timing frozen embryo transfer (FET). Nevertheless, it remains unclear whether or not women should receive luteal phase support (LPS) following natural cycle frozen embryo transfer (NC-FET). The aim of this systematic review and meta-analysis was to study whether the administration of LPS improves the reproductive outcome following NC-FET. We conducted a systematic search of the literature published in Medline/PubMed, Embase and the Cochrane Library, from January 2000 until December 2020. We included all original English, peer-reviewed articles, irrespective of the study design. The search strategy included keywords related to NC-FET and luteal phase support. Studies reporting the results of artificial or stimulated FET cycles were excluded. Our systematic search generated 416 records. After screening, eight studies were included in the review and seven studies were included in the meta-analysis. Two studies (n = 858) used hCG and six studies (n = 1507) used progesterone for luteal support. Four studies were randomised controlled trials (RCTs), whereas the other four were historic cohort studies. In a meta-analysis using a random effects model, hCG administration for LPS did not increase the clinical pregnancy rate (CPR) (two studies, odds ratio (OR) 0.85, 95% CI 0.64-1.14). On the other hand, progesterone LPS was associated with a higher CPR (five studies, OR 1.48, 95% CI 1.14-1.94), and a higher live birth rate (LBR) (three studies, OR 1.67, 95% CI 1.19-2.36). The association between progesterone LPS and the LBR remained significant after excluding non-randomised studies. The available evidence indicates that progesterone administration for LPS is beneficial following NC-FET. There is no evidence to support the administration of hCG for LPS in these cases. Additional large RCTs are necessary to improve the quality of evidence and validate our findings.

Luteal phase support for frozen embryo transfer cycles: intramuscular or vaginal progesterone?

Endometrin as luteal phase support in assisted reproduction

Study question What is the best progesterone administration for luteal phase support (LPS) in frozen-thawed embryo transfer cycle? Summary answer Different modes of hormonal luteal phase support do not affect clinical pregnancy rate (CPR) or live birth rate (LBR) in frozen-thawed embryo transfer (FET) cycles. What is known already FET has increased substantially over the last years. To support implantation, endometrial and embryo maturities must be synchronized; therefore, endometrial and follicular maturation are monitored either within the artificial cycle. Estrogen and progesterone are sequentially administered. The optimal endometrial preparation strategy remains unclear; this study aims to compare the reproductive and pregnancy outcomes between five different regimens of hormonal LPS for FET treatment. Study design, size, duration Single centre retrospective cohort study conducted between 2013 and 2019. Included were women (N = 402) aged 18–45 years undergoing FET. After an optimal endometrial preparation and endometrial thickness, the LPS was started. Thereafter, five different progesterone applications were compared: (1) oral dydrogesterone (10mg tid), (2) vaginal progesterone gel (90mg/d), (3) dydrogesterone (10mg tid) plus vaginal progesterone gel (90mg/d), (4) vaginal progesterone capsules (200mg tid), or (5) subcutaneous injection of 25mg daily. Participants/materials, setting, methods An ultrasound was performed 14 days of estrogene ( &amp;gt; =4mg/d) preparation. If the endometrial thickness was ≥7 mm and there was no dominant follicle, luteal support commenced four days before FET. Fourteen days after transformation, a serum beta-hCG test was performed. If positive (&amp;gt; 50 IU/L), a transvaginal ultrasound was performed to confirm clinical pregnancy, defined as gestational sac with fetal heart movement. CPR was assessed and delivery reports for LBR were collected later. Main results and the role of chance In total, 402 patients on an artificial cycle were included (mean age, 35 years (y); range, 26–46 y; standard deviation, 4.1 y). No differences in endometrial thickness and cause of infertility were found between groups. Multivariate logistic regression analysis revealed that the odds ratios (ORs) with 95% confidence intervals (CIs) for the CPR was significantly higher in the dydrogesterone only group (OR, 3.25; 95% CI, 1.7–6.2; p &amp;lt; 0.001) and in the combined group (3) (OR, 7.55; 95% CI, 2.7–21.10; p &amp;lt; 0.001). Statistically significant differences in live birth rate could not be found between the five groups; they were 33%, 54%, 8.3%, 4%, 0% for groups 1, 2, 3, 4, and 5 respectively. Overall satisfaction and tolerability were significantly higher in oral dydrogesterone compared to the vaginal progesterone. Limitations, reasons for caution This is a retrospective single-center study. Also, potentially confounding variables like ethnicity, parity, BMI were not accounted for, possibly contributing to bias. Further prospective randomized studies are needed. Wider implications of the findings: Oral dydrogesterone was found to be effective with equal CPR and LBR. Benefit is well-tolerated and accepted among patients; however we did not observe significant differences in the rates of live birth between the five regimens for used for LPS in women undergoing frozen-thawed embryo transfers. Trial registration number BASEC Switzerland 2020–01527

Study question In FET cycles, which are the mid-luteal values of progesterone and estradiol that better correlate with the live birth rate? Summary answer The optimal values associated with the highest live birth rate range between 10.8 and 18.0 ng/ml for progesterone and 350.0 and 490.3 pg/ml for estradiol. What is known already In the last years, the FET cycles are dramatically increasing for the great popularity gained by the freeze-all, the best strategy for minimizing OHSS. Endometrial preparations for FET include natural cycles (NC), modified NC or, more frequently, artificial cycles in which the endometrium is prepared with exogenous steroids. While there is a general agreement on the criteria for deciding the optimal timing for scheduling FET (an endometrial thickness ≥7 mm with a trilaminar pattern), no consensus has so far been reached on the endogenous progesterone and oestradiol values useful for individualizing the luteal phase support and ensuring the best success rates. Study design, size, duration A meta-analysis, based on PubMed, CENTRAL, Scopus, Web of Science, ClinicalTrials.gov, Embase, was conducted to evaluate the optimal mid-luteal progesterone and estradiol levels correlating with the highest live birth rate. Following PICO, inclusion criteria were: Population: infertile patients undergoing FET. Intervention: groups or subgroups of patients with different values of serum progesterone and/or estradiol. Comparison: not applicable. Outcome: live birth rate (LBR). Study design: prospective and retrospective cohort studies. This meta-analysis was submitted to PROSPERO (ID644713). Participants/materials, setting, methods Electronic and manual search, up to December 2024, identified 147 studies. Two researches (A.M.,S.G.) reviewed 115 studies independently (after removing 32 duplicates), excluded 59 studies after the first (title-abstract) screening and 44 studies after the second (full-text) screening. 12 studies were selected. Meta-regression is presented in terms of rate (for the outcome) and estimation of moderation effects (for progesterone and estradiol) with 95%CI and p-value (significance level at = 0.05); heterogeneity was assessed using I² statistics. Main results and the role of chance Serum mid-luteal progesterone was reported in all the studies (8.445 patients) (Alsbjerg et al, 2024; Álvarez et al, 2021; Alyasin et al, 2021; Cédrin-Durnerin et al, 2019; Gaggiotti-Marre et al, 2020; Kofinas et al, 2015; Labarta et al, 2021; Liu et al, 2023; Maignien et al, 2022; Yovich et al, 2015; Zhao et al, 2024; Zhu et al, 2023), while estradiol in 10 studies (excluding Kofinas et al, 2015; Zhu et al, 2023). 31 data points for progesterone (range 6.3-55.9 ng/ml) and 25 for estradiol (range 142.0-871.7 pg/ml), were obtained and they were classified into 4 categories for progesterone (&amp;lt;10.0; 10.0-19.9; 20.0-29.9; ≥30.0) and into 3 categories for estradiol (&amp;lt;300.0; 300.0-499.9; ≥500.0). The pooled estimate of LBR was 43.7% (95%CI=0.389-0.484, I2=71.2%); serum progesterone showed a significant effect of moderation (F(df1=3, df2=28) = 98.528, p&amp;lt;0.001), indicating that the highest LBR (56.6%) was found for values comprised between 10.8-18.0 ng/ml (estimate=0.566, 95%CI=0.427-0.796; p&amp;lt;0.01). Results from the studies reporting estradiol values showed a LBR of 44.2% (95%CI=0.385-0.499, I2=66.6%); estradiol showed a significant effect of moderation (F(df1=3, df2=22)=80.223,p&amp;lt;0.001), with the highest LBR (51.8%) for values comprised between 350.0-490.3 pg/ml (estimate=0.518, 95%CI=0.376-0.664; p &amp;lt; 0.01). The results were controlled for publication bias and effects of potential variables affecting the outcome (female’s age, endometrial preparation, endometrial thickness, number and stage of transferred embryos). Limitations, reasons for caution Although the majority of the included studies were prospective, 5 studies were retrospective; this could represent a reason for caution. The level of heterogeneity among the studies was quite high. Different routes of progesterone administration were considered. Only one study analysed the NC for the endometrial preparation (Gaggiotti-Marre et al,2020). Wider implications of the findings This meta-analysis demonstrated that, in FET cycles, the LBR can be reduced both for values below and above the identified range of mid-luteal progesterone and estradiol levels. For this reason, it is important to dose the mid-luteal hormones in FET cycles in order to individualize the luteal phase support. Trial registration number No

Objective: To determine the effect of vaginal progesterone as luteal support on pregnancy outcomes in infertile patients who undergo ovulation induction with gonadotropins and intrauterine insemination (IUI). Design: Prospective randomized trial. Setting: Tertiary referral center. Patient(s): About 398 patients with primary infertility were treated during 893 ovarian stimulation and IUI cycles from February 2010 to September 2012. Methods: All patients underwent ovarian stimulation with gonadotropins combined with IUI. Patients in the supported group received vaginal micronized progesterone capsules 200 mg once daily from the day after insemination until next menstruation or continuing for up to 8 weeks of pregnancy. Women allocated in the control group did not receive luteal phase support. Main outcome measure(s): Livebirth rate, clinical pregnancy rate and early miscarriage rate per cycle. Result(s): Of the 893 cycles, a total of 111 clinical pregnancies occurred. There were no significant differences between supported with progesterone and unsupported cycle in terms of livebirth rate (10.2% versus 8.3%, respectively, with a p value = 0.874) and clinical pregnancy rate (13.8% compared with 11.0% in unsupported cycle with a p value = 0.248). An early miscarriage rate of 3.6% was observed in the supported cycles and 2.7% in the unsupported cycles, with no significant differences between the groups (p value = 0.874). Conclusion(s): In infertile patients treated with mildly ovarian stimulation with recombinant gonadotropins and IUI, luteal phase support with vaginal progesterone is not associated with higher livebirth rate or clinical pregnancy rate compared with patients who did not receive any luteal phase support.

Study question Does the addition of oral dydrogesterone to vaginal progesterone as luteal phase support improve pregnancy outcomes during frozen embryo transfer (FET) cycles compared with vaginal progesterone alone? Summary answer Luteal phase support with oral dydrogesterone added to vaginal progesterone improves live birth rates and reduces miscarriage rates compared with vaginal progesterone alone. What is known already Progesterone is an important hormone that triggers secretory transformation of the endometrium to allow implantation of the embryo. During in vitro fertilization (IVF), exogenous progesterone is administered for luteal phase support. However, there is wide inter-individual variation in absorption of progesterone via the vaginal wall. Oral dydrogesterone is effective and well tolerated when used to provide luteal phase support after fresh embryo transfer. However, there are currently no data on the effectiveness of luteal phase support with the combination of dydrogesterone with vaginal micronized progesterone compared with vaginal micronized progesterone after FET. Study design, size, duration Prospective cohort study conducted at an academic infertility center in Vietnam from 26 June 2019 to 30 March 2020. Participants/materials, setting, methods We studied 1364 women undergoing IVF with FET. The luteal support regimen was either vaginal micronized progesterone 400 mg twice daily plus oral dydrogesterone 10 mg twice daily (second part of the study) or vaginal micronized progesterone 400 mg twice daily (first 4 months of the study). The primary endpoint was live birth after the first FET of the started cycle, with miscarriage &amp;lt;12 weeks as one of the secondary endpoints. Main results and the role of chance The vaginal progesterone + dydrogesterone group and vaginal progesterone groups included 732 and 632 participants, respectively. Live birth rates were 46.3% versus 41.3%, respectively (rate ratio [RR] 1.12, 95% confidence interval [CI] 0.99–1.27, p = 0.06; multivariate analysis RR 1.30 (95% CI 1.01–1.68), p = 0.042), with a statistically significant lower rate of miscarriage at &amp;lt; 12 weeks (3.4% vs 6.6%; RR 0.51, 95% CI 0.32–0.83; p = 0.009). Birth weight of both singletons (2971.0 ± 628.4 vs. 3118.8 ± 559.2 g; p = 0.004) and twins (2175.5 ± 494.8 vs. 2494.2 ± 584.7; p = 0.002) was significantly lower in the progesterone plus dydrogesterone versus progesterone group. Limitations, reasons for caution The study were the open-label design and the non-randomized nature of the sequential administration of study treatments. However, our systematic comparison of the two strategies was able to be performed much more rapidly than a conventional randomized controlled trial. In addition, the single ethnicity population limits external generalizability. Wider implications of the findings Oral dydrogesterone in addition to vaginal progesterone as luteal phase support in FET cycles can reduce the miscarriage rate and improve the live birth rate. Carefully planned prospective cohort studies with limited bias could be used as an alternative to randomized controlled clinical trials to inform clinical practice. Trial registration number NCT03998761

The efficiency of progesterone vaginal gel versus intramuscular progesterone for luteal phase supplementation in gonadotropin-releasing hormone antagonist cycles: a prospective clinical trial

Gonadotropin-releasing hormone analogue as sole luteal support in antagonist-based assisted reproductive technology cycles

The need for luteal phase support in IVF/ICSI is well established. A large effort has been made in the attempt to identify the optimal type, start, route, dosage and duration of luteal phase support for IVF/ICSI and frozen embryo transfer. These questions are further complicated by the different types of stimulation protocols and ovulation triggers used in ART. The aim of this review is to supply a comprehensive overview of the available types of luteal phase support, and the indications for their use. A review of the literature was carried out in the effort to find the optimal luteal phase support regimen with regards to pregnancy related outcomes and short and long term safety. The results demonstrate that vaginal, intramuscular, subcutaneous and rectal progesterone are equally effective as luteal phase support in IVF/ICSI. GnRH agonists and oral dydrogesterone are new and promising treatment modalities but more research is needed. hCG and estradiol are not recommended for luteal phase support. More research is needed to establish the most optimal luteal phase support in frozen embryo transfer cycles, but progesterone has been shown to improve live birth rate in some studies. Luteal phase support should be commenced between the evening of the day of oocyte retrieval, and day three after oocyte retrieval and it should be continued at least until the day of positive pregnancy test. So, in conclusion still more large and well-designed RCT's are needed to establish the most optimal luteal phase support in each stimulation protocol, and especially in frozen embryo transfer.