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    Oral dydrogesterone for luteal phase support in fresh in vitro fertilization cycles: a new standard? Griesinger Georg,Blockeel Christophe,Tournaye Herman Fertility and sterility Oral dydrogesterone has been used for luteal phase support on an empirical basis since the early days of in vitro fertilization (IVF) treatment. Systematic comparisons of oral dydrogesterone with vaginal progesterone, so far considered to be the standard of care, started to appear in the middle 2000s. Recently, a large, randomized, double-blind, double-dummy phase III trial on the use of daily 30 mg oral dydrogesterone versus daily 600 mg micronized vaginal progesterone for LPS in IVF was published. This company-sponsored trial confirmed the efficacy findings from previous independent researchers and firmly established the noninferiority of daily 30 mg oral dydrogesterone for luteal phase support. Despite oral administration and first pass through the liver, dydrogesterone was as well tolerated as vaginal progesterone in safety analyses. Moreover, no new fetal safety concerns have arisen from that trial. Given the widespread preference of women for an oral compound, dydrogesterone may well become the new standard for luteal phase support in fresh embryo transfer IVF cycles. 10.1016/j.fertnstert.2018.03.034
    Patient experience in a randomized trial of a weekly progesterone vaginal ring versus a daily progesterone gel for luteal support after in vitro fertilization. Ginsburg Elizabeth S,Jellerette-Nolan Teru,Daftary Gaurang,Du Yunling,Silverberg Kaylen M Fertility and sterility OBJECTIVE:To assess patient experience and convenience of using progesterone vaginal ring (VR) versus vaginal gel for women requiring luteal phase support during in vitro fertilization (IVF). DESIGN:Post hoc analysis of a prospective, randomized, single-blind, multicenter, phase 3 clinical trial. SETTING:Twenty-two U.S. IVF centers. PATIENT(S):Women undergoing IVF (N = 1,297). INTERVENTION(S):Randomization to weekly VR or daily gel the day after egg retrieval for up to 10 weeks, with fresh embryo transfer IVF per site-specific procedures. MAIN OUTCOME MEASURE(S):Patient satisfaction questionnaire completed at final study visit. RESULT(S):In the women who were taking ≥1 dose of either VR (n = 647) or gel (n = 650), >97% reported that learning to use the formulation, remembering to take it at the correct time, and using it as prescribed was "easy" or "somewhat easy." More VR than gel users reported noninterference with daily activity (93.3% vs. 74.7%, P<.001), sexual comfort (80.3% vs. 67.8%, P<.001), and sexual desire (73.8% vs. 61.8%, P<.001), as well as not being bothered during sexual intercourse (66.9% vs. 39.2%, P<.001). More gel than VR users reported no difficulty with application (97.4% vs. 80.9%, P<.001). Among women who had previously used progesterone during IVF, more VR users than gel users preferred their currently assigned treatment to their previous treatment (91.4% vs. 83.0%, P=.03). CONCLUSION(S):Weekly progesterone VR and daily progesterone gel were easy to use, with limited impact on quality of life. Overall, the VR appeared to interfere less with daily life, social activities, and sexual activity although the gel was less difficult or stressful to apply. CLINICAL TRIAL REGISTRATION NUMBER:NCT00615251. 10.1016/j.fertnstert.2018.07.014
    Vaginal use of micronized progesterone for luteal support.A randomized study comparing Utrogestan® and Crinone® 8. Michnova Lucie,Dostal Jiri,Kudela Milan,Hamal Petr,Langova Katerina Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia BACKGROUND AND OBJECTIVE:Luteal phase physiology is distorted by in vitro fertilization (IVF) cycles using gonadotropin-releasing hormone (GnRH) agonists and antagonists, Controlled ovarian hyperstimulation leads to luteal phase defect and for this reason, luteal phase support is now an integral part of IVF/ICSI-ET programs. The support is provided by hCG, progesterone or GnRH-a. This study compared the efficiency, safety and tolerance of two vaginal micronized progesterones, Utrogestan and Crinone 8%. METHODS:111 women, 18-40 years old, FSH < 10 IU/L and normal uterus findings were included. The efficiency of the two preparations to provide luteal support was evaluated by the fertilization, implantation, pregnancy and take-home baby rates. The safety was compared through the results of vaginal findings and vaginal inflammation markers before and after treatment. Comparison of tolerance was made by evaluating 21 subjective patient questionnaire parameters. RESULTS:There were no significant differences between the preparations in terms of efficiency or safety though Crinone 8% was better tolerated. CONCLUSION:The outcomes of this study suggest that a vaginal gel with micronized progesterone (Crinone 8%) is the optimal choice at this time for luteal support. 10.5507/bp.2017.007
    Luteal phase support in fresh and frozen embryo transfer cycles. Pabuçcu Emre,Pabuçcu Recai,Gürgan Timur,Tavmergen Erol Journal of gynecology obstetrics and human reproduction Nearly 5 million babies have been delivered following assisted conception (IVF/ICSI) and the demand is increasing. Meticulous ovarian stimulation and well programmed luteal phase support are the landmarks of treatment success. Although the importance of luteal phase support in IVF/ICSI cycles is well established, the optimal route, dose and duration of this support is still a matter of debate. Regardless of the ovarian stimulation, parenteral and vaginal progesterone has been one of the most common routes. However, oral or subcutaneous routes are also well-investigated and reveal satisfactory clinical outcomes. It is obviously critical to choose a progesterone with adequate clinical efficacy and patient tolerability as well. Moreover, fresh and frozen embryo transfer cycles markedly different from each other in terms of physiological changes and luteal support concept should be modified accordingly. The aim of this narrative review is to provide evidence-based take home messages for the luteal phase support in either fresh or frozen embryo transfer cycles in the context of a recent scientific evidence. 10.1016/j.jogoh.2020.101838
    Repeated GnRH agonist doses for luteal support: a proof of concept. Wiser Amir,Klement Anat Hershko,Shavit Tal,Berkovitz Arie,Koren Roni Rahav,Gonen Ofer,Amichay Keren,Shulman Adrian Reproductive biomedicine online RESEARCH QUESTION:What are the safety and feasibility of repeated subcutaneous doses of gonadotrophin-releasing hormone (GnRH) agonist for luteal support in IVF cycles triggered by a GnRH agonist? DESIGN:In this prospective trial, patients exhibiting oestradiol concentrations of over 2500 pg/ml after use of a GnRH agonist for triggering ovulation were initially randomized to GnRH agonist luteal support (0.1 mg subcutaneously every other day, starting on day 3 after embryo transfer) or to a control group supported by 80 µg of recombinant human chorionic gonadotrophin (HCG) on day 3 after embryo transfer. All patients underwent a day 5 blastocyst transfer. Randomization to the HCG luteal support was stopped owing to two cases of ovarian hyperstimulation syndrome (OHSS) and the study was continued solely with GnRH agonist luteal support. RESULTS:The study included 39 women in the repeated GnRH agonist luteal support group and seven in the HCG micro dose group. There were no cases of OHSS among patients supported by a GnRH agonist, and no other adverse events were recorded. There were no cases of bleeding before the pregnancy test, and hence no cases of an insufficient luteal phase. A clinical pregnancy rate of 43.6% was achieved with GnRH agonist luteal support. Hormone dynamics during the stimulation cycle reflected rising LH and progesterone concentrations after the introduction of GnRH agonist support. CONCLUSIONS:Repeated doses of GnRH agonist every other day as a method of luteal support provided safe and effective luteal support for women who underwent GnRH agonist triggering in a GnRH antagonist IVF cycle. 10.1016/j.rbmo.2019.07.031
    Combined use of oestradiol and progesterone to support luteal phase in antagonist intracytoplasmic sperm injection cycles of normoresponder women: a case-control study. Çakar Erbil,Tasan Habibe Ayvaci,Kumru Pınar,Cogendez Ebru,Usal Nazan Tarhan,Kutlu Hüseyin Tayfun,Özkaya Enis,Eser Semra Kayatas Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology We evaluated the effect of combined use of oral oestrogen (E2) and vaginal progesterone (P) to support luteal phase in antagonist intracytoplasmic sperm injection (ICSI) cycles. We analysed data from 176 patients who underwent ICSI cycles with antagonist protocol. P 90 mg vaginal gel once a day and micronised E2 of 4 mg/day, were started from the day of oocyte pick up and continued to the 12th day of embryo transfer. Group 1 ( = 79) patients received E2 + P for luteal phase support. In group 2 ( = 97) patients, only P 90 mg vaginal gel was used for luteal phase support. There were no significant differences between group 1 and group 2 patients in terms of clinical pregnancy rates (PRs) (26.58% vs. 20.62%,  = .352), early pregnancy loss rates (6.33% vs. 6.19%,  = .969), incidence of luteal vaginal bleeding (8.86% vs. 8.25%,  = .885) and implantation rates (22.8% vs. 16.9%,  = .298). In conclusion, our study showed no beneficial effect of addition of E2 to luteal phase support on clinical PR in antagonist IVF cycles.Impact statement Luteal phase deficiency is defined as a disruption in progesterone and oestrogen production after ovulation. It is clear that, luteal phase supplementation to improve the outcomes in fertilisation (IVF) cycles is mandatory. As an iatrogenic complication of assisted reproductive technique, decreased luteal oestrogen and progesterone levels lead to decreased pregnancy rates (PRs) and implantation rates. In this study, we aimed to present the role of luteal phase oestrogen administration in GnRH antagonist cycles. A total of 176 cases received progesterone vaginal gel form for luteal phase support. Study group received 4 mg oral oestradiol hemihydrate in addition to progesterone. Compared to previous studies, our study consisted of larger number of patients and we used oestradiol through oral route. We found out that luteal oestradiol support did not improve the clinical PR. Our study showed no beneficial effect of addition of oestradiol to luteal phase support on clinical PR in antagonist IVF cycles. 10.1080/01443615.2019.1631765
    Dydrogesterone as an oral alternative to vaginal progesterone for IVF luteal phase support: A systematic review and individual participant data meta-analysis. Griesinger Georg,Blockeel Christophe,Kahler Elke,Pexman-Fieth Claire,Olofsson Jan I,Driessen Stefan,Tournaye Herman PloS one The aim of this systematic review and meta-analysis was to conduct a comprehensive assessment of the evidence on the efficacy and safety of oral dydrogesterone versus micronized vaginal progesterone (MVP) for luteal phase support. Embase and MEDLINE were searched for studies that evaluated the effect of luteal phase support with daily administration of oral dydrogesterone (20 to 40 mg) versus MVP capsules (600 to 800 mg) or gel (90 mg) on pregnancy or live birth rates in women undergoing fresh-cycle IVF (protocol registered at PROSPERO [CRD42018105949]). Individual participant data (IPD) were extracted for the primary analysis where available and aggregate data were extracted for the secondary analysis. Nine studies were eligible for inclusion; two studies had suitable IPD (full analysis sample: n = 1957). In the meta-analysis of IPD, oral dydrogesterone was associated with a significantly higher chance of ongoing pregnancy at 12 weeks of gestation (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.08 to 1.61; P = 0.0075) and live birth (OR, 1.28; 95% CI, 1.04 to 1.57; P = 0.0214) compared to MVP. A meta-analysis combining IPD and aggregate data for all nine studies also demonstrated a statistically significant difference between oral dydrogesterone and MVP (pregnancy: OR, 1.16; 95% CI, 1.01 to 1.34; P = 0.04; live birth: OR, 1.19; 95% CI, 1.03 to 1.38; P = 0.02). Safety parameters were similar between the two groups. Collectively, this study indicates that a higher pregnancy rate and live birth rate may be obtained in women receiving oral dydrogesterone versus MVP for luteal phase support. 10.1371/journal.pone.0241044
    The efficacy of modified luteal phase support with intramuscular progesterone in IVF/ICSI cycles: a retrospective observational study. Conforti A,Strina I,Mollo A,Amoroso R,Marrone V,Alviggi C,Marci R,de Placido G European review for medical and pharmacological sciences OBJECTIVE:The use of gonadotropin-releasing hormone agonist for ovulation triggering has become an intriguing topic in the last few years. As long as adequate luteal phase support is provided, it may be a valuable alternative to standard hCG triggering, associated with a significant reduction in OHSS incidence. Several luteal phase support options have been proposed, but few studies have addressed the issue of the appropriate route for progesterone administration to women triggered with GnRHa. The aim of the study was to evaluate the effect of GnRHa triggering on IVF/ICSI outcomes, using modified luteal phase support with intramuscular progesterone. PATIENTS AND METHODS:A retrospective study was carried out between January 2014 and December 2015, comparing the reproductive outcome in GnRHa triggered women given modified luteal phase support with intramuscular progesterone (Group A) with the outcome in women triggered with standard hCG (Group B) in IVF/ICSI cycles. RESULTS:200 (Group A n = 100; Group B n = 100) consecutive normoresponder women were included. No differences with respect to Age, BMI, basal FSH, basal Estradiol and infertility diagnosis were observed between groups. Increased numbers of retrieved oocytes (8.1 ± 3.3 versus 6.8 ± 3.5, p = 0.009) and mature oocytes (5.8 ± 2.6 versus 5.1 ± 2.7, p = 0.03) were detected in Group A compared with Group B. Implantation, biochemical pregnancy and ongoing pregnancy rates were similar. CONCLUSIONS:Our findings confirmed that the GnRHa triggering strategy is associated with increased number of oocytes retrieved and of mature oocytes even in normoresponder women. Moreover, in these patients, the use of intramuscular progesterone during luteal phase support achieved satisfactory IVF outcomes.
    Short versus extended progesterone supplementation for luteal phase support in fresh IVF cycles: a systematic review and meta-analysis. Watters Marianne,Noble Matt,Child Tim,Nelson Scott Reproductive biomedicine online This review and meta-analysis aim to assess the effect of prolonged progesterone support on pregnancy outcomes in women undergoing fresh embryo transfer after IVF/intracytoplasmic sperm injection (ICSI). Two independent authors searched Embase, MEDLINE and grey literature from inception to January 2019 for randomized controlled trials (RCT) of prolonged progesterone support versus early cessation. Risk of bias was assessed. Outcome measures were live birth, miscarriage and ongoing pregnancy rate. The study was registered with PROSPERO (CRD42018088605). Seven trials involving 1627 participants were included: three reported live birth rate (672/830), seven the miscarriage rate (178/1627) and seven the ongoing pregnancy rate (1351/1627). Clinical outcomes were similar between early progesterone cessation versus progesterone continuation: live birth rate (risk ratio [RR] 0.94, 95% confidence interval [CI] 0.88-1.00), miscarriage rate (RR 0.91, 95% CI 0.69-1.20) and ongoing pregnancy rate (RR 0.98, 95% CI 0.91-1.05). Ongoing pregnancy rates were similar when analyses were restricted to those with cessation of progesterone on the day of a positive human chorionic gonadotrophin (RR 0.93, 95% CI 0.83-1.06). This meta-analysis suggests that prolonged progesterone support may be unnecessary after fresh embryo transfer. Further larger RCT would be useful to corroborate and lead to standardized duration of progesterone luteal phase support across IVF/ICSI centres. 10.1016/j.rbmo.2019.10.009
    No need for luteal phase support in IVF cycles after mild stimulation: proof-of-concept study. Ferraretti Anna Pia,Devroey Paul,Magli M Cristina,Gianaroli Luca Reproductive biomedicine online This is a pilot study performed in a private IVF unit. The objective of the study was to investigate whether luteal support is required in IVF cycles after mild stimulation with clomiphene citrate and low FSH doses. The study included 15 patients with good prognosis (defined as ≤38 years old with normal ovarian reserve and normovulatory cycles, body mass index <29 kg/m, no previous cycles, no severe endometriosis, no history of recurrent miscarriage, no endocrine/autoimmune diseases and no surgical semen extraction from the partner) undergoing IVF with mild stimulation. Patients were monitored during the luteal phase by serum progesterone and LH. The luteal support was started only when necessary. No patient needed luteal phase support because the resultant steroid environment was different from that associated with conventional stimulation techniques. The live birth rate was 40% (6/15) and the implantation rate 30% (6/20). There are several benefits to mild stimulation, including low cost, less patient distress and improved endometrial receptivity. Our study supports the concept that mild stimulation may have an additional benefit during the luteal phase, by obviating the need for luteal phase support. 10.1016/j.rbmo.2016.10.006
    Luteal Phase Support in IVF: Comparison Between Evidence-Based Medicine and Real-Life Practices. Di Guardo Federica,Midassi Habib,Racca Annalisa,Tournaye Herman,De Vos Michel,Blockeel Christophe Frontiers in endocrinology Luteal phase support (LPS) in assisted reproduction cycles has been widely investigated in recent years. Although progesterone represents the preferential product for luteal phase supplementation in cycles with fresh embryo transfer, there is ongoing debate as to when to start, which is the best route, dosage and duration, and whether there is a place for additional agents. Nevertheless, fertility specialists do not always adhere to evidence-based recommendations in their clinical practice. The aim of this worldwide web-based survey is to document the currently used protocols for luteal phase support and appraisal tendencies of drug prescription behavior and to compare these to the existing evidence-based literature. A questionnaire was developed and sent by secure e-mail to 1,480 clinicians involved in ART worldwide. One hundred and forty-eighth clinicians from 34 countries returned completed questionnaires. Progesterone support is usually started on the day of oocyte retrieval. Eighty percent of clinicians applied the administration of vaginal progesterone only. Intramuscular progesterone was prescribed by 6%, while oral progestin or subcutaneous progesterone were each prescribed by 5% of clinicians, respectively. Progesterone was administered until 8-10 weeks' gestation by 35% and 12 weeks by 52% of respondents. Vaginal administration was the preferred route for luteal phase support. The reported emerging use of the oral route confirms the expected shift in clinical practice as a result of recent evidence showing a reassuring safety score of oral progestins. In spite of the lack of evidence supporting the continuation of luteal support until 12 weeks' gestation, this practice was adhered to by more than half of the clinicians surveyed, highlighting the difference between evidence-based medicine and real-life practices. 10.3389/fendo.2020.00500
    The impact of luteal serum progesterone levels on live birth rates-a prospective study of 602 IVF/ICSI cycles. Thomsen L H,Kesmodel U S,Erb K,Bungum L,Pedersen D,Hauge B,Elbæk H O,Povlsen B B,Andersen C Y,Humaidan P Human reproduction (Oxford, England) STUDY QUESTION:Is the chance of a live birth following IVF treatment and fresh embryo transfer affected by early and mid-luteal serum progesterone (P4) levels? SUMMARY ANSWER:Low as well as high serum P4 levels in the early and mid-luteal phase reduce the chance of a live birth following IVF treatment with fresh embryo transfer. WHAT IS KNOWN ALREADY:Data from non-human studies and studies of frozen-thawed embryo transfer cycles indicate that low as well as high P4 levels during the mid-luteal phase decrease the chance of pregnancy. The altered P4 pattern may disrupt the endometrial maturation leading to asynchrony between embryonic development and endometrial receptivity, thereby, compromising implantation and early development of pregnancy. STUDY DESIGN, SIZE, DURATION:Prospective multicenter cohort study of 602 women undergoing IVF treatment. Patients were recruited from four Danish public Fertility Centers from May 2014 to June 2017. The study population was unselected, thus, representing a normal everyday patient cohort. Patients were treated in a long GnRH-agonist protocol or a GnRH-antagonist protocol and triggered for final oocyte maturation with either hCG or a GnRH-agonist. The same vaginal luteal support regimen was applied in all patients. PARTICIPANTS/MATERIALS, SETTING, METHODS:Serum P4 levels from the early or mid-luteal phase were correlated to positive hCG and live birth rates (delivery > gestational week 20). Patients were divided into four P4 groups based on raw data of P4 serum levels and reproductive outcomes during early luteal phase (P4<60 nmol/l, P4 60-100 nmol/l, P4 101-400 nmol/l and P4>400 nmol/l) and during mid-luteal phase (P4<150 nmol/l, P4 150-250 nmol/l, P4 251-400 nmol/l and P4>400 nmol/l). MAIN RESULTS AND THE ROLE OF CHANCE:The optimal chance of pregnancy was achieved with serum P4 levels of 60-100 nmol/l in the early luteal phase whereas the optimal P4 level during the mid-luteal phase was 150-250 nmol/l. Below, but most distinctly above these levels, the chance of pregnancy was consistently reduced. With an early luteal P4 level of 60-100 nmol/l, the chance of a positive hCG-test was 73%, 95% CI: [59, 84] following cleavage stage embryo transfer. In contrast, with P4 levels >400 nmol/l, the chance of a positive hCG-test was significantly reduced to 35%, 95% CI: [17, 57], thus, an absolute risk difference of -38%, P = 0.01. A similar negative association between early luteal P4 and live birth rate was found, although it did not reach statistical significance. During the mid-luteal phase, a P4 level of 150-250 nmol/l resulted in an optimal chance of live birth: 54%, 95% CI: [37, 70] compared to 38%, 95% CI: [20, 60] with a P4 level >400 nmol/l, thus, an absolute risk difference of -16%, P = 0.14. All estimates were adjusted for maternal age, maternal BMI, study site, final follicle count and late follicular P4 levels. LIMITATIONS, REASONS FOR CAUTION:This study is the first to explore the possible upper and lower thresholds for luteal P4 following IVF treatment and fresh embryo transfer, and the optimal P4 ranges found in this study should be corroborated in future clinical trials. Furthermore, the P4 thresholds in this study only apply to fresh IVF cycles, using vaginal luteal phase support, as the optimal P4 level in cycles using intramuscular P4 may be different. WIDER IMPLICATIONS OF THE FINDINGS:Future studies are necessary to explore whether additional exogenous luteal P4 supplementation in the low P4 group could increase the chance of a live birth following fresh embryo transfer, and whether patients with luteal P4 levels >400 nmol/l would benefit from segmentation followed by subsequent transfer in frozen/thawed cycles. TRIAL REGISTRATION NUMBER:NCT02129998 (Clinicaltrials.gov). STUDY FUNDING/COMPETING INTEREST(S):L.H.T. received an unrestricted grant from Ferring Pharmaceuticals, Denmark, to support this study. P.H. received unrestricted research grants from MSD, Merck, Gedeon Richter and Ferring Pharmaceuticals outside of this work as well as honoraria for lectures from MSD, Merck and Gedeon Richter outside of this work. U.K. received honoraria for lectures from MSD and Ferring Pharmaceuticals outside of this work. C.A. received unrestricted research grants from MSD, IBSA, and Ferring Pharmaceuticals outside of this work as well as honoraria for lectures from MSD and IBSA. H.O.E. and B.B.P. received an unrestricted research grant from Gedeon Richter outside of this work. K.E., L.B., D.P. and B.H. have no conflict of interest. Furthermore, grants from 'The Health Research Fund of Central Denmark Region', 'The Research Foundation of the Hospital of Central Jutland', 'The Research Foundation of A.P. Møller', 'The Research Foundation of Aase & Ejnar Danielsen', 'The Research Foundation of Dagmar Marshall', 'The Research Foundation of Dir. Jacob Madsen & Hustru Olga Madsen', 'The Research Foundation of Fam. Hede Nielsen' and 'The Danish Medical Research Grant' supported conducting this study. The providers of funding were neither involved in the conduction of the study nor in the writing of the scientific report. 10.1093/humrep/dey226
    Luteal granulosa cells from natural cycles are more capable of maintaining their viability, steroidogenic activity and LH receptor expression than those of stimulated IVF cycles. Bildik Gamze,Akin Nazli,Seyhan Ayse,Esmaeilian Yashar,Yakin Kayhan,Keles Ipek,Balaban Basak,Ata Baris,Urman Bulent,Oktem Ozgur Human reproduction (Oxford, England) STUDY QUESTION:Are there any differences in the molecular characteristics of the luteal granulosa cells (GC) obtained from stimulated versus non-stimulated (natural) IVF cycles that may help explain the defective luteal phase in the former? SUMMARY ANSWER:Luteal GC of stimulated IVF cycles, particularly those of agonist-triggered antagonist cycles, are less viable ex vivo, express LH receptor and anti-apoptotic genes at lower levels, undergo apoptosis earlier and fail to maintain their estradiol (E2) and progesterone (P4) production in comparison to natural cycle GC. WHAT IS KNOWN ALREADY:Luteal function is defective in stimulated IVF cycles, which necessitates P4 and/or hCG administration (known as luteal phase support) in order to improve clinical pregnancy rates and prevent miscarriage. The luteal phase becomes shorter and menstruation begins earlier than a natural cycle if a pregnancy cannot be achieved, indicative of early demise of corpus luteum (premature luteolysis). Supra-physiological levels of steroids produced by multiple corpora luteae in the stimulated IVF cycles are believed to inhibit LH release directly via negative feedback actions on the hypothalamic-pituitary-ovarian axis resulting in low circulating levels of LH and a defective luteal phase. We hypothesized that some defects in the viability and steroidogenic activity of the luteal GC of the stimulated IVF cycles might contribute to this defective luteal phase in comparison to natural cycle GC. This issue has not been studied in human before. STUDY DESIGN, SIZE, DURATION:A comparative translational research study of ex vivo and in vitro models of luteal GC recovered from IVF patients undergoing natural versus stimulated IVF cycles was carried out. Luteinized GC were obtained from 154 IVF patients undergoing either natural (n = 22) or stimulated IVF cycles with recombinant FSH and GnRH agonist (long) (n = 44), or antagonist protocol triggered conventionally either with recombinant hCG (n = 46) or with a GnRH agonist (n = 42). GC were maintained in vitro for up to 6 days. PARTICIPANTS/MATERIALS, SETTING, METHODS:Cellular viability (YO-PRO-1 staining), the expression of the steroidogenic enzymes, pro-apoptotic genes [Bcl-2-associated death promoter (BAD), Bcl-2-associated X protein (BAX) and Caspase-3 (CASP3)], anti-apoptotic genes [RAC-alpha serine/threonine-protein kinase (AKT-1) and Bcl-2-like protein 2 (BCL2-L2)], LH receptor, vascular endothelial growth factor (VEGF) (using real-time quantitative PCR at mRNA level and western blot immunoprecipitation assay at protein level) and in vitro E2 and P4 production (electrochemiluminescence immunoassay) were compared in GC among the groups. MAIN RESULTS AND THE ROLE OF CHANCE:Natural cycle GC were significantly more viable ex vivo (88%) compared to their counterparts of the stimulated IVF cycles (66, 64 and 37% for agonist and antagonist cycles triggered with hCG and GnRH agonist respectively, P < 0.01). They were also more capable of maintaining their vitality in culture compared to their counterparts from the stimulated IVF cycles: at the end of the 6-day culture period, 74% of the cells were still viable whereas only 48, 43 and 22% of the cells from the agonist and antagonist cycles triggered with hCG and agonist respectively, were viable (P < 0.01). The mRNA expression of anti-apoptotic genes (AKT-1 and BCL2-L2) was significantly lower, while that of pro-apoptotic genes (BAD, BAX and CASP3) was significantly higher in the stimulated cycles, particularly in the agonist-triggered antagonist cycles, compared to natural cycle GC (P < 0.01 for long protocol and antagonist hCG trigger, P < 0.001 for agonist trigger). The expression of steroidogenic enzymes (stAR, SCC, 3β-HSD and aromatase) and VEGF was significantly higher in the agonist and hCG-triggered antagonist cycles compared to natural cycle GC. Therefore, in vitro E2 and P4 production in cells from the stimulated IVF cycles was significantly higher than their counterparts obtained from the natural cycles in the first 2 days of culture. However, after Day 2, their viability and hormone production began to decline very rapidly with the most drastic decrease being observed in the agonist-triggered cycles. By contrast, natural cycle GC maintained their viability and produced E2 and P4 in increasing amounts in culture up to 6 days. In vitro P production and the mRNA and protein expression of LH receptor, VEGF and 3β-HSD were most defective in the agonist-triggered antagonist cycles compared to natural and agonist and hCG-triggered antagonist cycles. In vitro hCG treatment of a subset of the cells from the agonist-triggered cycles improved their viability, increased E2 and P4 production in vitro and up-regulated the mRNA expression of anti-apoptotic gene BCL-L2 together with steroidogenic enzymes stAR, SCC, 3B-HSD, LH receptor and VEGF. LARGE SCALE DATA:Not applicable. LIMITATIONS, REASONS FOR CAUTION:The limitations include analysis of luteinized GC only might not reflect the in vivo mechanisms involved in survival and function of the whole corpus luteum; GC recovered during oocyte retrieval belong to a very early stage of the luteal phase and might not be representative; effects of ovulation triggered with hCG may not equate to the endogenous LH trigger; the clinical characteristics of the patients may vary among the different groups and it was not possible to correlate stimulation-related molecular alterations in luteal GC with the clinical outcome, as no oocytes have been utilized yet. Therefore, our findings do not conclusively rule out the possibility that some other mechanisms in vivo may also account for defective luteal function observed in stimulated IVF cycles. WIDER IMPLICATIONS OF THE FINDINGS:Ovarian stimulation is associated with significant alterations in the viability and steroidogenic activity of luteal GC depending on the stimulation protocol and mode of ovulation trigger. Reduced survival and down-regulated expression of 3B-HSD, LH receptor and VEGF leading to compromised steroid production in stimulated cycles, and particularly in the agonist-triggered cycles, may at least in part help explain why the luteal phase is defective and requires exogenous support in these cycles. STUDY FUNDING/COMPETING INTEREST(S):This study was funded by the School of Medicine, the Graduate School of Health Sciences of Koc University and Koç University Research Center for Translational Medicine (KUTTAM), equally funded by the Republic of Turkey Ministry of Development Research Infrastructure Support Program. All authors declare no conflict of interest. 10.1093/humrep/dey353
    Increasing vaginal progesterone gel supplementation after frozen-thawed embryo transfer significantly increases the delivery rate. Alsbjerg Birgit,Polyzos Nikolaos P,Elbaek Helle Olesen,Povlsen Betina Boel,Andersen Claus Yding,Humaidan Peter Reproductive biomedicine online The aim of this study was to evaluate the reproductive outcome in patients receiving frozen-thawed embryo transfer before and after doubling of the vaginal progesterone gel supplementation. The study was a retrospective study performed in The Fertility Clinic, Skive Regional Hospital, Denmark. A total of 346 infertility patients with oligoamenorrhoea undergoing frozen-thawed embryo transfer after priming with oestradiol and vaginal progesterone gel were included. The vaginal progesterone dose was changed from 90 mg (Crinone) once a day to twice a day and the reproductive outcome during the two periods was compared. The pregnancy rate increased significantly after doubling of the progesterone dose (26.7% (90 mg) versus 38.4% (180 mg); P=0.021). Moreover, the early pregnancy loss rate decreased significantly (67.4% versus 43.7%, respectively; P=0.014), which significantly increased the delivery rate (8.7% versus 20.5%, respectively; P=0.002). Doubling of the vaginal progesterone gel supplementation during frozen-thawed embryo transfer cycles decreased the early pregnancy loss rate, resulting in a significantly higher delivery rate. This study evaluated the reproductive outcome of 346 women with oligoamenorrhoea (cycle length >34 days) or amenorrhoea undergoing oestradiol and progesterone priming prior to frozen-thawed embryo transfer. Patients treated with vaginal progesterone gel (Crinone 90 mg) twice daily had a lower risk of pregnancy loss (43.7%) compared with women treated once a day (67.4%). This resulted in a significantly higher delivery rate (20.5% versus 8.7%, respectively). 10.1016/j.rbmo.2012.10.012
    Intramuscular progesterone versus 8% Crinone vaginal gel for luteal phase support following blastocyst cryopreserved single embryo transfer: a retrospective cohort study. Bakkensen Jennifer B,Racowsky Catherine,Thomas Ann M,Lanes Andrea,Hornstein Mark D Fertility research and practice Background:The optimal route of progesterone administration for luteal support in cryopreserved embryo transfer (CET) has been the subject of much debate. While most published research has pertained to day 3 transfers, recent data on blastocyst CET has suggested that intramuscular progesterone (IMP) is superior to twice daily vaginal Endometrin suppositories for luteal phase support, resulting in significantly higher ongoing pregnancy rates. This study aimed to determine whether IMP is similarly superior to 8% Crinone vaginal gel for luteal phase support following blastocyst CET. Methods:Autologous and donor oocyte blastocyst cryopreserved single embryo transfer (SET) cycles from January 2014-January 2019 utilizing either 50 mg IMP daily or 90 mg 8% Crinone gel twice daily for luteal support were included. The primary outcome was live birth. Secondary outcomes included biochemical pregnancy, spontaneous abortion, and clinical pregnancy. All analyses were adjusted a priori for oocyte age. Log-binomial regression analysis was performed with differences in outcomes reported as relative risk (RR) with 95% confidence intervals (CI). Results:A total of 1710 cycles were included, of which 1594 utilized IMP and 116 utilized 8% Crinone gel. Demographic and cycles characteristics were similar between the two groups. Compared to cycles utilizing IMP, cycles utilizing Crinone gel resulted in similar rates of live birth (RR 0.91; 95% CI 0.73-1.13), biochemical pregnancy (RR 1.12, 95% CI 0.65-1.92), spontaneous abortion (RR 1.41, 95% CI 0.90-2.20), and clinical pregnancy (RR 1.00, 95% CI 0.86-1.17). Conclusions:Compared to cryopreserved blastocyst SET cycles utilizing IMP for luteal support, cycles utilizing 8% Crinone gel resulted in similar likelihood of live birth. 10.1186/s40738-020-00079-y
    Efficacy, safety and tolerability of progesterone vaginal pessaries versus progesterone vaginal gel for luteal phase support after in vitro fertilisation: a randomised controlled trial. Saunders Helen,Khan Cass,D'Hooghe Thomas,Magnúsdóttir Thora Björg,Klingmann Ingrid,Hrafnsdóttir Sigrún, Human reproduction (Oxford, England) STUDY QUESTION:Are progesterone vaginal pessaries 400 mg twice a day (bid) non-inferior to progesterone vaginal gel (90 mg) once a day (od) in the primary endpoint of clinical pregnancy rate after 38 days of luteal phase support in women undergoing in vitro fertilisation (IVF)? SUMMARY ANSWER:Non-inferiority of progesterone vaginal pessaries 400 mg bid to progesterone 8% vaginal gel (90 mg od) was shown for clinical pregnancy rate after 38 days of luteal phase support. WHAT IS KNOWN ALREADY:To maximise successful embryo transfer after IVF, additionally administered progesterone is used for proper endometrium transformation in the luteal phase. Vaginally administered progesterone results in adequate secretory transformation of the endometrium. STUDY DESIGN, SIZE, DURATION:This multicentre, multinational, open, randomised, two-parallel group, non-inferiority Phase 3 clinical trial was carried out at 17 study sites in five European countries (Belgium, Bulgaria, Czech Republic, Hungary and Serbia) between October 2013 and August 2014. An interactive web response system (IWRS) was implemented for treatment allocation at the sites. Power analysis, based on the assumptions of a non-inferiority margin of -9%, a significance level of α 2.5% (one-sided), power 90%, at a reference pregnancy rate for the progesterone vaginal gel group of 30%, as well as applying a dropout rate of 10%, yielded a total number of 766 patients to be randomised. PARTICIPANTS/MATERIALS, SETTING, METHODS:Women aged between 18 and 40 years with a clinical indication for IVF/intracytoplasmic sperm injection (ICSI) and embryo transfer were eligible to participate. The clinical pregnancy rate was assessed by fetal heart movement measured by transvaginal ultrasound at day 38 (D38) (primary endpoint) and D70. Also assessed were biochemical pregnancy rate (assessed by serum β-hCG ≥25 IU/L), clinical implantation rates at D38, patient evaluation of vaginal bleeding and discharge (assessed by diary) and adverse event (AE) incidence, severity and relationship to study medication. MAIN RESULTS AND THE ROLE OF CHANCE:A total of 769 female patients were randomised to progesterone 400 mg vaginal pessaries bid (n = 385, 50.1%) or progesterone 90 mg vaginal gel od (n = 384, 49.9%). Patients receiving progesterone vaginal pessaries and progesterone vaginal gel were comparable in demographics, baseline characteristics and number of retrieved oocytes. In the full analysis set (FAS; n = 369 progesterone vaginal pessaries and n = 368 progesterone vaginal gel), clinical pregnancy rates on D38 were 38.3% for progesterone vaginal pessaries and 39.9% for progesterone vaginal gel. In the per protocol analysis set (PP; n = 357 progesterone vaginal pessaries and n = 356 progesterone vaginal gel), clinical pregnancy rates on D38 were 38.1% for progesterone vaginal pessaries and 40.4% for progesterone vaginal gel. For the differences in pregnancy rates between the progesterone vaginal pessaries group and the progesterone vaginal gel, the lower limit of the 97.5% CI was -8.6 and -9.5% for the FAS and PP datasets, respectively. The original prespecified non-inferiority margin of -9% was thus met in the FAS dataset but was marginally below this in the PP dataset. However, the pregnancy rate of the comparator was higher than the anticipated rate of 30%, and a predetermined logistic regression model including treatment group, country and age group effects without interaction terms showed non-inferiority of progesterone vaginal pessaries to progesterone vaginal gel for both the FAS and PP populations, in that the lower limits of the 95% CIs were above 0.7 for both analyses. As a result of this, the relevant authorities accepted to widen the acceptable non-inferiority margin to -10%, and as such both the FAS and PP populations succeeded in showing non-inferiority. Biochemical pregnancy and clinical implantation rates were comparable for both treatments. Both treatment groups showed similar high compliance throughout the study, and the safety profiles were also comparable between the groups. Drug-related AEs occurred with frequencies of 15.1% with progesterone vaginal pessaries and 14.4% with progesterone vaginal gel. LIMITATIONS, REASONS FOR CAUTION:Clinical pregnancy rate is a surrogate for the outcome of live birth rate. WIDER IMPLICATIONS OF THE FINDINGS:Progesterone 400 mg pessaries bid for luteal phase support is an effective, safe and tolerable treatment option for women undergoing IVF during ART. STUDY FUNDING/COMPETING INTEREST(S):This work was funded by Actavis Group PTC ehf., Iceland, part of Teva Pharmaceuticals, and by L.D. Collins & Co. Ltd. Gedeon Richter plc has recently entered into a license and distribution agreement to commercialise the vaginal pessaries in the European Union (except Ireland/UK). The progesterone vaginal pessaries studied are now marketed as Cyclogest®, Amelgen®, Cyclovita®, Luteum and Cygest® throughout the EU, Asia and Middle East & North Africa. The competing interests are as follows. H.S.: employee of Gedeon Richter plc/PregLem S.A. C.K.: consultant to L.D. Collins & Co. Ltd and received consulting fees for work performed. T.D.H.: at the initiation and completion of this study, full professor at KU Leuven and Head of Leuven University Fertility Center at the University Hospital Gasthuisberg, Leuven, Belgium. In October 2015, T.D.H. became vice president of Global Medical Affairs Fertility at the pharmaceutical company Merck-marketing authorisation holder of the Progesterone vaginal gel (Crinone®)-and has remained a part-time professor at KU Leuven (Belgium) and adjunct professor at Yale University (New Haven, CT, USA). T.B.M.: at the initiation and completion of this study, employee of Actavis Group PTC ehf. I.K.: consultant to Actavis, later TEVA and received consulting fees for work performed. S.H.: at the initiation and completion of this study, employee of Actavis Group PTC ehf. TRIAL REGISTRATION NUMBER:EudraCT number 2013-001105-81. TRIAL REGISTRATION DATE:2 July 2013. DATE OF FIRST PATIENT’S ENROLMENT:9 October 2013. 10.1093/humrep/dez261
    Effect on endometrial histology and pharmacokinetics of different dose regimens of progesterone vaginal pessaries, in comparison with progesterone vaginal gel and placebo. Duijkers I J M,Klingmann I,Prinz R,Wargenau M,Hrafnsdottir S,Magnusdottir Th B,Klipping C Human reproduction (Oxford, England) STUDY QUESTION:Which progesterone vaginal pessary dose regimen induces adequate secretory transformation of the endometrium, in comparison with progesterone vaginal gel and placebo? SUMMARY ANSWER:The best secretory transformation of the endometrium was observed during treatment with 400 mg progesterone vaginal pessaries, administered twice daily. WHAT IS KNOWN ALREADY:Vaginally administered progesterone is widely used for luteal phase support (LPS) in assisted reproductive techniques (ART). Although several vaginal formulations using various doses are available, little is known on the impact of formulation and doses at the endometrial level. STUDY DESIGN, SIZE, DURATION:The study had a randomised, observer-blind design and comprised two parts. The participants used study medication during two or three treatment periods, separated by washout periods. Subjects in Part 1 (n = 61 treated) received 200 mg progesterone vaginal pessaries twice daily (bid), 400 mg pessaries bid and the comparator 90 mg progesterone vaginal gel once daily (od) in a 3-way crossover design. Subjects in Part 2 (n = 64 treated) received 100 mg pessaries bid in one period and 400 mg pessaries od in the other period in a 2-way crossover design. A subgroup of these subjects (n = 22 treated) received placebo vaginal pessaries bid in a third period in a non-randomised manner. The study was performed from May 2012 until April 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS:The study was performed at a clinical research centre in healthy female volunteers of reproductive age. The subjects used 2 mg estradiol bid for 24 days in each treatment cycle. Progesterone or placebo was administered vaginally from Day 15 onwards during 10 days. In each treatment period, an endometrial biopsy for histological evaluation was performed on Day 23 and pharmacokinetic parameters were determined after the first progesterone dose on Day 15 and after the last dose on Day 24. MAIN RESULTS AND THE ROLE OF CHANCE:Frequencies of (early and late) secretory transformation of the endometrium, i.e. adequate responses, during treatment with 200 mg and 400 mg vaginal pessaries bid were comparable with those during 90 mg vaginal gel treatment (90-94%), whereas lower secretory transformation rates were observed during treatment with 100 mg bid and 400 mg od (64-75%). At the time of the endometrial biopsy in the cycle the late secretory state of the endometrium, which is characteristic of adequate luteal support, was observed more often with 400 mg pessaries bid (90%) than with vaginal gel (82%) and with lower pessary doses (64-78%). Pharmacokinetic parameters after repeated dosing of vaginal pessaries showed a dose-dependent, but not dose-proportional, increase of plasma progesterone levels. The lowest incidence of bleeding and spotting was reported during treatment with 400 mg pessaries bid. LIMITATIONS REASONS FOR CAUTION:The primary outcome parameter, rate of secretory transformation of the endometrium, is a surrogate for endometrial receptivity and for the actual clinical efficacy. WIDER IMPLICATIONS OF THE FINDINGS:Delivery of progestesterone through 400 mg pessaries bid is an effective alternative method for luteal support in ART. STUDY FUNDING/COMPETING INTEREST(S):The study was funded by Actavis Group PTC ehf., Iceland, part of Teva Pharmaceuticals, and L.D. Collins. I.D. and C.K. are directors of Dinox, a contract research organisation. I.K. is Managing Director of Pharmaplex and M.W. is Managing Director of M.A.R.C.O., service organisations involved in organisation/supervision and evaluation/reporting of clinical trials. All received funding for the conduct of the study from Actavis. S.H. and Th.M. are employees of Actavis. TRIAL REGISTRATION NUMBER:EudraCT number 2012-001726-95. 10.1093/humrep/dey288
    Vaginal Progesterone Gel for Luteal Support After Cleavage Stage Embryo Transfer: Once or Twice a Day? Urman Bulent,Celik Serdar,Yakin Kayhan,Alper Ebru,Balaban Basak,Ata Baris The Journal of reproductive medicine OBJECTIVE: To determine whether twice daily dosing of progesterone vaginal gel (PVG) is better for luteal phase support (LPS) than once daily dosing.STUDY DESIGN: Retrospective study including 456 women aged ≤42 years who underwent assisted reproductive technology with long GnRH agonist protocol. Blastocyst transfers and difficult embryo transfers were excluded. LPS was started with 90 mg PVG once daily on the evening of oocyte retrieval and continued until negative pregnancy test or 10th week of pregnancy in both groups. PVG dosage was doubled on the day of embryo transfer in the twice-daily group.RESULTS: Age, duration of infertility, and number of oocytes collected were similar. Numbers of embryos transferred were 2.9 and 2.8 in the once-daily and twice-daily groups, respectively (p=0.04). Embryo implantation (23.96% vs. 27.95%) and clinical pregnancy (50.9% vs. 56.5%) rates favored twice-daily dosage; however, differences were statistically nonsignificant, and the study had 20% power to demonstrate significance. When our results were pooled with a prior trial comparing once and twice daily dosing, twice daily dosing seemed to significantly increase clinical pregnancy rate (rate ratio: 1.18, 95% CI 1.01-1.38).CONCLUSION: Trends favoring twice daily dosing are encouraging findingsand require further investigation.