Progesterone For Luteal Phase Support Research Articles

Progesterone versus combined estrogen and progesterone for luteal phase support (LPS) in women with unexplained infertility undergoing ICSI cycle: A randomized controlled, double-blinded study

Progesterone versus combined estrogen and progesterone for luteal phase support (LPS) in women with unexplained infertility undergoing ICSI cycle: A randomized controlled, double-blinded study

Oral dydrogesterone versus micronized vaginal progesterone for luteal phase support: a double-blind crossover study investigating pharmacokinetics and impact on the endometrium.

Oral dydrogesterone versus micronized vaginal progesterone for luteal phase support: a double-blind crossover study investigating pharmacokinetics and impact on the endometrium.

P-519 Is oral dydrogesterone a good alternative to vaginal micronized progesterone for luteal phase support in women receiving oocyte donation?

Abstract Study question Does oral dydrogesterone (OD) in luteal phase support (LPS) provide equivalent clinical pregnancy and miscarriage rates as micronized vaginal progesterone (MVP) in oocyte donation recipients? Summary answer No significant difference in clinical pregnancy and miscarriage rates was observed when using OD instead of MVP for LPS in oocyte donation. What is known already Dydrogesterone has a higher bioavailability than MVP due to its high specificity for progesterone receptors allowing the use of lower doses limiting side effects. In addition, because of its route of administration, its tolerance is better. The use of OD for LPS in fresh IVF cycles is now well recognized. However, few data are available on its use in frozen-thawed embryo transfer especially in artificial cycles. In this situation, the lack of corpus luteum leads to a total dependence on exogenous progestogens for implantation and maintenance of the pregnancy. Study design, size, duration A retrospective observational study was performed from prospectively collected data in the ART Department of Lille University Hospital from July 2018 to July 2022. Participants/materials, setting, methods Our study analysed 372 oocyte donation cycles with embryo transfer. Recipients underwent endometrial preparation by hormone replacement treatment (artificial cycles). LPS was provided by weekly intramuscular progesterone (500 mg/2ml) and either OD 40 mg per day or MVP 800 mg per day for 12 weeks if the pregnancy test was positive. The primary endpoint was clinical pregnancy rate. Main results and the role of chance This study compared the outcome of 162 transfers with dydrogesterone + IM progesterone to the outcome of 210 transfers with the MVP + IM progesterone. No significant difference was found between the two groups except for the number of embryos transferred, embryo quality, donor BMI and fresh or frozen status of the embryo. After adjustment for these criteria, our two groups were comparable in clinical pregnancy rates with 36.67% in the MVP group versus 30.25% in the OD group (OR 0.868 [0.529 ; 1.423], p = 0.57), ongoing pregnancy rates (29.05% versus 25.31%, OR 0.993 [0.591; 1.669], p = 0.97), miscarriage rates (7.62% versus 4.94%, OR 0.640 [0.248; 1.650], p = 0.35) and live birth rates (26.67% versus 17.69%, OR 0.727 [0.412; 1.284], p = 0.27). Limitations, reasons for caution The main limitation of this study is the non-randomisation of data between the two treatment groups. Wider implications of the findings Our study suggests that dydrogesterone has a place in our LPS strategies in artificial cycle for frozen embryo transfers or in oocyte donation, especially as this route is often preferred by patients and very well tolerated. Further prospective cohorts or randomized trials could continue to inform clinical practice on LPS. Trial registration number DEC 16-25

P-555 Do IVF patients prefer the rectal route to the vaginal for luteal phase progesterone administration? - a cohort study

Abstract Study question How do IVF patients perceive rectal administration of progesterone for luteal phase support compared to vaginally administered progesterone? Summary answer Rectal administration of progesterone causes less discomfort in IVF patients, undergoing Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) and is preferred compared to vaginal administration. What is known already Progesterone is essential for implantation and normal development of pregnancy in spontaneous pregnancies as well as in ART pregnancies. In IVF, progesterone is most often administered vaginally in Europe for luteal phase support, although, this route may cause cumbersome discharge, vaginal bleeding, and irritation of the vulva. For many years the vaginal route has been the gold standard, although, progesterone is well absorbed rectally and recent studies have shown that rectally administered micronized progesterone was well accepted among IVF patients. Until now, in IVF very little focus has been on patient convenience as regards luteal phase support. Study design, size, duration An interventional cohort study, conducted from January 2020 to November 2022 in a public fertility clinic. A total of 479 patients received a questionnaire (Q1) by e-mail during the period between the embryo transfer and the pregnancy test; A second questionnaire (Q2) was answered at the time of the first ultrasound scan in gestational week 7. Participants/materials, setting, methods Patients underwent an HRT-FET protocol, including vaginal progesterone (VP) (400mg/12hours). In patients with serum progesterone levels lower than 11 ng/ml on the 6th day of progesterone, additional progesterone was administered rectally (RP) (400mg/12hours) from that day until the day of pregnancy testing, and in pregnant patients until the first scan in week 7. Side effects and patient convenience of both routes were reported in a questionnaire, including 27 questions, using a visual analog scale (0-100). Main results and the role of chance A total of 73% of HRT-FET patients (349/479) answered Q1 before the pregnancy test and a total of 27 % (93/349) of the cohort received progesterone both vaginally and rectally. The response rate of Q2 in gestational week 7 was 100 % (221/221) and a total of 28 % of patients (62/221) administered progesterone both vaginally and rectally. In Q1, a total of 60% of patients (54/90) preferred RP over VP in the cohort of patients treated with both administration regimens. In Q2, a total of 62% of patients (37/60) preferred RP over VP in the cohort of patients treated with both administration regimens. The overall discomfort was lower in relation to RP in both questionnaires and, especially discharge was lower in RP compared to VP; median interquartile range (IQR) in Q1: 11 (3-23) vs. 50 (25-66) and Q2: 19 (9-28) vs. 47 (22-62), respectively. Changes in defecation pattern after RP were reported in Q1 as well as Q2, 48% (45/92) and 55% (34/61), however, the discomfort was reported as mild. An increased flatulence was reported by 50% (46/92) in Q1 and 63% (39/92) in Q2, however, again the discomfort was reported as mild. Limitations, reasons for caution Currently, it is unknown whether the present results apply to progesterone products other than the one used in the present study (Cyclogest®). The questionnaire used, although having been used in another published study with another progesterone product, was not specifically validated for this product. Wider implications of the findings The rectal route should be remembered for luteal phase support in IVF, and some patients might choose the rectal route over the vaginal for their luteal phase support due to less discharge. Trial registration number EudraCT no.: 2019-001539-29

O-023 ‘The PiNC Trial’: Progesterone in Natural Cycles for the treatment of unexplained infertility

Abstract Study question Does exogenous progesterone for luteal phase support in natural cycles affect the biochemical, clinical pregnancy, livebirth or miscarriage rates in women with unexplained infertility (UI)? Summary answer Progesterone luteal support lead to an increase in livebirth rate from 7% to 15.3% and a decrease in miscarriage rates from 40% to 20%. What is known already Unexplained infertility is a diagnosis likely to encompass a population with varying underlying subtle pathologies. The only treatments currently recommended for treating UI are intrauterine insemination (IUI) and IVF/ICSI which are both expensive and invasive. The evidence for IUI with and without controlled ovarian hyperstimulation (COH) is inconclusive. A recent systematic review and meta-analysis reported a progesterone-mediated reduction in endometrial receptivity as a possible mechanism in the pathogenesis of UI. No trial has been published investigating the effectiveness of exogenous progesterone for luteal support in otherwise natural, unmedicated cycles to improve reproductive outcomes in couples with UI. Study design, size, duration We conducted an open-label, parallel arm, single centre, randomised controlled trial of an investigational medicinal product (cTIMP) from February 2020 to November 2022. We randomised 143 couples with UI to either luteal phase progesterone support or no luteal phase support and analysed the results on an intention-to-treat basis. Each couple participated for 3 menstrual cycles and they were followed up until either the end of a 3rd non-conceptual cycle or any resulting pregnancy. Participants/materials, setting, methods Couples with normal semen analysis (WHO 2020), regular ovulation, bilateral patent tubes, female partner aged ≤42yrs and BMI ≤30 were recruited and randomised following screening and informed consent. Participants timed their luteinising hormone (LH) surge using digital ovulation kits and had timed intercourse for 3 cycles. The treatment group took progesterone suppositories 400mg bd for 14 days after the LH surge. All pregnancies were scanned at 6-7/40 and ongoing pregnancies followed up to delivery. Main results and the role of chance 143 couples were recruited and randomised. Livebirth rates were 11/72 (15.3%) in the treatment group vs. 5/71 (7.0%) in the control group (Odds Ratio (OR) 2.38, 95%CI 0.78-7.24). Biochemical pregnancy rates (defined by a positive urinary pregnancy test) were 15/72 (20.8%) (treatment) vs 10/71 (14.1%) (control) (OR 1.61, 95%CI 0.67-3.86). Clinical pregnancy rates (defined by a gestation sac seen on ultrasound at a minimum of 6/40 gestation) were 14/72 (19.4%) (treatment) vs 9/71 (12.7%) (control) (OR 1.66, 95% CI 0.67-4.13). The miscarriage rate including biochemical losses was 3/15 (20%) of all pregnancies (treatment) vs. 4/10 (40%) (control). One pregnancy in the control group was terminated due to fetal anomalies. There was one ectopic pregnancy in the treatment group. Logistic regression demonstrated that none of the pregnancy outcomes were affected by participant age, BMI, ovarian reserve markers, previous parity or semen analysis parameters. The two participants in the treatment group who experienced miscarriages were both off-protocol. Although the results did not reach statistical significance, the 15.3% livebirth rate and OR of 2.37 for livebirths are clinically significant (equivalent to the success rates of stimulated intrauterine insemination treatment) as is the miscarriage rate of 0/11 clinical intra-uterine pregnancies for women taking progesterone as per protocol.Limitations, reasons for caution Despite the lack of statistical significance, differences in livebirth and miscarriage rates are clinically significant compared with alternative treatments. The trial was unblinded but the objective outcomes are unlikely to be affected by this. A larger trial using the effect size from this study to guide sample size is planned. Wider implications of the findings The treatment investigated here represents a simple, non-invasive and inexpensive option that is acceptable to couples with UI and may increase their chance of pregnancy and livebirth. If this treatment offers similar success rates to stimulated IUI it is likely to become a first-line option for many couple worldwide. Trial registration number 2019-003468-27

P-491 The efficacy of subcutaneous versus vaginal progesterone for luteal phase support - a comparison in 723 blastocyst hormone replacement therapy frozen embryo transfer cycles

Abstract Study question Are ongoing pregnancy rates (OPRs) similar between subcutaneous (sc) progesterone (P) and vaginal P administration in hormone replacement therapy (HRT) frozen embryo transfer (FET) cycles? Summary answer The OPRs were similar between sc and vaginal P administration; however, 15.8% of patients in the vaginal group needed additional P as rescue therapy. What is known already There is a paucity of data comparing sc and vaginal P administration in HRT-FET cycles. In HRT-FET cycles, there seem to be marked interpersonal differences in serum progesterone (P4) levels following the same dose and route of P administration. Impaired reproductive outcomes have been reported when serum P4 levels are below a certain threshold (10 ng/ml) on the FET/FET-1 day; rescue with supplemental sc P in these cases might rectify reproductive outcomes. With sc P, only one study reported comparable OPRs in four quartiles of serum P4 on the day of FET in HRT cycles. Study design, size, duration A cohort study was conducted during December 2019-November 2022, including a total of 723 consecutive warmed blastocyst transfer cycles, employing HRT. Each patient was included only once. The inclusion criteria were female age ≤44 years old, BMI ≤40 kg/m2, and having available day-5/6 vitrified blastocyst(s) after warming. Pre-implantation genetic testing cycles for aneuploidy (PGT-A) were included, whereas PGT for monogenic disorders/structural re-arrangements and the presence of uterine anomalies were excluded from the study. Participants/materials, setting, methods Following estrogen priming, sc P 25 mg twice-daily (n = 249) or vaginal P gel 90 mg twice-daily (n=474) were administered. The serum P4 level was measured on the FET-1 day, i.e., day 5 of P supplementation. In patients with serum P4 levels <8.75 ng/ml on the FET-1-day, additional exogenous sc P, 25 mg/day (rescue), was provided. The primary outcome measure was OPR. A generalized additive model was performed to study functional relationships between P4 and OPR. Main results and the role of chance The mean circulating P4 levels on the FET-1 day were 26.1 ± 8.1 ng/ml and 13.8 ± 5.5 ng/ml in the sc P and vaginal P gel groups, respectively (p < 0.001). In the vaginal P group, 15.8 % of patients needed sc P rescue, whereas no patient required rescue in the sc P group. All unadjusted reproductive outcome measures, including positive hCG per embryo transfer, implantation, clinical pregnancy, pre-clinical loss, miscarriage rates, and OPRs, were comparable between the sc P and vaginal P gel groups. After P rescue, when logistic regression analysis was performed to delineate the independent predictor(s) of ongoing pregnancy, only female age, number of blastocysts transferred, blastocyst morphology, and PGT-A were found to be the significant predictors. Importantly, sc P administration, necessitating no rescue, provided similar OPRs (adjusted OR = 1.22 95% CI:0.87-1.80) compared to vaginal P, in which rescue was needed in 15.8% of the patients. The impact of serum P4 levels on adjusted reproductive outcome measures was evaluated by percentiles (<10th, 10–49th, 50–90th, and >90th percentiles). All serum P4 percentiles had similar OPRs, and no significant association was observed between serum P4 levels and OPRs in both sc and vaginal P (with rescue if needed) groups. Limitations, reasons for caution Cohort study, lack of cost and side-effect analyses. Wider implications of the findings Subcutaneous P 25 mg twice-daily secures a serum P4 above 8.75 ng/ml, whereas additional exogenous P (rescue) was needed in 15.8% of patients receiving vaginal P administration only. The OPR was similar between the sc P alone and vaginal P groups after sc P rescue of the vaginal group. Trial registration number Not applicable

Association between serum progesterone levels on the day of frozen-thawed embryo transfer and pregnancy outcomes after artificial endometrial preparation

BackgroundPrevious studies have examined that a range of optimal serum P level during the implantation period was associated with optimal live birth rates. However, those results obtained with vaginal or intramuscular route of progesterone administration for luteal phase support (LPS) alone. Is there a relationship between the serum progesterone (P) on the day of frozen-thawed embryo transfer (FET) with the likelihood of a live birth (LB) in artificial cycles (AC) when using a combination of oral dydrogesterone and vaginal progesterone for LPS?MethodsThis was a retrospective study of 3659 FET cycles with artificial endometrial preparation in a Chinese tertiary-care academic medical centre from January 2015 to February 2017. Endometrial preparation was performed using estradiol (E2) valerate (Fematon-red tablets) 8 mg/d beginning on day 3 of the cycle, followed by administration of P both orally (8 mg/d Fematon-yellow tablets) and vaginally (400 mg/d; Utrogestan). The primary endpoint was live birth rate (LBR). The association between the serum P level on the embryo transfer day and pregnancy outcomes was evaluated by univariable and multivariable logistic regression analysis.ResultsThe LBRs according to the serum P quartiles were as follows: Q1: 35.7%; Q2: 37.4%; Q3: 39.1% and Q4: 38.9%. Logistic regression analysis showed that the odds of a LB were not significantly different between the low (P < 7.9 ng/mL) and high (P ≥ 7.9 ng/mL) progesterone groups before or after adjustment (crude OR = 0.89, 95% CI: 0.76–1.04; adjusted OR = 0.89, 95% CI: 0.75–1.04).ConclusionThe present study suggests that the serum P levels on the day of embryo transfer (ET) do not correlate with the likelihood of a LB in artificial cycles when using a combination of oral dydrogesterone and vaginal progesterone for luteal phase support.

Low Molecular Weight Heparin-Aspirin-Prednisolone Combination Does Not Increase the Live Birth Rate in Recurrent Implantation Failure: A Retrospective Cohort Study.

This study investigates the triple combination of adjuvants (low molecular weight heparin (LMWH)-aspirin-prednisolone) whether it improves the live birth rates of IVF&ICSI patients with previous implantation failure. This retrospective study included 1095 patients with >2 failed either fresh or frozen single embryo transfer cycles between 2014 Jan and 2021 Jan. Patients were divided into two subgroups. Group A consisted of patients with only vaginal progesterone for luteal phase support. Group B consisted of patients with triple (daily subcutaneous LMWH, daily 150 mg aspirin, and daily 16 mg prednisolone) luteal phase supplementation to vaginal progesterone. Demographic parameters, cycle characteristics, embryology, and pregnancy outcomes were compared, and the study's primary outcome was the live birth rate. Demographic parameters were similar between the groups. Positive b-hCG, miscarriage, and live birth rates were similar between groups as Group A vs. Group B, positive b-hCG 30.8% (190/617) vs. 35.4% (169/478), miscarriage rates 4.4% (27/617) vs. 6.7% (32/478), and live birth rates 20.4% (126/617) vs. 23.8% (114/478), respectively. When patients were stratified according to previous failures, live birth rates were still similar. Pregnancy outcomes were significantly improved in only patients with diminished ovarian reserve (Group A vs. Group B, positive b-hCG 24.2% vs. 34.3%, live birth rate 12.1% vs. 21.9%, p < 0.01). Whether the embryo transfer was fresh or frozen-thawed did not affect the results. A combined supplementation of LMWH, aspirin, and prednisolone in the luteal phase does not improve live birth rates of IVF&ICSI patients with previous implantation failure except potentially for patients with diminished ovarian reserve.

Сравнительный анализ эффективности и безопасности гестагенов в поддержке лютеиновой фазы в свежих циклах ЭКО/ИКСИ с переносом одного эмбриона

Objective. To study the efficacy and safety of dydrogesterone and micronized vaginal progesterone for luteal phase support in fresh IVF/ICSI cycles with single embryo transfer. Patients and methods. A retrospective comparative analysis including 146 women aged 23 to 44 years who entered an assisted reproductive technology (ART) program in 2020 was performed. Patients were divided into two groups: group 1 (n = 67) received dydrogesterone for luteal phase (LP) support in ART, while group 2 (n = 79) received micronized vaginal progesterone (MVP). All patients underwent a single good-quality embryo transfer in a fresh IVF/ICSI cycle. The rate of clinical pregnancy was considered as the primary endpoint, while the rate of live births and the safety profile of medications for mothers and neonates were considered as secondary endpoints. In addition, the incidence of adverse events with dydrogesterone and MVP was evaluated. Results. Clinical pregnancy and live birth rates with dydrogesterone as LP support in ART programs were 25/67 and 19/67 (37.3% and 28.4%, respectively), with MVP – 27/79 and 19/79 (34.2% and 24.1%, respectively). Thus, there was a tendency to improve the results of ART programs in the dydrogesterone group, but no statistically significant difference in outcomes was found (p &gt; 0.05). In the MVP group, one child was diagnosed with a malformation, syndactyly of the second and third toes. In the dydrogesterone group, one term stillbirth was registered due to chronic fetoplacental insufficiency and intrauterine growth restriction (IUGR). The suspected cause of pathological changes was COVID-19 at 30 weeks’ gestation. Based on the global report, the background risk of congenital malformations due to environmental and genetic factors is 6% of worldwide births. The results obtained did not exceed the population average, indicating a high safety profile of gestagens for a fetus in both groups. The incidence of side effects and adverse reactions was significantly lower in the group of women receiving dydrogesterone compared to MVP (3/67 (4.5%) and 11/79 (13.9%) cases, respectively, p &lt;0.05). Conclusion. LP support with gestagens in fresh IVF/ICSI cycles with single embryo transfer showed comparable efficacy. Oral dydrogesterone therapy tended to increase the rate of clinical pregnancy and live births in IVF/ICSI cycles with single embryo transfer and demonstrated a favorable safety profile. The benefits of dydrogesterone included good tolerability and positive patient satisfaction. The oral route of dydrogesterone administration was reported as the most preferred one among patients and physicians. Key words: ART cycles, single embryo transfer, gestagens, dydrogesterone, micronized progesterone

Tailored progesterone for luteal phase support: the way to go.

Tailored progesterone for luteal phase support: the way to go.

Addition of intramuscular to vaginal progesterone for luteal phase support in fresh embryo transfer cycles: A cross-sectional study.

Luteal phase deficiency is common in assisted reproductive technology and is characterized by inadequate progesterone production. Various studies have shown that administration of progesterone in fresh embryo transfer cycles increases the rate of clinical pregnancy and live birth rate. Progesterone administration has variable types: oral, vaginal, oil-based intramuscular, and subcutaneous. This study aims to compare the effect of adding intramuscular progesterone to the vaginal progesterone for luteal phase support in the fresh embryo transfer cycle. This study reviewed the information related to 355 women who had a fresh embryo transfer between March 2020 and February 2021 at the Yazd Reproductive Sciences Institute, Yazd, Iran. The participants population were divided into 2 groups based on the type of luteal phase support regime: group I (n = 173) received 400 mg vaginal progesterone alone twice a day from the day of ovum pick up; and group II (n = 182) received 50 mg IM of progesterone in addition to vaginal progesterone 400 mg twice a day from the day of ovum pick up. Chemical and clinical pregnancy rates were compared between groups. The basic characteristics of groups were statistically similar. The rates of chemical and clinical pregnancy were higher in the vaginal plus IM progesterone group than in the vaginal progesterone group. Moreover, chemical pregnancy showed a significant difference between the groups (p = 0.011). Our findings demonstrated that the addition of IM progesterone to the vaginal progesterone improves the chemical pregnancy rate in fresh embryo transfer.

P-419 Does adjuvant usage in the luteal phase improve live birth rates of ICSI - ET patients with previous implantation failure?

Abstract Study question Does adjuvant usage in the luteal phase improve live birth rates of ICSI-ET (intracytoplasmic sperm injection - embryo transfer) patients with previous implantation failure? Summary answer Combination of low molecular weight heparin, aspirin, and prednisolone in the luteal phase doesn't improve live birth rates of ICSI-ET patients with previous implantation failure. What is known already RIF affects around 10% of patients undergoing IVF worldwide. The exact pathology of implantation failure, although transferring a good quality embryo, is still unknown. There are numerous treatment options, However, there is no conclusive evidence that prophylactic treatment improves the pregnancy rate in infertile women during IVF. Study design, size, duration This retrospective study included 1095 patients with &amp;gt; 2 failed either fresh or frozen embryo transfer cycles between 2014 Jan – 2021 Jan. Participants/materials, setting, methods Patients were divided into two groups. Group-A consisted of patients with only vaginal progesterone for luteal phase support. Group-B consisted of patients with triple (daily subcutaneous low molecular weight heparin, daily p.o. 150 mg aspirin, and daily p.o. 16 mg prednisolone) luteal phase supplementation to vaginal progesterone. Demographic parameters, cycle characteristics, embryology, and pregnancy outcomes were compared, and the live birth rate was the study's primary outcome. Main results and the role of chance There were 5910 ICSI&amp;ET cycles between the years Jan 2014 and Jan 2021. A total of 3853 Patients with single day5-6 good quality blastocyst transfer was selected from the database, and appropriate patients for inclusion criteria with at least two previous failure implantation history were included. As a result, a total of 1095 fresh or frozen-thawed ET cycles were included in the study. There were 617 patients without (Group A) and 478 patients with adjuvant use (Group B). Demographic parameters were similar between groups. Although higher embryology outcomes (Group A vs. B, No.of oocyte; 11 (7-17) vs. 13 (8-19), No. of MII; 9(5-14) vs. 10 (6-15), No. of 2PN; 5 (3-9) vs. 6 (4-10), p &amp;lt; 0.01), positive b-hCG rates, miscarriage rates, live birth rates were similar between groups (Group A vs. B, positive b-hCG; 30.8% (190/617) vs. 35.4% (169/478), Miscarriage rates; 4.4% (27/617) vs. 6.7% (32/478), Live Birth Rates; 20.4% (126/617) vs. 23.8% (114/478)). When the live birth rates were stratified depending on the number of previous failed transferred cycles, the live birth rates were still comparable between the groups. Limitations, reasons for caution The study's retrospective design limits the power of the results. The study's main limitation is the lack of the euploidy information of transferred embryos. Wider implications of the findings Our findings suggest that empirical usage of adjuvants such as low molecular weight heparin, aspirin, and prednisolone does not improve live birth rates in patients with previous implantation failure. These results support the present literature. Trial registration number Not applicable

Dydrogesterone and 20α-dihydrodydrogesterone plasma levels on day of embryo transfer and clinical outcome in an anovulatory programmed frozen-thawed embryo transfer cycle: a prospective cohort study.

Dydrogesterone and 20α-dihydrodydrogesterone plasma levels on day of embryo transfer and clinical outcome in an anovulatory programmed frozen-thawed embryo transfer cycle: a prospective cohort study.

Evaluating interventions and adjuncts to optimize pregnancy outcomes in subfertile women: an overview review.

There is a wealth of information regarding interventions for treating subfertility. The majority of studies exploring interventions for improving conception rates also report on pregnancy outcomes. However, there is no efficient way for clinicians, researchers, funding organizations, decision-making bodies or women themselves to easily access and review the evidence for the effect of adjuvant therapies on key pregnancy outcomes in subfertile women. The aim was to summarize all published systematic reviews (SRs) of randomized controlled trials (RCTs) of interventions in the subfertile population, specifically reporting on the pregnancy outcomes of miscarriage and live birth. Furthermore, we aimed to highlight promising interventions and areas that need high-quality evidence. We searched the Cochrane Database of Systematic Reviews and PubMed clinical queries SR filter (inception until July 2021) with a list of key words to capture all SRs specifying or reporting any miscarriage outcome. Studies were included if they were SRs of RCTs. The population was subfertile women (pregnant or trying to conceive) and any intervention (versus placebo or no treatment) was included. We adopted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) for determining the quality of the evidence. Exclusion criteria were overview reviews, reviews that exclusively reported on women conceiving via natural conception, reviews including non-randomized study designs or reviews where miscarriage or live birth outcomes were not specified or reported. The primary outcome was miscarriage, defined as pregnancy loss <24 weeks of gestation. Data were also extracted for live birth where available. We included 75 published SRs containing 121251 participants. There were 14 classes of intervention identified: luteal phase, immunotherapy, anticoagulants, hCG, micronutrients, lifestyle, endocrine, surgical, pre-implantation genetic testing for aneuploidies (PGT-As), laboratory techniques, endometrial injury, ART protocols, other adjuncts/techniques in the ART process and complementary interventions. The interventions with at least moderate-quality evidence of benefit in reducing risk of miscarriage or improving the chance of a live birth are: intrauterine hCG at time of cleavage stage embryo transfer, but not blastocyst transfer, antioxidant therapy in males, dehydroepiandrosterone in women and embryo medium containing high hyaluronic acid. Interventions showing potential increased risk of miscarriage or reduced live birth rate are: embryo culture supernatant injection before embryo transfer in frozen cycles and PGT-A with the use of fluorescence in situ hybridization. This review provides an overview of key pregnancy outcomes from published SRs of RCTs in subfertile women. It provides access to concisely summarized information and will help clinicians and policy makers identify knowledge gaps in the field, whilst covering a broad range of topics, to help improve pregnancy outcomes for subfertile couples. Further research is required into the following promising interventions: the dose of progesterone for luteal phase support, peripheral blood mononuclear cells for women with recurrent implantation failure, glucocorticoids in women undergoing IVF, low-molecular-weight heparin for unexplained subfertility, intrauterine hCG at the time of cleavage stage embryo or blastocyst transfer and low oxygen concentrations in embryo culture. In addition, there is a need for high-quality, well-designed RCTs in the field of reproductive surgery. Finally, further research is needed to demonstrate the integrated effects of non-pharmacological lifestyle interventions.

Luteal Phase Support in Intrauterine Insemination Cycles: A Randomized Clinical Trial of Vaginal Versus Intramuscular Progesterone Administration.

Background:Different progesterone doses and routes are used for luteal phase support in stimulated intrauterine insemination (IUI) cycles, but the optimal supplementation scheme has not yet been determined. Therefore, our aim was to compare the administration of two different doses of vaginal progesterone with two doses of intramuscular (IM) progesterone for luteal phase support in patients undergoing IUI cycles.Methods:In this randomized clinical trial, 312 women with unexplained or malefactor infertility intending to start IUI cycles between April 2015 and January 2018 were included. They were randomized into four groups (n=78/each) including group 1 who received IM progesterone in oil (25 mg daily), group 2 who received IM progesterone in oil (50 mg daily), group 3 who received progesterone suppository (400 mg daily), and group 4 who received progesterone suppository (800 mg daily; 400 mg twice daily). The primary outcome was the clinical pregnancy rate. The ongoing pregnancy rate, abortion rate, and patients’ satisfaction, and convenience the secondary outcomes.Results:In our study, the overall clinical and ongoing pregnancy rates per cycle with COS and IUI were 16.02% and 12.8%, respectively. There were no significant differences in clinical pregnancy, ongoing pregnancy, and abortion rates among groups (p=0.84). The overall patients’ satisfaction and convenience was significantly higher in the vaginal progesterone suppository groups than the IM progesterone groups (p=0.001).Conclusion:The results of this study showed that vaginal progesterone administration provides a more easy-to-use and convenient method than IM progesterone administration for luteal phase support in IUI cycles with comparable pregnancy rates.

Co-administration of GnRH agonists with vaginal progesterone compared to vaginal progesterone in luteal phase support of the frozen-thawed embryo transfer cycle: An RCT.

BackgroundSince progesterone alone does not seem to be enough for luteal phase support (LPS), especially in frozen embryo transfer (FET) cycles, so gonadotropin-releasing hormone agonist (GnRH-a) is suggested as an adjuvant therapy in combination with progesterone for LPS.ObjectiveTo evaluate the effects of the administration of GnRH-a with vaginal progesterone compared to vaginal progesterone alone in luteal phase support of the frozen-thawed embryo transfer cycles.Materials and Methods In this randomized controlled clinical trial, 240 infertile women who were candidates for FET were evaluated into two groups (n = 120/each). Group I received 400 mg vaginal progesterone twice a day from the time of transfer. The second group received vaginal progesterone and also 0.1 mg diphereline on days 0, 3, and 6 of FET for LPS. Finally, the clinical and ongoing pregnancy rates, and the implantation, and spontaneous abortion rates were compared in two groups.ResultsResults showed that there was no significant difference between the mean age of women and the duration of infertility (p = 0.78, p = 0.58, respectively). There were no significant differences between groups in the terms of implantation and spontaneous abortion rates (p = 0.19, p = 0.31, respectively). However, in terms of clinical and ongoing pregnancy rates, the significant differences were seen between groups (p = 0.008 and p = 0.005, respectively).ConclusionCo-administration of GnRH-a and vaginal progesterone in LPS may be superior to vaginal progesterone alone in women who underwent a frozen-selected embryo transfer cycle.

LOW PLASMA DYDROGESTERONE (DYD) LEVEL ON DAY OF ET IS ASSOCIATED WITH REDUCED ONGOING PREGNANCY RATE IN HRT PROGRAMMED FET CYCLES: A PROSPECTIVE OBSERVATIONAL STUDY

In an artificial FET-cycle, a corpus luteum is absent and therefore the exogenous support by progestogens is key to pregnancy establishment. Dydrogesterone (DYD) is an oral, systemic alternative to vaginal progesterone for luteal phase support. Measurement of DYD and and its metabolite, 20α-Dihydrodydrogesterone (DHD), is only feasible by LC/MS. While oral DYD is widely used in fresh IVF cycles, circulating concentrations vs. successful treatment have never been explored. This study determines plasma concentrations of DYD and DHD, measured on day of ET in a programmed anovulatory FET cycle, and describes the association with the outcome.

NATURAL PROLIFERATIVE PHASE FROZEN EMBRYO TRANSFERS (NPP-FET) – A NEW APPROACH THAT FACILITATES SCHEDULING WITHOUT HINDERING PREGNANCY OUTCOMES

Despite increasing evidence pointing towards a potential benefit in performing natural cycle frozen embryo transfers (NC-FET), multiple centers still prefer artificial cycles (AC-FET) to avoid difficulties in cycle monitoring and scheduling. Specifically, conventional NC-FET frequently require consecutive patient visits to determine the ideal FET timing according to ovulation (either following a spontaneous LH surge or exogenous hCG triggering of an adequately-sized dominant pre-ovulatory follicle). This study assessed progesterone-programmed FET (PP-FET), a new approach in regularly cycling women in which vaginal progesterone for luteal phase support is initiated in the late-follicular phase as soon as an endometrial thickness of at least 7 mm is reached after endogenous estradiol stimulation and without LH surge monitoring and/or hCG triggering. This was a retrospective analysis of FETs performed in our center between 2010-2019 using either autologous of donated oocytes. All conventional NC-FET or cycles in which the endometrial thickness on the day of planning was below 7 mm were excluded. Our main outcome measure was livebirth. We performed multivariable generalized estimating equations (GEE) regression analysis to account for the following potential confounding variables: female age, oocyte source (autologous versus donated), embryo developmental stage (cleavage versus blastocyst) and number of embryos transferred. Finally, we also performed a subgroup analysis according to oocyte source. When compared to AC-FET (n=1155), the PP-FET (n=79) subgroup presented, on average, a higher female age (31.8±5.8 vs 33.2±5.5, p=0.04), performed less oocyte donation (36.2% vs 21.5%, p=0.01) and blastocyst stage (83.8% vs 69.6%, p<0.01) cycles, while having more single embryo transfers (26.7% vs 45.6%, p<0.01) performed. Despite, at first glance, having more unfavorable baseline characteristics, the livebirth rates were higher in the PP-FET group (32.7% vs 46.2%, p=0.02), an association which remained statistically significant even following confounder adjustment in the multivariable GEE regression model (adjusted odd-ratio 1.79, 95% CI 1.11-2.87). This tendency for better livebirth rates in PP-FET was also found in the subgroup analysis according to whether the oocyte used were autologous (30.1% vs 42.6%, respectively, p=0.04) or donated (37.3% vs 58.8%, respectively, p=0.07). PP-FET were associated with better livebirth outcomes.

Analysis of serum and endometrial progesterone in determining endometrial receptivity.

Is there a relationship between serum and endometrial progesterone (P4) levels, including P4 and metabolites (oestrone, oestradiol and 17α-hydroxyprogesterone), and endometrial receptivity? Serum P4 levels were not correlated with endometrial P4, nor associated with endometrial receptivity as determined by the ERA® test; however, endometrial P4 and 17α-hydroxyprogesterone levels were positively correlated and related to endometrial receptivity by ERA. Acquisition of endometrial receptivity is governed by P4, which induces secretory transformation. A close relationship between serum P4 and pregnancy outcome is reported for hormone replacement therapy (HRT) cycles. However, the relationship between serum and uterine P4 levels has not been described, and it is unknown whether uterine receptivity depends more on serum or uterine P4 levels. A prospective cohort study was performed during March 2018-2019 in 85 IVF patients undergoing an evaluation-only HRT cycle with oestradiol valerate (6 mg/day) and micronised vaginal progesterone (400 mg/12 h). Patients were under 50 years of age, had undergone at least one failed IVF cycle, had no uterine pathology, and had adequate endometrial thickness (> 6.5 mm). The study was conducted at IVI Valencia and IVI Foundation. An endometrial biopsy and a blood sample were collected after 5 days of P4 vaginal treatment. Measures included serum P4 levels, ERA®-based evaluation of endometrial receptivity, and endometrial P4 levels along with metabolites (oestrone, oestradiol and 17α-hydroxyprogesterone) measured by ultra-performance liquid chromatography-tandem mass spectrometry. Seventy-nine women were included (mean age: 39.9 ± 4.6, BMI: 24.2 ± 3.9 kg/m2, endometrial thickness: 8.2 ± 1.4 mm). The percentage of endometria indicated as receptive by ERA® was 40.5%. When comparing receptive versus non-receptive groups, no differences were observed in baseline characteristics nor in steroid hormones levels in serum or endometrium. No association between serum P4 and endometrial steroid levels or ERA result was found (P < 0.05). When the population was stratified according to metabolite concentration levels, endometrial P4 and 17α-hydroxyprogesterone were significantly associated with endometrial receptivity (P < 0.05). A higher proportion of receptive endometria by ERA was observed when endometrial P4 levels were higher than 40.07 µg/ml (relative maximum) and a lower proportion of receptive endometria was associated with endometrial 17α-hydroxyprogesterone lower than 0.35 ng/ml (first quartile). A positive correlation R2 = 0.67, P < 0.001 was observed between endometrial P4 and 17α-hydroxyprogesterone levels. This study did not analyse pregnancy outcomes. Further, the findings can only be extrapolated to HRT cycles with micronised vaginal progesterone for luteal phase support. Our findings suggest that the combined benefits of different routes of progesterone administration for luteal phase support could be leveraged to ensure an adequate concentration of progesterone both in the uterus and in the bloodstream. Further studies will confirm whether this method can optimise both endometrial receptivity and live birth rate. Additionally, targeted treatment to increase P4 endometrial levels may normalise the timing of the window of implantation without needing to modify the progesterone administration day. This research was supported by the IVI-RMA Valencia (1706-VLC-051-EL) and Consellería d'Educació, Investigació, Cultura, i esport Generalitat Valenciana (Valencian Government, Spain, GV/2018//151). Almudena Devesa-Peiro (FPU/15/01398) and Cristina Rodriguez-Varela (FPU18/01657) were supported by the FPU program fellowship from the Ministry of Science, Innovation and Universities (Spanish Government). P.D.-G. is co-inventor on the ERA patent, with non-economic benefits. The other authors have no competing interests. NCT03456375.

Subcutaneous progesterone versus vaginal progesterone for luteal phase support in in vitro fertilization: A retrospective analysis from daily clinical practice.

ObjectiveProgesterone application for luteal phase support is a well-established concept in in vitro fertilization (IVF) treatment. Water-soluble subcutaneous progesterone injections have shown pregnancy rates equivalent to those observed in patients receiving vaginal administration in randomized controlled trials. Our study aimed to investigate whether the results from those pivotal trials could be reproduced in daily clinical practice in an unselected patient population.MethodsIn this retrospective cohort study in non-standardized daily clinical practice, we compared 273 IVF cycles from 195 women undergoing IVF at our center for luteal phase support with vaginal administration of 200 mg of micronized progesterone three times daily or subcutaneous injection of 25 mg of progesterone per day.Results Various patient characteristics including age, weight, height, number of oocytes, and body mass index were similar between both groups. We observed no significant differences in the clinical pregnancy rate (CPR) per treatment cycle between the subcutaneous (39.9%) and vaginal group (36.5%) (p=0.630). Covariate analysis showed significant correlations of the number of transferred embryos and the total dosage of stimulation medication with the CPR. However, after adjustment of the CPR for these covariates using a regression model, no significant difference was observed between the two groups (odds ratio, 0.956; 95% confidence interval, 0.512–1.786; p=0.888).ConclusionIn agreement with randomized controlled trials in study populations with strict selection criteria, our study determined that subcutaneous progesterone was equally effective as vaginally applied progesterone in daily clinical practice in an unselected patient population.