Dydrogesterone Research Articles

P-653 Impact of dydrogesterone use in cycles with low progesterone levels on the day of frozen embryo transfer

Abstract Study question Assessing if Frozen Embryo Transfer (FET) outcomes in hormonal replacement treatment with dydrogesterone (DYD) for low progesterone levels match those with normal progesterone (P4) values Summary answer The live birth rate showed no significant difference between patients with low and normal serum P4 levels in FET, utilizing DYD as rescue therapy What is known already The number of IVF/ICSI cycles and frozen embryo transfers (FET) is increasing. The preparation for FET can occur in natural or artificial cycles, showing no significant differences in clinical pregnancy and live birth rates. Artificial cycles involve exogenous estradiol supplementation, starting after menses, and progesterone (P4) addition post-endometrial proliferation. Numerous studies consistently indicate that diminished P4 levels are correlated with inferior outcomes in hormonal replacement treatment, showing a potential decrease of up to 30% in ongoing pregnancy rates. Despite a suggested rescue strategy, evidence supporting its efficacy using an oral route is insufficient. Study design, size, duration This was a retrospective cohort study, of single embryo transfers (SET) from FET cycles conducted between July 2019 and March 2022, after artificial endometrial preparation with valerate-estradiol and micronized vaginal P4. In cases of low serum P4 (up to 12,5ng/dl) on the planned transfer day, 10 mg of dydrogesterone (DYD) three times daily was added. Solely blastocyst single embryo transfers (SET) were included. The primary endpoint was the live birth rate> 24 weeks. Participants/materials, setting, methods 535 FET-SET cycles were analyzed. Patients with an endometrial layer thinner than 7 mm, endocavitary pathology or serum P4 values< 4ng/dl were excluded. The explanatory variables evaluated were: relevant female characteristics, previous IVF/ICSI cycle and relevant FET cycle parameters (endometrial thickness, serum P4 value on the FET day, days in culture before blastocyst freezing) and use of DYD as rescue therapy. Statistical analysis was performed using IBM®SPSS® statistics v22.0 and R4.2.2 for Windows. Main results and the role of chance Out of the 535 FET cycles analyzed, 136(25.4%) underwent treatment with DYD. There were 337 pregnancies (63%), 207 live births (38.6%) and 130 miscarriages (38.5%). Serum P4 varied from 4.2-32.3 ng/dl, with an average of 14.93 ng/dl (SD 4.52). The best model to explain serum P4 distribution considered a gamma distribution for P4. Female age on the FET day, female ethnicity and female weight seemed to explain P4 variation. A sensitivity analysis on the P4 values was performed. The data were divided into 5 groups according to P4 levels and the rate of live birth per quintile was evaluated. There were no statistically significant differences between the groups. Patients with low P4 which had DYD added had no statistical differences regarding deliveries, 40% vs 36% (p = 0,354). The multivariable model revealed that older females at pick up, a thinner endometrial measure and transferring a day 6 blastocyst were negativey associated with live birth (p < 0,05), but not P4 levels or medication with DYD. A sub-group analyses was performed according to the median value of P4 (9.6 ng/ml) of those to whom DYD was added. No statistically significant differences were identified for biochemical pregnancy 59% vs 60% (p = 1) and live birth rate 34%vs38% (p = 0,653). Limitations, reasons for caution This retrospective study lacks an untreated control group, causing inherent heterogeneity. It’s unclear if there’s an upper limit for P4 levels to restrict DYD supplementation or a minimum level rendering this strategy unsuitable. Monitoring DYD’s fetal/neonatal safety is imperative. Wider implications of the findings The supplementation with oral DYD in hormonal replacement FET cycles is an easy and cheap strategy in patients with for low P4 levels. The duration of DYD administration should be further evaluated. Trial registration number not applicable

O-208 The Programmed Ovulatory Frozen-Thawed Embryo Transfer Cycle (PO-FET): a suggested FET protocol integrating aspects of embryo transfer scheduling, efficacy optimization and maternal/fetal safety

Abstract Study question What is the effect of 30mg oral dydrogesterone (DYD), given to induce endometrial receptivity in natural-proliferative-phase-FET-cycles (NPP-FET), on ovulation, progesterone and DYD/DHD-levels, respectively, and outcomes? Summary answer Oral DYD 30mg allows scheduling endometrial receptivity in natural cycles while not interfering with ovulation in the vast majority of patients. What is known already Globally, approximately 60% of all ETs are performed after cryopreservation. Hormone Replacement Treatment (HRT)-FET cycle-regimens have come under scrutiny, because of i) risk of insufficient progesterone exposure with conventional dosing-schemes and ii) maternal/fetal risks stemming from the iatrogenic lack of a corpus luteum. Oral DYD 10mg (tid) supposedly does not interfere with ovulation/corpus luteum formation, and does not cross-react with progesterone in ELISA. It could thus be used for inducing endometrial receptivity (scheduling, in a natural cycle, the time point of ET) and luteal phase support, while allowing ovulation dissociated from the window-of-implantation and monitoring of endogenous progesterone serum levels. Study design, size, duration Within a multi-centric, prospective, clinical cohort study (NCT03507673), 559 normally cycling women from the routine care population who underwent FET after IVF/ICSI in a natural cycle (2/2021 – 8/2023) had serum/plasma samples prospectively collected/stored on day of FET for measurement of E2, progesterone and DYD/DHD in Roche Elecsys®-Immunoassay and liquid chromatography/tandem mass spectroscopy (LC-MS/MS), respectively. FET was performed on day 2/3 (cleavage-stage) or day 4/5 (morula/blastocyst) in 17.4% and 82.6% of FETs, respectively. Participants/materials, setting, methods From cycle day 10, women underwent endocrine (E2, LH and P) and sonographic monitoring until E2 >180pg/ml, leading follicle >16mm and endometrial thickness was >6mm. Physicians could then initiate oral DYD10mg (tid) or–in absence of LH rise–postpone initiation, under 2-daily monitoring, to meet the organizational preferences of the patient and/or center (for example, avoiding weekends). FET was performed for day 2 (cleavage), 3, 4 or 5 (blastocyst) on day 3-6 of DYD-intake, respectively. Main results and the role of chance Previously reported PK of 10mg DYD (tid) are confirmed/extended. While log-levels of DYD and DHD were highly correlated (0.95), P-levels were not (0.02, 0.02). In 94.4% of patients, ovulation could be confirmed by serum-P levels on the day of FET or in late luteal phase. Medians (IQR) of DYD and P on day 3 and days 5, respectively, were 0.93ng/ml (0.93ng/ml) and 2.96ng/ml (3.19ng/ml), and 1.13ng/ml (1.09ng/ml) and 8.50ng/ml (4.40ng/ml). Serum-P levels increased with the FET day (medians 2.0, 3.0, 6.6, and 8.5 ng/ml on days 2, 3, 4, and 5) and only very weakly correlated with LH, E2 levels, and follicular diameter at last monitoring. 42.5% and 34.8% of patients had positive hCG and ongoing clinical pregnancy, respectively. Ongoing pregnancy was independent from plasma-DYD levels (< 25th percentile [<0.66 ng/ml] 37.9% vs. ≥25thperc. [≥0.66 ng/ml] 34.3%, RD 1.5%, 95%CI: -16.5% to 17.4%, p = 0.334), yet dependent from serum-P levels (< 25thperc [<4.85 ng/ml] 25.9% vs. ≥25thperc [≥4.85 ng/ml] 35.3%, RD 9.4%, 95% CI 0.4% to 17.6%, p = 0.0161).However, neither of the two serum hormone values is predictive of a dichotomous outcome in isolation, nor do they demonstrate predictive interaction when considered together in logistic regression modelling. Limitations, reasons for caution DYD, like hCG or any other progestin given for LPS, may negatively interfere with LH surge, ovulation and luteal phase characteristics. Controlled studies on different progestin types and doses are necessary to better understand how to optimize luteal phase and thereby optimally support embryo nidation, pregnancy maintenance and maternal/fetal health. Wider implications of the findings The PO-FET protocol induces the implantation window, thus offers (some) flexibility in FET timing, shows little interference with ovulation/corpus luteum formation, provides double gestagenic support with no need for monitoring P or DYD levels, however allows corpus luteum activity monitoring in luteal phase and early pregnancy, is injection-free, and low-cost. Trial registration number NCT03507673

P-449 Association of corpus luteum activity in early pregnancy and live birth after assisted reproductive technology (ART) and intrauterine insemination (IUI)

Abstract Study question What is the incidence of low corpus luteum activity in early pregnancy, and how are endogenous progesterone levels and live birth achievement associated? Summary answer Frequently occurring low corpus luteum activity (progesterone-level) in early pregnancy after ART and IUI strongly predicts pregnancy demise, though not independent of trophoblast activity (hCG-level). What is known already Ovarian stimulation and human chorion gonadotropine (hCG) administration may induce a luteal phase defect via negative feedback on the hypothalamic-pituitary-ovarian (HPO) axis. Luteal phase support (LPS) is routinely administered with bio-identical progesterone or oral dydrogesterone (DYD). DYD has high oral availability, minimal interaction with the pituitary gland, and no cross-reactivity in enzyme-linked immunosorbent assay (ELISA) with progesterone. Therefore, utilizing DYD as LPS in IVF/ICSI or ovulatory IUI cycles provides a unique perspective to assess endocrine luteal activity. While various studies explored progesterone and hCG post-IVF or IUI, none focused solely on the corpus luteum’s sole endocrine function and its outcomes. Study design, size, duration This single-center, retrospective study (with institutional review board approval) investigated hCG and progesterone serum levels after IVF/ICSI cycles or IUI cycles supported with DYD as the sole LPS. The study aims to assess their predictive value, individually and in combination, for sustaining pregnancy. Data from 189 IVF/ICSI and 198 IUI early pregnancies, respectively, with positive hCG test between January 2017 and June 2022, was extracted from the patient management system at the University Fertility Center. Participants/materials, setting, methods Included were only first IVF/ICSI and IUI treatment-cycles with serum hCG value ≥ limit of detection (0.6 IU/l) between days 9 and 16 after fresh embryo transfer or IUI, respectively. Additionally to hCG, endogenous progesterone was determined and the relationship between these and pregnancy maintenance was investigated using logistic regression analysis. Inclusion criteria encompassed hCG-triggered cycles using DYD as the sole LPS, administered at 30 and 20 mg daily for IVF/ICSI and IUI therapy, respectively. Main results and the role of chance The 10th, 25th, 50th and 75th quantiles of serum progesterone are at 0.28, 3.75, 33.0 and 98.7 µg/l in IVF/ICSI cycles and 0.48, 2.70, 18.40 and 26.6 µg/l in IUI cycles. Women in the first quartile of progesterone levels had nearly exclusively pregnancy demise: live birth rate 3/47 (7%, 95% confidence interval (CI) 1-19%) and 0/47 (0%, 95% CI 0-7.5%) in IVF/ICSI and IUI cycles, respectively. In both IVF/ICSI and IUI, progesterone and hCG were highly correlated (correlation coefficient 0.83 in both cases). Accordingly, the association of serum hCG levels with live birth achievement was similar in quartile analyses. Using receiver operating characteristic (ROC) curves and Youden’s indices, the optimal cut-off values for predicting live birth were determined as follows: 16.49 µg/l (89 % sensitivity (SN) and 59 % specificity (SP)) for IVF/ICSI and 15.89 µg/l (90 % SN and 70 % SP) for IUI therapy. Logarithmic regression analysis also revealed a significant correlation between progesterone levels and live birth in IVF/ICSI and IUI therapy, with a p-value of < 0.001. Limitations, reasons for caution Low progesterone in early pregnancy may be a consequence or a cause for pregnancy demise. DYD, like any other progesterone for LPS, might adversely impact corpus luteum formation and maintenance through HPO axis interaction, especially in mono-ovulatory cycles or in older women with inherently higher risk of luteal phase defect. Wider implications of the findings Ovarian stimulation and hCG-administration may induce a luteal phase defect with insufficient luteal activity in early pregnancy, even up to luteolysis, with potential consequences for pregnancy maintenance and maternal/fetal health. Future treatment protocols may require exploring an optimal luteotropic state at pregnancy’s outset, necessitating the establishment of relevant markers. Trial registration number not applicable

P-642 The effect of oral dydrogesterone (DYD) on the hypothalamic-pituitary-ovarian (HPO) axis (gonadotropin and sex-steroid levels) and ovulation inhibition: a double-blind, phase I, randomized-controlled, parallel-group trial

Abstract Study question What is the effect of oral dydrogesterone (three cycles daily 20mg/30mg) on pituitary, ovarian and adrenal hormones, ovulation inhibition and endometrium in healthy ovulatory women? Summary answer Daily oral dydrogesterone, 20mg or 30mg, suppresses LH and inhibits ovulation in 33% and 73% of subjects, respectively, while not reducing E2 and other hormones. What is known already Dydrogesterone, a stereoisomer of progesterone, has high oral bioavailability and has demonstrated clinical utility in several indications, including endometriosis and assisted reproduction technologies. Progestin primed ovarian stimulation (PPOS) provides a cost effective and convenient alternative to the GnRH antagonist protocol to suppress a premature LH surge during ovarian stimulation in preparation for frozen embryo transfer IVF. In PPOS, studies have shown that dydrogesterone provides a comparable number of mature oocytes as a standard GnRH antagonist. The effects of various formulations and routes of administration of different progestins on sex hormones and the HPO has not been determined across the indications. Study design, size, duration A single-centre, double-blind, randomised, multiple-dose, parallel-group study of two doses of oral dydrogesterone over three 28-day treatment cycles: dydrogesterone 30mg, 10mg in the morning, afternoon and evening; dydrogesterone 20mg, afternoon dose replaced with placebo. The primary efficacy outcome was the number of subjects with “no ovulation at all” (Hoogland and Skouby score [HSS] 1-4) or “ovulation without pregnancy risk” (HSS 5-6 with negative Landgren criterion) recorded in all treatment cycles. Participants/materials, setting, methods The study population was 44 healthy, pre-menopausal women aged 18–35 years, with proven pre-treatment ovulation. The inclusion/exclusion criteria were defined to reflect the intended target population and the general contraindications for hormonal preparations. The primary objective was to compare the effect of the two self-administered doses of dydrogesterone on ovarian follicular growth leading to ovulation and E2 suppression. Secondary objectives included effect on other HPO hormones, the endometrium, PK characteristics and safety. Main results and the role of chance The number of responders to ovulation inhibition was dose-dependent: DYD 30mg, 72.7%, 95% CI: 49.78–89.27%; DYD 20mg, 33.3%, 95% CI: 14.59–56.97%. Based on HSS and Landgren criteria, there was 42.4% and 15.15% ovulation with pregnancy risk with the 20mg and 30mg doses, respectively. Neither dose had any clinically relevant influence on the average E2 concentration or FSH, androstenedione, dehydroepiandrosterone sulphate, testosterone and sex hormone binding globulin levels, while both doses suppressed the pre-ovulatory LH surge. Endometrial proliferation was mildly suppressed to a comparable extent with both daily doses. Hyperechogenic endometrium pattern was observed in 50% and 72% of treatment cycles in ovulating women in the 20mg and 30mg groups, respectively. Treatment with DYD did not significantly delay follicular growth or postpone ovulation in ovulating women. The more pronounced progesterone suppression with the higher 30mg dose may be due to the higher number of subjects without ovulation and thus without a post-ovulatory progesterone rise in that group. Return of ovulation after treatment cessation occurred in 91% women in the 42-day post-treatment period. The most frequently reported TEAE was ‘ovarian cyst’; all cases were of mild intensity and resolved at the end of the trial. No severe TEAE was reported. Limitations, reasons for caution Only two doses were studied in healthy, ovulatory women. DYD is used in various clinical contexts with concomitant other medications, such as gonadotropins for ovarian stimulation, or under luteotropic circumstances with human chorionic gonadotropin activity from exogenous or endogenous sources. Only limited morning PK sampling was performed. Wider implications of the findings Oral dydrogesterone used for endometriosis symptom reduction may be associated with a low risk of long-term adverse events from hypoestrogenism and suppression of androgens. Oral dydrogesterone displays relevant and short-term effects on LH levels, supporting its use in PPOS protocols. At therapeutic doses, dydrogesterone does not completely inhibit ovulation. Trial registration number EudraCT-No.: 2021-004747-24

P-585 Vaginal progesterone associated with oral dydrogesterone versus vaginal progesterone for luteal support in letrozole-hcg cycles for thawed embryo transfer: a non-inferiority prospective cohort study

Abstract Study question Does micronized vaginal progesterone (MVP) associated with oral dydrogesterone (DYG) an alternative for luteal support in Letrozole-hcg cycles for thawed embryo transfer? Summary answer The association of MVP and DYG is a non-inferior alternative to only MVP for luteal support in thawed embryo transfer in Letrozole-hcg cycles. What is known already Endometrial preparation is essential for thawed embryo transfer. Several protocols involving different luteal support with progesterones are available. Moreover, the presence of corpus luteum decreases the obstetrical morbidity mainly linked to hypertensive disorders. Letrozole-hcg administration is a good alternative for frozen embryo transfer (FET). However, the literature lacks information about the comparison among the different protocols for luteal support in Letrozole-hcg cycles. Dydrogesterone is an oral progesterone with some unique characteristics which could be utilized with some advantage for luteal support, including oral administration and some immunological activity. Study design, size, duration This is a prospective non-inferiority cohort study performed at an infertility clinic including patients performing the first FET cycle during 2023. Reproductive outcomes were compared between patients receiving 600 mg (3x200 mg) of MPV or 40 mg of DYG plus 400 mg of MVP after Letrozole-hcg administration. Participants/materials, setting, methods All patients (aged 23-39 years) undergoing their first FET cycle during 2023 were included in this study (n = 169), divided into two groups: MVP+DYG (n = 54) or MVP (n = 115) for luteal support after Letrozole-hcg. Letrozole was administered for 5 days (2,5 mg/bid) and hcg was done when a dominant follicle reached 18 mm with a follicular endometrium measuring at least 7 mm. Main results and the role of chance Both groups were equivalent in terms of age, infertility aetiology, BMI and AMH (P > 0.05). Moreover, the proportion of cleavage or blastocyst stage was also similar between both groups (57% blastocyst transfer for MVP+DYG and 50% blastocyst transfer for MVP group, P > 0.05). The number of transferred embryos was (mean ±SD) 1.6±0.5 for both groups, P > 0.05. Furthermore, the number of top-quality embryos (cleavage stage or blastocyst) was also similar, P > 0.05. Moreover, clinical pregnancy (> 12 weeks) was 42% in MVP+DYG group versus 31% in the MVP group (-0.22-1.27, P = 0.156) and the early pregnancy loss per positive hcg test did not differ (18% for MVP+DGY and 22% for MVP, P = 0.687). In addition, we performed a multivariable analysis controlling possible confounders for clinical pregnancy: BMI, age, AMH, embryo quality, infertility aetiology and embryo stage during the transfer, and only age (0.86; 95%CI -0.229 to -0.064, P = 0.001) was related to clinical pregnancy. Limitations, reasons for caution The main limitation is the cohort design of our study, with an inherent risk of bias (selection bias). Moreover, we calculated this study to achieve the power for a non-inferiority comparison, not superiority comparison. Wider implications of the findings This is the first study comparing MVP+DYG to only MVP in patients submitted to FET using the Letrozole-hcg protocol. We demonstrated in this non-inferiority study the usefulness of adding DYG. Moreover, our results were promising showing a trend towards better pregnancy rates after MVP+DYG. Trial registration number not applicable

O-205 Dydrogesterone versus micronized vaginal progesterone for luteal phase support in hormone replacement therapy frozen embryo transfer cycles (REMODEL): an exploratory randomized controlled trial

Abstract Study question Is dydrogesterone (DYD) comparable to micronized vaginal progesterone (MVP) for luteal phase support (LPS) in hormone replacement therapy frozen embryo transfer (HRT-FET) cycles? Summary answer Ongoing pregnancy rates (OPR) at 12 weeks’ gestation were comparable between the study group using DYD and the control group using MVP. What is known already Thanks to vitrification, the number of frozen embryo transfer cycles has significantly increased, prompting for a thorough optimization. Few studies have prospectively compared different progesterone regimens in artificial frozen embryo transfer cycles. Currently, MVP is most commonly used for LPS in this setting, but side effects such as vaginal discharge cannot be neglected. Dydrogesterone, a selective progesterone receptor agonist with a high oral bioavailability, could be considered due to its more patient-friendly administration. Two randomized controlled trials confirmed the non-inferiority of dydrogesterone to MVP for LPS in fresh cycles, but robust data on its use in HRT-FET cycles remain limited. Study design, size, duration An exploratory randomized controlled trial was conducted at a university hospital from October 2021 to September 2023. Subjects were randomly allocated 1:1 to the study group using DYD (10mg three times daily) for LPS or the control group using MVP (2x200mg twice daily), all performing FET in a HRT cycle. The primary outcome was ongoing pregnancy rate at 12 weeks (OPR). Secondary objectives included biochemical pregnancy loss, early pregnancy loss (EPL) and live birth rate. Participants/materials, setting, methods Patients under 41 years of age with a normal BMI undergoing a single blastocyst transfer in a HRT-FET cycle without endometrial abnormalities were eligible for inclusion. Patients who required more than 14 days of estradiol valerate priming (2mg three times daily) to achieve an endometrial thickness of at least 7 mm were not included. Of the 170 patients screened, 19 did not meet the randomization criteria and 3 withdrew after randomization. Main results and the role of chance Demographic characteristics such as age, BMI, cause of infertility and regular cycle were comparable between the study and control groups, as were the frozen transfer cycle characteristics. With three drop-outs after randomization, both a per-protocol (PP) and an intention-to-treat (ITT) analysis were performed for the primary outcome. According to the PP analysis, the OPR was 31.5% in the study group and 45.3% in the control group (p = 0.08, difference in proportions (%) -14, 95% CI: -39-11). The ITT analysis showed similar results (OPR 31.1% versus 44.2% in the study and control groups, respectively, p = 0.10). Multivariate regression adjusting for age, BMI, endometrial thickness and parity showed no significant association between the type of LPS administered and OPR (OR 1.92, 95% CI 0.95-3.86, p = 0.07). Positive hCG rates were comparable between both groups (58.9% versus 61.3% in the study and control groups, p = 0.76). Differences in biochemical pregnancy loss (14.0% versus 2.2% in the study and control groups, respectively, p = 0.05) and EPL (32.6% versus 23.9% in the study and control groups, respectively, p = 0.37) did not reach statistical significance. The live birth rate did not differ significantly between the two groups (26.8% versus 41.9%, p = 0.06), but the delivery outcome of 3 patients is missing to date. Limitations, reasons for caution Despite the randomized nature of the study, the exploratory design warrants cautious interpretation of the results due to the primary outcome’s insufficient statistical power. The dosages of the LPS medication used are based on common clinical practice, but due to the absence of dose-finding studies, this may impact the results. Wider implications of the findings The results, although not statistically significant, may raise clinical implications and call for larger studies. A forthcoming analysis will assess progesterone levels throughout the cycle in these study patients, examining their impact on pregnancy outcomes. Given differences in pharmacological profiles, various dosages may also be explored. Trial registration number NCT04758871

Vaginal micronized progesterone on preventing luteinizing hormone untimely surge in ART cycles: A prospective proof-of-concept study.

A new approach to evaluate whether Progestin-Primed Ovarian Stimulation with micronized vaginal progesterone was as effective as using dydrogesterone in suppress LH pulse surge in young women under stimulation in an oocyte donor programme. This prospective study included 21 patients aged 19 to 32 years-old stimulated with Elonva® 150, associated or not with Menopur® or Merional® (75 or 150IU) since the beginning of the cycle, plus HMG 150-225IU after the 8th day or just HMG 150-300IU per day. Patients were placed in a PPOS protocol with micronized vaginal progesterone (MVP) 200 mg (Gynpro® Exeltis or Junno Farmoquimica) every 12 hours or dydrogesterone (Duphaston® Abbott) 10 mg every 8 hours from the start of stimulation until the day after the GnRH trigger with Triptorelin 0.2 mg (Gonapeptyl daily®). The primary endpoint was the prevention of untimely LH surge, and secondarily the number of 16 mm follicles, retrieved oocytes and metafase II. Fourteen oocyte donor patients were prescribed MVP while seven others received dydrogesterone (DYG).The gonadotropin protocols included 04 with Corifollitropin alfa 150 plus HMG since the beginning and complemented after the 7th day, and 17 times of just HMG. There was no diferences in the number of follicles >10≤15mm, ≥16mm or number of metafase II oocytes. There was no untimely LH surge on both groups and no OHSS was developed after the agonist trigger. Progestin-Primed Ovarian Stimulation with micronized vaginal progesterone seems to be a compelling choice for preventing premature ovulation without compromising oocyte quality in women undergoing ovarian stimulation.

Impact of dydrogesterone use in cycles with low progesterone levels on the day of frozen embryo transfer.

This study aims to evaluate whether the clinical outcomes of cycles with frozen embryo transfer (FET) in hormonal replacement treatment supplemented with dydrogesterone (DYD) following detection of low circulating levels of progesterone (P4) were comparable to the results of cycles with otherwise normal serum P4 values. Extended analyses of a retrospective cohort that included FET cycles performed between July 2019 and March 2022 after a cycle of artificial endometrial preparation using valerate-estradiol and micronized vaginal P4 (400mg twice daily). Whenever the serum P4 value was considered low on the morning of the planned transfer, 10mg of DYD three times a day was added as a supplement. Only single-embryo transfers of a blastocyst were considered. The primary endpoint was live birth rate. Five-hundred thirty-five FET cycles were analyzed, of which 136 (25.4%) underwent treatment with DYD. There were 337 pregnancies (63%), 207 live births (38.6%), and 130 miscarriages (38.5%). The P4 values could be modeled by a gamma distribution, with a mean of 14.5ng/ml and a standard deviation of 1.95ng/ml. The variables female age on the day of FET, ethnicity, and weight were associated with a variation in the serum P4 values. There were no differences in the results between cycles with or without the indication for DYD supplementation. Live birth rate did not vary significantly in females with low and normal serum P4 levels on the day of FET when DYD was used as rescue therapy.

The combination of dydrogesterone and micronized vaginal progesterone can render serum progesterone level measurements on the day of embryo transfer and rescue attempts unnecessary in an HRT FET cycle.

To evaluate the role of serum progesterone (P4) on the day of embryo transfer (ET) when dydrogesterone (DYD) and micronized vaginal progesterone (MVP) are combined as luteal phase support (LPS) in a hormone replacement therapy (HRT) frozen ET (FET) cycles. Retrospective study, including single euploid HRT FET cycles with DYD and MVP as LPS and P4 measurement on ET day. Initially, patients with P4 levels < 10 ng/ml increased MVP to 400 mg/day; this "rescue" was abandoned later. 560 cycles of 507 couples were included. In 275 women, serum P4 level was < 10 ng/ml on the ET day. Among those with low P4 levels, MVP dose remained unchanged in 65 women (11.6%) and was increased in 210 women (37.5%). Women with P4 levels ≥ 10 ng/ml continued LPS without modification. Overall pregnancy rates in these groups were 61.5% (40/65), 54.8% (115/210), and 48.4% (138/285), respectively (p = n.s.). Association of serum P4 levels with ongoing pregnancy rates was analyzed in women without any additional MVP regardless of serum P4 levels (n = 350); multivariable analysis (adjusted for age, BMI, embryo quality (EQ)) did not show a significant association of serum P4 levels with OPR (OR 0.96, 95% CI 0.90-1.02; p = 0.185). Using inverse probability treatment weights, regression analysis in the weighted sample showed no significant association between P4 treatment groups and OP. Compared to fair EQ, the transfer of good EQ increased (OR 1.61, 95% CI 1.22-2.15; p = 0.001) and the transfer of a poor EQ decreased the odds of OP (OR 0.73, 95% CI 0.55-0.97; p = 0.029). In HRT FET cycle, using LPS with 300 mg/day MVP and 30 mg/day DYD, it appears that serum P4 measurement and increase of MVP in patients with P4 < 10 ng/ml are not necessary.

The Mechanism of Bushen Zhuyun Prescription in Regulating Luteal Phase Deficiency via Intervention of the Kiss1/GPR54 System in the Hypothalamus

Luteal phase deficiency (LPD) is a significant contributor to infertility and miscarriage. Bushen Zhuyun Prescription (BSZY) is a traditional Chinese medicine formula that has potential to treat LPD. To investigate the effect of BSZY in treating LPD, SD rats with complete estrous cycles were divided into blank, model, dydrogesterone (DYD), high-dose BSZY (BSZY-HD), and low-dose BSZY (BSZY-LD) groups. All the groups were received mifepristone gavage except for the blank group. The pathological changes were observed in the hypothalamus, and the analysis of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), progesterone (P), gonadotropin-releasing hormone (GnRH), and cyclic adenosine monophosphate (cAMP) levels in serum. Additionally, the mRNA and their protein expression levels of estrogen receptor α (ERα), ERβ, G protein-coupled receptor 30 (GPR30), kisspeptin 1 (Kiss1), and GPR54 were assessed; and the key molecules expression in cAMP/protein kinase A (PKA) pathway were analyzed. The results revealed that mifepristone treatment caused a decrease in FSH and cAMP levels and an increase in E2 and LH levels, which were normalised in the BSZY treatment groups. The expression of ERα and ERβ mRNA and protein in the hypothalamus was higher in the BSZY groups compared to the blank group. BSZY also resulted in increased expression of Kiss-1, GPR54, and PKA, as well as decreased expression of cAMP-response element binding protein (CREB), c-Fos, phospho-CREB (p-CREB), and p-c-Fos, compared to model group. No significant difference observed in GPR30 expression between the mifepristone and BSZY groups. The mRNA and protein of Kiss1 and GPR54 were decreased in model group and increased after BSZY treatment, while the mRNA and protein expression of PKA, CREB, c-Fos, p-CREB, and p-c-Fos were also decreased significantly. In conclusion, the findings demonstrate that BSZY could effectively regulate hypothalamic ER, interfere with the Kiss1/GPR54 signal transduction system, activate the cAMP/PKA pathway, and regulate key transduction molecules expression of PKA, CREB, c-Fos, there by effecting the level of reproductive hormones and has the potential to treat LPD-related infertility.

Comparison of the effects and safety of dydrogesterone and medroxyprogesterone acetate on endometrial hyperplasia without atypia: a randomized controlled non-inferior phase Ⅲ clinical study

Objective: To compare the effects and safety of dydrogesterone (DG) and medroxyprogesterone acetate (MPA) on the treatment in patients with endometrial hyperplasia without atypia (EH). Methods: This was a single-center, open-label, prospective non-inferior randomized controlled phase Ⅲ trial. From February 2019 to November 2021, patients with EH admitted to the Obstetrics and Gynecology Hospital of Fudan University were recruited. Enrolled patients were stratified according to the pathological types of simple hyperplasia (SH) or complex hyperplasia (CH), and were randomised to receive MPA or DG. Untill May 14, 2022, the median follow-up time after complete response (CR) was 9.3 months (1.1-17.2 months). The primary endpoint was the 6-month CR rate (6m-CR rate). The secondary endpoints included the 3-month CR rate (3m-CR rate), adverse events rate, recurrence rate, and pregnancy rate in one year after CR. Results: (1) A total of 292 patients with EH were enrolled in the study with the median age of 39 years (31-45 years). A total of 135 SH patients were randomly assigned to MPA group (n=67) and DG group (n=68), and 157 CH patients were randomly assigned to MPA group (n=79) and DG group (n=78). (2) Among 292 patients, 205 patients enrolled into the primary endpoint analysis, including 92 SH patients and 113 CH patients, with 100 patients in MPA group and 105 in DG group, respectively. The 6m-CR rate of MPA group and DG group were 90.0% (90/100) and 88.6% (93/105) respectively, and there were no statistical significance (χ2=0.11, P=0.741), with the rate difference (RD) was -1.4% (95%CI:-9.9%-7.0%). Stratified by the pathology types, the 6m-CR rate of SH patients was 93.5% (86/92), and MPA group and DG group were respectively 91.1% (41/45) and 95.7% (45/47); and the 6m-CR rate of CH patients was 85.8% (97/113), and MPA group and DG group were 89.1% (49/55) and 82.8% (48/58) respectively. The 6m-CR rates of the two treatments had no statistical significance either (all P>0.05). A total of 194 EH patients enrolled into the secondary endpoint analysis, including 88 SH patients and 106 CH patients, and 96 patients in MPA group and 98 in DG group, respectively. The 3m-CR rate of SH patients were 87.5% (77/88), while the 3m-CR rates of MPA group and DG group were 90.7% (39/43) and 84.4% (38/45), respectively; the 3m-CR rate of CH patients was 66.0% (70/106), and MPA group and DG group had the same 3m-CR rate of 66.0% (35/53). No statistical significance was found between the two treatments both in SH and CH patients (all P>0.05). (3) The incidence of adverse events between MPA group and DG group had no statistical significance (P>0.05). (4) A total of 93 SH patients achieved CR, and the cumulative recurrence rate in one year after CR were 5.9% and 0 in MPA group and DG group, respectively. While 112 CH patients achieved CR, and the cumulative recurrence rate in one year after CR were 8.8% and 6.5% in MPA group and DG group, respectively. There were no statistical significance between two treatment groups (all P>0.05). Among the 93 SH patients, 10 patients had family planning but no pregnancy happened during the follow-up period. Among the 112 CH patients, 21 were actively preparing for pregnancy, and the pregnancy rate and live-birth rate in one year after CR in MPA group were 7/9 and 2/7, while in DG group were respectively 4/12 and 2/4, and there were no statistical significance in pregnancy rate and live-birth rate between the two treatment groups (all P>0.05). Conclusions: Compared with MPA, DG is of good efficacy and safety in treating EH. DG is a favorable alternative treatment for EH patients.

Efficacy of Oral Medications or Intrauterine Device-Delivered Progestin in Patients with Endometrial Hyperplasia with or without Atypia: A Network Meta-Analysis.

The aim of this systematic review was to evaluate the efficacy of oral medication or intrauterine device-delivered progestins in patients with endometrial hyperplasia (EH) with or without atypia. We systematically examined PubMed, EMBASE, the Cochrane Library, and clinicaltrials.gov to identify studies reporting the regression rate of patients with EH who received progestins or non-progestins. The regression rates after different treatments were compared using a network meta-analysis in terms of the relative ratios (RRs) and 95% confidence intervals (CIs). Begg-Mazumdar rank correlation and funnel plots were performed to evaluate the publication bias. Five non-randomized studies and 21 randomized controlled trials involving 2268 patients were included in the network meta-analysis. The levonorgestrel-releasing intrauterine system (LNG-IUS) was associated with a higher regression rate than medroxyprogesterone acetate (MPA) (RR 1.30, 95% CI 1.16-1.46) in patients with EH. Among those without atypia, the LNG-IUS was associated with a higher regression rate than any of the three types of oral medications (MPA, norethisterone, or dydrogesterone (DGT)) (RR 1.35, 95% CI 1.18-1.55). According to the network meta-analysis, combining the LNG-IUS with MPA or metformin increased regression rate, while DGT was associated with the highest regression rate among all oral medications. The LNG-IUS may be the best choice for patients with EH, and combining it with MPA or metformin may further improve its efficacy. DGT may be the preferred choice for patients who are unwilling to use the LNG-IUS or who cannot tolerate its side effects.

Formulation and characterization of thiolated chitosan/polyvinyl acetate based microneedle patch for transdermal delivery of dydrogesterone

Microneedle patches are promising transdermal drug delivery platforms with minimal invasiveness in a painless manner. Microneedle patch could be a promising alternate route for delivery of drugs having poor solubility and low bioavailability. This research work therefore, aimed to develop and characterize microneedle patch of thiolated chitosan (TCS) and polyvinyl acetate (PVA) for the systemic delivery of dydrogesterone (DYD). TCS-PVA-based microneedle patch was fabricated with 225 needles having a length of 575 µm with the sharp pointed end. Different ratios of TCS-PVA-based patch were employed to investigate the effects of mechanical tensile strength and percentage elongation. The scanning electron microscopy (SEM) revealed intact sharp-pointed needles. In vitro dissolution studies of microneedle patch (MN-P) were carried out by modified Franz-diffusion cell revealing the sustained release of DYD 81.45 ± 2.768 % at 48 hrs as compared to pure drug that showed 96.7 ± 1.75 % at 12 hrs. The transport of DYD (81%) across skin reaching the systemic circulation was evaluated through ex vivo permeation studies of MN-P. The skin penetration study through the parafilm M method showed good penetration with no deformation and breakage of needles along with no visible signs of skin irritation. Histological study of mice skins clearly showed the deeper penetration of needles into the skin. In summary, as-prepared MN-P show potential in developing an effective transdermal delivery system for DYD.

The Addition of Dydrogesterone after Frozen Embryo Transfer in Hormonal Substituted Cycles with Low Progesterone Levels.

To determine whether a rescue strategy using dydrogesterone (DYD) could improve the outcomes of frozen embryo transfer cycles (FET) with low progesterone (P4) levels on the day of a blastocyst transfer. Retrospective cohort study including FET cycles performed between July 2019 and October 2020 following an artificial endometrial preparation cycle using estradiol valerate and micronized vaginal P4 (400 mg twice daily). Whenever the serum P4 value was below 10 ng/mL on the morning of the planned transfer, DYD 10 mg three times a day was added as supplementation. The primary endpoint was ongoing pregnancy beyond 10 weeks. The sample was subdivided into two groups according to serum P4 on the day of FET: low (< 10 ng/mL, with DYD supplementation) or normal (above 10 ng/mL). We performed linear or logistic generalized estimating equations (GEE), as appropriate. We analyzed 304 FET cycles from 241 couples, 11.8% (n = 36) of which had serum P4 below 10 ng/mL on the FET day. Baseline clinical data of patients was comparable between the study groups.Overall, 191 cycles (62.8%) had a biochemical pregnancy, of which 131 (44,1%) were ongoing pregnancies, with a 29,8% miscarriage rate. We found no statistically significant differences in the hCG positive (63 vs 64%) or ongoing pregnancy rates (50 vs 43,3%) between those FETs with low or normal serum P4 values, even after multivariable logistic regression modelling. Our results indicate that DYD 10 mg three times a day administered in women who perform FET with P4 serum levels < 10 ng/mL, allows this group to have pregnancy rates beyond 12 weeks at least as good as those with serum levels above 10 ng/mL.

Oral, vaginal or intramuscular progesterone in programmed frozen embryo transfer cycles: a pilot randomized controlled trial

Research questionWhat should be the optimal route of luteal support in programmed frozen embryo transfer (FET) cycles? DesignThis was a randomized, parallel, phase IV pilot trial with three groups of women undergoing FET along with hormone replacement therapy for endometrial preparation at a tertiary private IVF centre (NCT03948022). Women with at least one autologous cryopreserved blastocyst were included. After preparing the endometrium with oestradiol, 151 women were randomly assigned to one of the following three progesterone arms before embryo transfer: oral (10 mg) dydrogesterone (DYD), total daily dose 40 mg (n = 52); 8% (90 mg) progesterone vaginal gel (VAG), total daily dose 180 mg (n = 55); or intramuscular progesterone (IMP) 50 mg/ml in oil, total daily dose 100 mg (n = 44). One or two vitrified-warmed blastocysts were transferred after 5 days’ progesterone support. ResultsBaseline demographic features and embryological data were comparable among the groups. Ongoing pregnancy rates (40.4%, 38.2% and 45.5% in the DYD, VAG and IMP arms; P = 0.76) and live birth rates (40.4%, 38.2% and 43.2% in the DYD, VAG and IMP arms, P = 0.61) were statistically similar. Biochemical pregnancy rates and clinical miscarriage rates were also statistically similar among the groups. Significantly more patients with at least one side effect and moderate-to-severe side effects were documented in the IMP arm than the other groups (P < 0.001). ConclusionsTreatment with 40 mg/day oral DYD, 180 mg/day progesterone VAG gel or 100 mg/day IMP revealed similar reproductive outcomes in programmed FET cycles. Side effects were significantly more frequent in the IMP arm.

P-661 dydrogesterone as an alternative to supress LH surge in single stimulus protocols with follitropin delta

Abstract Study question Is oral dydrogesterone (DYG) 30 mg daily efficient on prevention of premature luteinizing hormone (LH) surge in ART cycles? Summary answer Oral dydrogesterone demonstrated to be as safe and effective as GnRH-ant in IVF/ICSI cycles intended to freeze-all / PGT-A, oocyte preservation and embryo banking programs What is known already The use of progesterone (PG) to inhibit pituitary LH surge during ovarian stimulation have been described over the last decades. Due to its harmful effect on the endometrium, PG suppression is mainly reserved for freeze-all cycles. Dydrogesterone (DYG), a known and safe synthetic progesterone, has been tested for this purpose based on the concept of its more selective PG receptors activity, which could reduce the inconveniences of side effects with less relevant androgenic, estrogenic, glyco or mineralocorticoid activity. Accordind to some recent work, DYG would be an effective tool both in cycles intended to freeze-all or in oocyte preservation strategies. Study design, size, duration Observational, comparative single center study, comparing the effect of DYG and gonadotropin releasing hormone (GnRH) antagonists on prevention of premature luteinizing hormone (LH) surge as well as to evaluate the number of metaphase II oocytes. From January 2019 to January 2020, 143 no age restrictions patients underwent both IVF/ICSI or oocyte preservation, all of them receiving the same single stimulus protocol with follitropin delta (Rekovelle). Participants/materials, setting, methods 92 IVF/ICSI plus 51 oocyte cryopreservation cycles underwent deltafollitropin (Rekovelle®, Ferring Pharmaceuticals) in a fixed daily and individualized SC-dose. Clinical decision led to a GnRH-antagonist (CTA-Cetrorelix acetate, Cetrotide®, Merck) 0,25 mg/d initiated in a flexible schedule in presence of one follicle ≥14 mm and continued throughout the stimulation period (48 cycles) or dydrogesterone (DYG), 10mg 8/8 hours (Duphaston®, Abbott) combined to gonadotrophin from the beginning of stimulation until the day after the trigger (95 cycles). Main results and the role of chance DYG-group had a mean age significantly higher (37.8 x 35.8-p 0.002) but there were no differences in mean parameters of BMI (24.08 x 24.81), days of stimulation (9.95 x 10.08), AMH (2.30 x 2.52), AFC (14.6 x 16.2). In the same way, no differences were observed between follicles 15 mm to 18 mm (3.06 x 3.68) and ≥ 18 mm (4.56 x 3.9), with a tendency for a greater number of larger follicles in the DYG-group. Metaphase II oocytes (7.48 x 7.33) was similar in both groups. One patient from each group experienced a premature LH surge (3.54 x 3.06) and one case in the DYG-group had no oocyte in a single 20mm aspirated follicle. There happened no cancelling. No patients experienced moderate to severe ovarian hyper stimulation syndrome, even when AMH&amp;gt;3 ng/mL. Cancelling criteria: no follicles with a diameter 17 mm by day 15. Oocyte retrieval took place 36 hours after trigging. Primary outcome was the incidence of premature LH surge. Secondary outcomes included follicles ≥ 15 mm and &amp;lt; 18 mm and ≥ 18 mm on hCG day, metaphase II oocytes, number of cancelled cycles and OHSS symptoms. Statistics were performed by Mann-Whitney test. Limitations, reasons for caution The main limitation point is the small number of patients. Despite having relative experience with the use of DYG, in this work we limited the sample to consider only one type of stimulus protocol, making the groups more homogeneous for the analysis. Wider implications of the findings Dydrogesterone is as effective as GnRH-ant in reducing premature LH surge. It can be considered for IVF/ICSI cycles intended to freeze-all / PGT-A, oocyte preservation and for embryo banking strategies, representing lower costs in these cases. Trial registration number not applicable

P-615 Lack of analytical interference of dydrogesterone in progesterone immuno-assays: a multi-laboratory spike and recovery study of widespread used assays

Abstract Study question Does dydrogesterone (DYD) and its active metabolite 20-α-dihydrodydrogesterone (DHD) interfere with routinely used progesterone assays? Summary answer This multi-laboratory spike-and-recovery study does not indicate any relevant interference of DYD/DHD within routinely used progesterone assays. What is known already Progesterone (P4), a sex steroid, is measured in serum or plasma by competitive immunoassay or Liquid Chromatography mass spectrometry (LC-MS) in a variety of clinical contexts. One potential limitation of steroid hormone immunoassays is interference caused by compounds with structural similarity to the target steroid of the assay. Dydrogesterone, an orally active close stereoisomer of progesterone, is used for various indications in women’s health, including luteal phase support. To date, the potential interference of DYD/DHD with P4 immunoassays has not systematically been studied. Study design, size, duration The present systematic in-vitro study investigated potential interferences of DYD/DHD in seven widely used, commercially available P4 immunoassays and a LC-MS method over a range of concentrations of DYD/DHD and P4. The study was performed in collaboration with participants in the endocrine section of the Dutch foundation for quality assessments in medical laboratories. For each assay method, each laboratory received a set of nine blinded human plasma samples (containing different P4 and/or DYD/DHD concentrations). Participants/materials, setting, methods Routine human plasma samples were anonymized and pooled to create three graded concentration levels of progesterone (P4 high, P4 medium, P4 low). Each pooled P4 plasma sample (6-7 ml) was spiked at high, medium and “none” DYD/DHD concentration and was divided into 0.5 ml aliquots. The blinded aliquots were analyzed by seven different laboratories with their routine progesterone assay (six different immunoassays and LC-MS assay, respectively). Main results and the role of chance High, medium, and low P4 samples had concentrations of approximately 60 nmol/l progesterone, 20 nmol/l progesterone and &amp;lt;10 nmol/l (male plasma), respectively. The immuno- assays tested were Immulite 200XPI (Siemens Healthineers), Advia Centaur (Siemens Healthineers), Atellica (Siemens Healthineers), Architect I2000 (Abbott Diagnostics), Cobas 8000 (Roche Diagnostics), UniCel DxI 800 (Beckman-Coulter) and LC-MS (Agilent). The sample recovery rate (P4 result obtained by the assays tested for sample spiked with DYD/DHD, divided by the result obtained for the corresponding sample with no DYD/DHD x 100) was within a +/-10% window for the medium P4 and high P4 concentrations, but more variable for the low P4 samples. The latter is, however, attributable to high inter- and intra-method variability, especially at low P4 concentrations. The P4 plasma concentrations generally showed considerable inter-assay variability at each concentration level, with Immunlite 2000 at the lower end and Cobas 8000/801 and Dxi at the higher end of the reported results for the High and Medium P4 samples as compared to LC-MS. The study confirms the inherent method variability of P4 immunoassays casting doubts on the clinical use of P4 cut-offs to guide clinical management, especially at low concentrations. Limitations, reasons for caution Only one sample per concentration level was provided to the laboratories which didn't allow for a systematic quantification of intra-method variability. The concentrations of DYD/DHD haven't been verified by means of a validated bioanalytical method. Measurement of DYD and DHD is to date only feasible by a highly-selective LC-MS method. Wider implications of the findings The present study is strongly indicative that relevant interference of DYD/DHD does not exist. This finding implies that a clinician can reliably distinguish P4 concentrations from DYD/DHD concentrations in a blood sample within a routine care-setting. Trial registration number not applicable

Lack of analytical interference of dydrogesterone in progesterone immunoassays

Progesterone, a sex steroid, is measured in serum by immunoassay in a variety of clinical contexts. One potential limitation of steroid hormone immunoassays is interference caused by compounds with structural similarity to the target steroid of the assay. Dydrogesterone (DYD), an orally active stereoisomer of progesterone, is used for various indications in women's health. Herein, we report a systematic in vitro investigation of potential interference of DYD and its active metabolite 20α-dihydrodydrogesterone (DHD) in seven widely used, commercially available progesterone assays. Routine human plasma samples were anonymized and pooled to create three graded concentration levels of progesterone (P4 high, P4 medium, P4 low). Each pooled P4 plasma sample (6-7mL) was spiked at high, medium, and "none" concentration with DYD/DHD and was divided into 0.5mL aliquots. The blinded aliquots were analyzed by seven different laboratories with their routine progesterone assay (six different immunoassays and one liquid chromatography-tandem mass spectrometry assay, respectively) within the Dutch working group on endocrine laboratory diagnostics of the Dutch Foundation for Quality Assessments in Medical Laboratories. The sample recovery rate (P4 result obtained for sample spiked with DYD/DHD, divided by the result obtained for the corresponding sample with no DYD/DHD × 100) was within a ±10% window for the medium and high P4 concentrations, but more variable for the low P4 samples. The latter is, however, attributable to high inter- and intra-method variability at low P4 concentrations. This study does not indicate any relevant interference of DYD/DHD within routinely used progesterone assays.

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.

Addition of dydrogesterone to vaginal progesterone and transfer postponement improve outcomes in patients with low progesterone levels in hormonally substituted cycles for frozen-thawed embryo transfer

Purpose: Adding dydrogesterone (DYD) to vaginal micronized progesterone (VMP) and postponing embryo transfer in order to improve outcomes in patients with low progesterone (P) levels in hormonally substituted cycles prior to frozen/thawed embryo transfer (FET). Methods: Endometrial preparation comprised sequential administration of vaginal estradiol until endometrial thickness reached 7 mm, followed by transdermal estradiol combined with 800 mg/day VMP. Our previous analysis of serum P levels on FET day showed that the optimal P level was &gt; 11 ng/mL for live birth. Serum P was measured on day1 (D1) following exogenous VMP introduction in the evening. When P levels were &gt; 11 ng/mL, FET was performed “in phase” on day-2, day-3, or day-5 depending on embryo stage at cryopreservation (n = 139 cycles). When P levels were &lt; 11 ng/mL, DYD 10 mg three times a day orally, was added to VMP and FET was postponed by one day (n = 237 cycles, 63%). The primary endpoint was the comparison of live birth rates (LBR) between the two groups. Results: Mean serum P level on D1 was 10.2 + 3.7 ng/mL. Characteristics of patients in both groups were similar for age, body mass index, endometrial thickness prior to P introduction, quality of transferred embryos, and embryo transfer stage. Regarding the primary endpoint, LBR was similar between the VMP+DYD group and the VMP group (26.1% vs. 27.3%, NS). Conclusion: These results suggest that adding DYD to VMP and postponing the transfer in patients with low P levels in hormonally substituted FET cycles might optimize outcomes.