STUDY QUESTION Is there a serum progesterone (P) threshold on the day of embryo transfer (ET) in artificial endometrium preparation cycles below which the chances of ongoing pregnancy are reduced? SUMMARY ANSWER Serum P levels <8.8 ng/ml on the day of ET lower ongoing pregnancy rate (OPR) in both own or donated oocyte cycles. WHAT IS KNOWN ALREADY We previously found that serum P levels <9.2 ng/ml on the day of ET significantly decrease OPR in a sample of 211 oocyte donation recipients. Here, we assessed whether these results are applicable to all infertile patients under an artificial endometrial preparation cycle, regardless of the oocyte origin. STUDY DESIGN, SIZE, DURATION This prospective cohort study was performed between September 2017 and November 2018 and enrolled 1205 patients scheduled for ET after an artificial endometrial preparation cycle with estradiol valerate and micronized vaginal P (MVP, 400 mg twice daily). PARTICIPANTS/MATERIALS, SETTING, METHODS Patients ≤50 years old with a triple-layer endometrium ≥6.5 mm underwent transfer of one or two blastocysts. A total of 1150 patients treated with own oocytes without preimplantation genetic testing for aneuploidies (PGT-A) (n = 184), own oocytes with PGT-A (n = 308) or donated oocytes (n = 658) were analyzed. The primary endpoint was the OPR beyond pregnancy week 12 based on serum P levels measured immediately before ET. MAIN RESULTS AND THE ROLE OF CHANCE Women with serum P levels <8.8 ng/ml (30th percentile) had a significantly lower OPR (36.6% vs 54.4%) and live birth rate (35.5% vs 52.0%) than the rest of the patients. Multivariate logistic regression showed that serum P < 8.8 ng/ml was an independent factor influencing OPR in the overall population and in the three treatment groups. A significant negative correlation was observed between serum P levels and BMI, weight and time between the last P dose and blood tests and a positive correlation was found with age, height and number of days on HRT. Multivariate logistic regression showed that only body weight was an independent factor for presenting serum P levels <8.8 ng/ml. Obstetrical and perinatal outcomes did not differ in patients with ongoing pregnancy regardless of serum P levels being above/below 8.8 ng/ml. LIMITATIONS, REASONS FOR CAUTION Only women with MVP were included. Extrapolation to other P administration forms needs to be validated. WIDER IMPLICATIONS OF THE FINDINGS This study identified the threshold of serum P as 8.8 ng/ml on the day of ET for artificial endometrial preparation cycles necessary to optimize outcomes, in cycles with own or donated oocytes. One-third of patients receiving MVP show inadequate levels of serum P that, in turn, impact the success of the ART cycle. Monitoring P levels in the mid-luteal phase is recommended when using MVP to adjust the doses according to the needs of the patient. STUDY FUNDING/COMPETING INTEREST(S) None. TRIAL REGISTRATION NUMBER NCT03272412.
STUDY QUESTION Is there a relationship between serum and endometrial progesterone (P4) levels, including P4 and metabolites (oestrone, oestradiol and 17α-hydroxyprogesterone), and endometrial receptivity? SUMMARY ANSWER 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. WHAT IS KNOWN ALREADY 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. STUDY DESIGN, SIZE, DURATION 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). PARTICIPANTS/MATERIALS, SETTING, METHODS 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. MAIN RESULTS AND THE ROLE OF CHANCE 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. LIMITATIONS, REASONS FOR CAUTION 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. WIDER IMPLICATIONS OF THE FINDINGS 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. STUDY FUNDING/COMPETING INTEREST(S) 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. TRIAL REGISTRATION NUMBER NCT03456375.
Study question Is there an optimal serum progesterone (P) threshold in frozen embryo transfer (FET) modified natural cycles when luteal phase support (LPS) is given? Summary answer Serum P measured on the day of ET is not related with ongoing pregnancy outcome when doing a modified natural cycle with LPS. What is known already Recent publications showed that there is a minimum threshold of serum P that needs to be reached in artificial cycles to optimize pregnancy rates. When using micronized vaginal P (MVP), about 30% of patients show low levels of serum P (<9 ng/mL) leading to a significant decrease in ongoing pregnancy; although this situation can be reverted by increasing and modifying the route of exogenous P. In pure natural cycles without LPS, serum P below 10 ng/mL impairs pregnancy outcome. Nevertheless, there is no data about the impact of serum P levels in modified natural cycles in which LPS is given. Study design, size, duration Prospective cohort unicentric study performed in IVI RMA Valencia (Spain), including 244 cycles from February 2020 to January 2021. Participants/materials, setting, methods Infertile patients <50 y.o. and BMI<40Kg/m2 undergoing a FET of a maximum of 2 blastocysts, from own or donated oocytes. FET were performed in the context of a modified natural cycle (single injection of rec-hCG when dominant follicle reached 17mm and endometrial thickness >6.5mm). MVP was used for LPS (200mg/12h). Ongoing pregnancy rate (OPR) was correlated with serum P levels on the FET day, measured within two hours before transfer. Main results and the role of chance A total of 241 patients were analyzed. Mean age was 38.1 + 3.8 years, with a mean BMI of 23.3 + 3.9. On the rec-hCG day the mean leading follicle size was 17.7±0.1 mm. The endometrium displayed a trilaminar pattern, with a mean thickness of 7.8±3.3 mm, and mean P and estradiol (E2) levels were 0.30±0.03 ng/ml and 249.39±11.03 pg/ml, respectively. A mean of 1.1 blastocysts were transferred (90.9% were single embryo transfers), 27.4% (66) from donated and 72.6 % (175) from own oocytes. On the day of FET, the mean serum P and E2 levels were 26.19 + 8.97ng/mL and 154.12 + 96.08pg/mL, respectively. The overall OPR was 51.5% (124). OPR according to quartiles of serum P (ng/mL) was 56.7% (Q1, P < 20.2), 47.5% (Q2, P > 20.2-24.8), 51.7% (Q3, P > 24.8-31.1), 50.0% (Q4, P > 31.1), p = 0.78). Multivariate logistic regression showed that serum P was not related with OPR after adjusting for age, BMI, E2 and origin of oocytes (aOR:0.98, 95% CI:0.93-1.04, p = 0.47). Only 2 patients had serum P levels below 10 ng/mL, with values of 8.6 and 8.8 ng/mL on the ET day and had a negative pregnancy test. Limitations, reasons for caution As part of our routine clinical practice, MVP (200mg/12h) is given for LPS in patients undergoing a FET in the context of a modified natural cycle. Thus, these results cannot be extrapolated to LPS-free or any other LPS protocol in FET modified natural cycles. Wider implications of the findings The majority of patients undergoing FET in modified natural cycles when using LPS have adequate levels of serum P and thus, do not have an impact on pregnancy outcome. According to our data, there is no need to measure serum P levels on the luteal phase of modified natural cycles. Trial registration number NCT04259996
Anatomical and cyclical differences exist between the left (LO) and right ovary (RO). For example, the RO has more ''efficient'' vascularization as it drains directly into the inferior vena cava, whereas the LO first drains to the left renal vein. Differences in response between the LO and RO during controlled ovarian stimulation (COS) have been less well-studied. The goals of this study were to evaluate COS response according to ovarian laterality by assessing follicular count on the day of trigger and to determine patient-specific variables associated with laterality response.MATERIALS AND METHODS: This was a retrospective study of all patients who underwent COS resulting in egg retrieval between 10/2019 -9/ 2020 at an academic fertility center. The number of follicles >10mm on the day of trigger from the RO vs. LO were measured. Patient variables including AMH, BMI and age were collected. Cycles were stratified into 3 groups: equal follicular count documented on both sides (R¼L), more follicles documented on right (R>L), and more follicles documented on left (L>R). Patients with only a 1 or 2 follicular difference were excluded from the R>L and L
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