Abstract
Purpose
Does an association exist between serum progesterone and estradiol levels and live birth rates in artificial cycle frozen embryo transfer (AC-FET)?
Methods
Retrospective cohort study was based on prospectively collected data at a university-affiliated fertility center. Included were all cycles using an artificial endometrial preparation with estradiol hemihydrate (Estrofem, 2 mg/8 h) and vaginal progesterone (Endometrin 100 mg/8 h), autologous oocytes, and cleavage stage embryo transfers. Serum progesterone and estradiol levels were measured 14 days after FET. A total of 921 cycles in 568 patients from to December 2010 to June 2019 were investigated. Live birth was the primary outcome measure.
Results
Significant association was found between live birth and progesterone as well as estradiol levels (progesterone 14.65 vs 11.62 ng/ml, p = 0.001; estradiol 355.12 vs 287.67 pg/ml, p = 0.001). A significant difference in live birth rate was found below and above the median progesterone level (10.9 ng/ml, p = 0.007). Lower estradiol level was significantly associated with lower live birth rate (< 188.2 pg/ml 8.3%, > 263.1 pg/ml 16%, p = 0.02).
Conclusions
Serum progesterone and estradiol levels impact live birth rate in AC-FET.
Keywords: Artificial cycle frozen embryo transfer (AC-FET), Frozen embryo transfer (FET), Live birth rate, Progesterone, Estrogen/estradiol
Introduction
The use of frozen embryo transfer cycles (FET) has progressively increased, and its proportion in the USA has doubled from 16 in 2007 to 32.7% in 2016 [1]. Some even advocate freeze all as the preferred treatment protocol [2].
Embryo quality is a key factor affecting assisted reproductive technology (ART) outcome, but successful implantation requires not just good quality embryos but also a receptive endometrium and a synchronized dialogue between the two [3]. Endometrial receptivity is achieved after sequential actions of estrogen and progesterone, either naturally secreted by the ovary or exogenously supplied. Several methods of endometrium preparation for FET have been developed, and regarding live birth rate, none has proven superior to others, although stimulated cycles may improve clinical pregnancy rate [4].
A common and effective method for endometrial preparation prior to frozen embryo transfer is a sequential regimen with estrogen and progesterone, aiming to mimic the endocrine exposure of the endometrium in a natural cycle. It is usual to administer estrogen until sufficient endometrial thickness is reached and then to add progesterone for the number of days as determined by the stage of development of the embryo being transferred [5]. It is assumed that this regimen results in receptive endometrium; however, this may not always be true. Even when euploid embryos are transferred, many of the cycles do not result in successful pregnancy (71% pregnancy rates, 57% live birth rate) [6], which may result from inappropriate endometrial receptivity.
Different routes and doses of estrogen administration have been used in order to provide adequate endometrial preparation [4]. Estrogen biology is complex, with multiple factors impacting estradiol kinetics (e.g., genetic variation, exposure to estrogen-like chemicals), which might cause personal variations in the biological targets affected by the hormone [7].
Progesterone and progestins can be administered by intramuscular, vaginal, oral, and rectal routes and recently also subcutaneously [1, 8]. Different progesterone levels and endometrial effect might result from the diverse administration routes and preparations, drug interaction, hormonal milieu, compliance, and metabolism. Vaginal progesterone leads to lower serum progesterone levels [9]. Whether those levels are related to the treatment outcome is of clinical importance.
Recent findings suggested that there is a minimum threshold of serum P levels that needs to be reached in order to obtain the best pregnancy results, and not all patients achieve this optimal level [10].
The aim of the present study was to investigate the impact of serum progesterone and estradiol levels on reproductive outcomes in AC-FET using oral estrogen and vaginal progesterone.
Materials and methods
Retrospective cohort study based on prospectively collected data on AC-FET cycles was performed from December 2010 to June 2019. The study was approved by the hospital’s institutional review board.
All cycles of patients undergoing FET using autologous oocytes on the protocol detailed below were screened. Patients without hormonal tests results 14 days after the embryo transfer were excluded from the study.
The primary endpoint was live birth. The secondary endpoints were pregnancy and implantation rate (the number of gestational sacs observed divided by the number of embryos transferred).
Treatment protocol
Endometrial preparation started on days 1–3 of menstruation with oral administration of estradiol hemihydrate (Estrofem®, NOVO NORDISK A/S, DENMARK), 6 mg/day. After 8–10 days on estrogens, a vaginal 2D ultrasound was performed. Patients were considered ready for embryo transfer when endometrial thickness was ≥ 7 mm with triple layer pattern and ultrasound detected quiescent ovaries. If endometrium thickness was < 7 mm, estrogen therapy was prolonged and/or dose increased. At the time of ultrasound, if the endometrium is of a proliferative tri-phasic pattern and the ovaries are devoid of follicular or luteal cysts, progesterone is commenced, and embryo transfer is scheduled. P was administered 48–72 h before ET, corresponding with the age of the embryo (2–3 days). Progestogen supplementation was performed with vaginal tablets (ENDOMETRIN® Vaginal Insert, Ferring Pharmaceuticals Ltd, Israel) at a dose of 100 mg/8 h. Embryo transfer was performed under ultrasound guidance by one of 6 specialist physicians. No pretreatment (e.g., GnRH agonist, combined oral contraceptive) was used. Embryo scoring was performed on days 2 and 3 after OPU according to the scoring criteria of Alpha and ESHRE [11]; grade 1 embryos were considered of good quality. The freezing technique before 2017 was slow freeze. After 2019 the technique was vitrification. During the transition period between 2017 and 2019, some embryos underwent slow freeze, while others were frozen by vitrification.
Serum progesterone and estradiol levels were measured 14 days after FET using commercially available kits (ADVIA Centaur, Siemens). The ADVIA Centaur Progesterone assay measures progesterone concentrations up to 60 ng/mL with a minimum detectable concentration (analytical sensitivity) of 0.21 ng/mL. The ADVIA Centaur Enhanced Estradiol assay measures estradiol concentrations up to 3000 pg/mL. The functional sensitivity of the ADVIA Centaur Enhanced Estradiol assay is 19 pg/mL.
In conceptus cycles, the hormonal treatment was maintained until the 12th gestational week.
Statistical methods
Continuous data were presented as mean and standard deviation (median and range) and categorical data as number and percent. Patient parameters were assessed via t-test or Mann–Whitney U test in the case of non-normally distributed data for continuous data or χ2 or Fisher’s exact tests where appropriate for categorical data. Generalized estimating equations were performed to account for multiple cycles from the same patient.
Generalized estimating equation model for a repeated measures logistic regression using GEE was performed in order to test whether progesterone or estradiol levels predicted live births or other secondary outcome measures.
Results
A total of 1344 FET cycles, in 747 patients, using the medical regimen investigated were performed during the study period. Of these, 921 cycles in 568 patients had progesterone/estradiol data and were included in the analysis.
The mean age of patients at freezing was 30.8 ± 5.6 [29.9; 20.0–45.0], and the mean age at study entry was 31.8 ± 5.7 [31.1; 20.5–49.6] years. The mean BMI was 25.53 ± 5.45 [24.38; 15.62–51.27] kg/m2 (Table 1). The mean number of embryos transferred was 1.9 ± 0.7 [2; 1–4]. Two-thirds of the transfers were of day 2 embryos, and the rest were day 3.
Table 1.
Patient demographics and cycle characteristics (N = 568)
| Age at study entry (years) | 31.8 ± 5.7 |
| Age at freezing (years) | 30.8 ± 5.6 |
| Infertility duration (years) | 2.9 ± 2.4 |
| BMI | 25.5 ± 5.4 |
| Gravidity | 1.1 ± 1.2 |
| Parity | 0.5 ± 0.7 |
| Endometrial thickness (mm) | 8.9 ± 1.7 |
| At least one good quality embryo transferred | 330 (64.3) |
| Number of embryos transferred | 1.9 ± 0.7 [2; 1–4] |
Continuous data is mean ± sd; binary data is N (%)
Two hundred and seventy-three cycles (29.6%; 95% CI: 26.7–32.7%) resulted in a pregnancy (in 235 patients) and 124 (13.5%; 11.3–15.8%) in a live birth. Biochemical pregnancy occurred in 74 treatment cycles (8.0%), 66 (7.2%) of pregnancies resulted in a miscarriage, 3 pregnancies were terminated, and in 6 (0.7%), an ectopic pregnancy was diagnosed. The implantation rate was 10.9% (95% CI: 9.2–12.6%). There was no statistically significant difference in the rate of live births over the study period (χ2 = 5.44, p = 0.66).
Live birth was associated with maternal age (30.8 vs 31.8 years, p = 0.052), age at freezing (29.5 vs 30.7 years, p = 0.02), and the transfer of at least one good quality embryo (p = 0.001). No association was found between live birth and endometrial thickness (8.91 vs 8.88 mm). Significant association was found between live birth and progesterone as well as estradiol levels (progesterone 14.65 vs 11.62 ng/ml, p = 0.001; estradiol 355.12 vs 287.67 pg/ml, p = 0.001) (Table 2). For every 1 ng/ml increase in progesterone level, the odds of a live birth increased by 4%, and for every 10 pg/ml increase in estradiol level, the odds of a live birth increased by 1.7%.
Table 2.
Patient and treatment parameters by live birth
| Live birth | No live birth | χ2 | P | OR (95% CI) | |
|---|---|---|---|---|---|
| Patient no | 120 | 448 | |||
| Treatment cycle no | N = 124 | N = 797 | |||
| Maternal age (years) | 30.8 ± 5.3 | 31.8 ± 5.4 | 3.79 | 0.052 | 0.96 (0.93–1.00) |
| Age at freezing (years) | 29.5 ± 5.1 | 30.7 ± 5.5 | 5.73 | 0.02 | 0.96 (0.92–0.99) |
| Infertility duration (years) | 2.9 ± 2.1 | 2.9 ± 2.1 | 0.08 | 0.77 | 0.99 (0.91–1.07) |
| BMI | 25.6 ± 5.7 | 25.5 ± 5.2 | 0.04 | 0.85 | 1.00 (0.97–1.04) |
| Gravidity | 1.1 ± 1.2 | 1.3 ± 1.4 | 1.72 | 0.19 | 0.91 (0.80–1.05) |
| Parity | 0.6 ± 0.7 | 0.6 ± 0.7 | 1.05 | 0.31 | 1.12 (0.90–1.41) |
| Endometrial thickness (mm) | 8.9 ± 1.5 | 8.8 ± 1.6 | 0.04 | 0.84 | 1.01 (0.91–1.12) |
| Embryo stage at freezing | |||||
| 48 h | 88 (72.4) | 521 (65.4) | 2.21 | 0.14 |
1.00 (reference) 1.39 (0.90–2.13) |
| 72 h | 34 (27.6) | 276 (34.6) | |||
| At least one good quality embryo | 98 (79.7) | 510 (64.5) | 10.67 | 0.001 | 2.16 (1.36–3.43) |
| Number of embryos transferred | 2.1 ± 0.7 | 2.0 ± 0.7 | 1.86 | 0.17 | 1.22 (0.92–1.62) |
| FSH (IU/L) | 6.7 ± 2.6 (6.50; 2.60–21.81) | 6.4 ± 2.4 (6.15; 0.03–34.79) | 1.16 | 0.28 | 1.04 (0.97–1.13) |
| Progesterone level (ng/ml) | 14.6 ± 9.4 | 11.6 ± 6.7 | 14.35 | 0.001 | 1.04 (1.02–1.07) |
| Estradiol level (pg/ml) | 355.1 ± 229.5 | 287.6 ± 229.5 | 13.06 | 0.001 | 1.002 (1.001–1.003) |
1Some patients appear in the live and non-live columns; otherwise, each patient appears once regardless of number of cycles
Continuous data is mean ± sd; binary data is N (%)
When a multivariate analysis was performed, after adjusting for infertility etiology, age at freezing, and transfer of at least one good embryo, progesterone remained associated with live birth (χ2 = 15.14, p < 0.001; OR: 1.05, 95% CI: 1.03–1.08). With the addition of estradiol to the model, both progesterone and estradiol were associated with live birth (χ2 = 9.88, p < 0.002; OR: 1.05, 95% CI: 1.02–1.08; χ2 = 8.30, p < 0.004; for 10-point increase OR: 1.02, 95% CI: 1.005–1.027, respectively).
Spearman correlation revealed that progesterone level was statistically significantly negatively correlated with BMI (p < 0.001). This was not the case for estradiol.
To further explore correlation between progesterone and estradiol levels and live births, serum levels of progesterone and estradiol were classified into four quartiles according to the 25th, 50th, and 75th percentiles. The serum P intervals for each quartile were Q1: < 8.35 ng/ml, Q2: 8.35–10.9 ng/ml, Q3: 10.91–14 ng/ml, and Q4: > 14 ng/ml. Implantation and pregnancy rates were statistically significantly lower for the Q1 as compared to the other quartiles (p = 0. 004, p = 0.02, respectively). Regarding live birth, a significant difference was found below and above the median (≤ 10.9 ng/ml, 10.9%; > 10.9 16.7%; p = 0.007) (Table 3).
Table 3.
Quartiles of progesterone
| Quartile | Q1 | Q2 | Q3 | Q4 | p |
|---|---|---|---|---|---|
| Progesterone ng/ml | < 8.35 | 8.35–10.90 | 10.91–14.00 | > 14.00 | |
| n | 230 | 231 | 230 | 230 | |
| Embryo stage at freezing | |||||
| 48 h | 143 (62.2) | 142 (61.4) | 166 (72.2) | 159 (69.4) | 0.05# |
| 72 h | 87 (37.8) | 89 (38.6) | 64 (27.8) | 70 (30.6) | |
| At least one good quality embryo | 150 (65.8) | 151 (65.4) | 159 (70.0) | 148 (64.9) | 0.63 |
| Number of embryos transferred | 2.0 ± 0.7 (1.9–2.1) | 2.0 ± 0.7 (2.0–2.1) | 2.0 ± 0.6 (1.9–2.1) | 2.0 ± 0.6 (1.9–2.1) | 0.61 |
| Implantation rate | 6.6 (4.0–9.2) | 9.9 (6.6–13.2) | 12.0 (8.5–15.6) | 15.1 (10.9–19.3) | 0.004* |
| Pregnancy | 48 (20.9%) | 72 (31.2%) | 74 (32.2%) | 79 (34.3%) | 0.02* |
| Biochemical pregnancy | 13 (5.7%) | 25 (10.8%) | 17 (7.4%) | 19 (8.3%) | 0.23 |
| Clinical miscarriage | 17 (7.4%) | 13 (5.6%) | 22 (9.6%) | 14 (6.1%) | 0.36 |
| Live birth | 18 (7.8%) | 29 (12.6%) | 32 (13.9%) | 45 (19.6%) | 0.007 |
Continuous data is mean ± sd [median, range]; binary data is N (%)
#Q1 as compared to Q3
*Q1 as compared to the other quartiles
The serum estradiol intervals were Q1: < 188.2 pg/ml, Q2:188.2–263.0 ng/ml, Q3: 263.1–364.5 ng/ml, and Q4 > 364.6 ng/ml). The implantation rate was statistically significantly lower for the Q1 of estradiol as compared to the fourth quartile (p = 0.05). The pregnancy rate was statistically significantly lower for the Q1 as compared to the other quartiles (p = 0.02). The live birth rate was statistically significantly lower for the Q1 as compared to the third and fourth quartiles (< 188.2 ng/ml, 8.3%; > 263.1 ng/ml, 16%, p = 0.02) (Table 4).
Table 4.
Quartiles of estradiol
| Quartile | Q1 | Q2 | Q3 | Q4 | p |
|---|---|---|---|---|---|
| Estradiol (pg/ml) | < 188.2 | 188.2–263.0 | 263.1–364.5 | > 364.6 | |
| n | 230 | 230 | 230 | 230 | |
| Embryo stage at freezing | |||||
| 48 h | 162 (70.4) | 154 (67.3) | 142 (61.7) | 151 (65.7) | 0.26 |
| 72 h | 68 (29.6) | 75 (32.7) | 88 (38.3) | 79 (34.3) | |
| At least one good quality embryo | 149 (65.6) | 150 (65.5) | 162 (71.1) | 146 (63.8) | 0.39 |
| Number of embryos transferred | 2.0 ± 0.7 (1.9–2.0) | 2.0 ± 0.7 (1.9–2.1) | 2.0 ± 0.7 (1.9–2.1) | 2.0 ± 0.6 (2.0–2.1) | 0.50 |
| Implantation rate | 7.5 (4.3–10.6) | 10.1 (6.9–13.3) | 11.6 (8.0–15.3) | 14.5 (10.7–18.3) | 0.05* |
| Pregnancy | 50 (21.7%) | 68 (29.6%) | 76 (33.0%) | 79 (34.3%) | 0.02# |
| Biochemical pregnancy | 21 (9.1%) | 14 (6.1%) | 18 (7.8%) | 21 (9.1%) | 0.60 |
| Clinical miscarriage | 7 (3.0%) | 19 (8.3%) | 25 (10.9%) | 15 (6.5%) | 0.01^ |
| Live birth | 19 (8.3%) | 30 (13.0%) | 33 (14.3%) | 42 (18.3%) | 0.02& |
Continuous data is mean ± sd [median, range]; binary data is N (%)
*Q1 as compared the Q4
#Q1 as compared to the other quartiles
^Q1 as compared to the second and third quartiles
&Q1 as compared to the third and fourth quartiles
Seventy-seven patients had both progesterone and estradiol levels in the lower quartile; only one of them had a live birth (1.3%). Among the 65 patients with both values in the upper quartile, 16 (24.6%) gave birth (p < 0.001).
To define the predictive capability of serum progesterone and estradiol on the live birth, a receiving operating characteristic (ROC) curve was defined. Progesterone level above 10.71 correctly identified 62.5% of the live births (78 of the 124 live births); overall it classifies correctly 52.1% of the cases. Likewise, estradiol level above 259.4 correctly identified 61.3% of the live births (76/124); overall it classifies 51.6% of the cases.
Discussion
The current study found a significant correlation between serum progesterone and estradiol levels 2 weeks after embryo transfer and live birth rate in AC-FET. A similar correlation was noted for pregnancy and implantation rate. Live birth rate was significantly lower in cycles in which the progesterone level was below 10.9 ng/ml or the estradiol level was below 188.2 pg/ml. When progesterone and estradiol levels were both in the lower quartiles, the live birth rate was negligible.
During the natural cycle, measuring the serum progesterone level is of limited value, due to the pulsatile release of progesterone from the corpus luteum, echoing the pulsatile release of LH from the pituitary. Serum progesterone levels can fluctuate eightfold in a 90-min period during the midluteal phase and range from 2.3 to 40.1 pg/mL [12]. In fresh ART cycles, involving controlled ovarian hyperstimulation and oocyte aspiration, the luteal phase is dysfunctional, but the presence of corpora lutea with pulsatile, although defective, progesterone release mitigates the usefulness of serum progesterone measurements. In AC-FET, no CL is formed; thus, there is no endogenous source of progesterone, so measuring its serum levels represent the absorption, distribution, and metabolism of the drug and may be beneficial.
Few studies investigated the correlation between progesterone levels in AC-FET and clinical outcome. The treatment protocols, the medical preparation, and the administration route vary between studies and so do their conclusions. When using vaginal micronized progesterone, lower pregnancy rates in correlation with lower progesterone levels were observed by some [13], but not by others [14–16]. Additionally, lower progesterone levels were correlated with lower implantation rates [15], higher miscarriage rates [14, 16, 17], lower ongoing pregnancy rates [13, 15, 18, 19], and lower live birth rates [20–22]. Under vaginal micronized progesterone treatment, levels between 8.8 and 11 ng/l were offered as cut-offs [13–15, 21]. Optimal progesterone levels between 22 and 31 ng/l were reported when using progesterone pessary [23]. When intramuscular progesterone was used for luteal support, high levels of progesterone (> 20 ng/ml) were correlated with higher clinical pregnancy and live birth rate in some studies [24–26]but with lower ongoing pregnancy and live birth rate in another [27].
The effect of BMI on serum progesterone concentrations was studied previously. Levy et al. found no significant difference in pharmacokinetics in relation to weight, height, or BMI in post-menopausal women [28]. However, others found a negative correlation between progesterone levels and BMI when administered either via intramuscular or vaginal route [18–20, 24]. We describe similar results, showing that BMI is an independent factor that affects serum progesterone concentrations. This might be one of the mechanisms explaining the known negative correlation between BMI and live birth rate [6].
The timing of the progesterone measurements differs between the studies. In our study, the assay was performed 2 weeks after embryo transfer. When administered vaginally, progesterone is preferentially absorbed by uterine endometrial tissue, whereas a small percentage is distributed into the systemic circulation. On multiple dosing, steady-state concentrations are attained within approximately 1 day after initiation of treatment [29, 30]. For this reason, the diversity in progesterone values between the different studies cannot be explained by the variability in the assay timing. The wide range of progesterone serum values between different patients may be explained by the inter-individual variability in vaginal progesterone uptake, distribution, and metabolism that have been described previously [31, 32].
Data about estradiol levels and clinical outcome in AC-FET cycles are conflicting. Contrary to our findings, other studies found no correlation between estradiol levels in AC-FET cycles and clinical outcomes [13, 18, 33–35]. Moreover, one study suggested that elevated E2 levels in artificial autologous FET cycles are associated with lower ongoing pregnancy and live birth rates [36]. The inconsistent results may be due to the different regimes used (e.g., GnRH agonist down regulation, monitoring estradiol levels, and adjusting the dose or canceling the cycle with low levels). It is also important to note that estradiol and progesterone levels are not independent variables, rather adequate estrogen levels increase vaginal progesterone absorption, further confounding the picture [37].
Since endogenous progesterone and estradiol levels in conceptus cycles do not start to rise before 16 days after embryo transfer [38], the levels measured in this study represent the sole effect of the medication and the personal uptake and metabolism of the patient.
The current study adds to the knowledge gathered recently regarding the importance of luteal phase monitoring in AC-FET. Strengths of this study are the inclusion of a large number of ART cycles and the setting of live birth outcomes as the primary outcome. It presents the outcome of a single uniform FET protocol, with cleavage stage embryos. Cleavage stage embryos are still used worldwide[39] as clear benefit of blastocyst transfer, especially in frozen cycles, has not been demonstrated [4]. The main limitations of the study are its retrospective design and covering a long period.
In summary, low serum progesterone and estradiol levels in AC FET cycles may negatively impact the clinical outcome. Optimization of ART success rates relies not only on the creation of high-quality embryos but also on the establishment of a receptive endometrium. Although significant research has been directed toward optimization of AC-FET cycles, the ideal protocol has not been identified yet. The reason might be that no single regimen fits all, requiring a personalized approach. Measuring progesterone and estradiol levels and adjusting the treatment accordingly might improve the clinical outcome of AC-FET. Larger prospective studies are needed to confirm our results and further elucidate the optimal way to proceed in the presence of low serum hormonal levels.
Contributions
Ronit Beck Fruchter and Amir Weiss contributed to the study conception and design. Material preparation, data collection and analysis were performed by Ronit Beck Fruchter, Simon Nothman, Shira Baram, Yoel Geslevich and Amir Weiss. The first draft of the manuscript was written by Ronit Beck Fruchter and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Code availability
Not applicable.
Declarations
Ethics approval
This research study was conducted retrospectively from data obtained for clinical purposes. Approval was obtained from the ethics committee of HaEmek medical center.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Conflict of interest
The authors declare that they have no conflicts of interest.
Footnotes
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
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Data Availability Statement
Not applicable.