Abstract
Doudou Liu 1 a Ling Liu2b*
1 Clinical Medical College, Southwest Medical University, Luzhou 646000, Sichuan, China
2.Southwest medical university affiliated hospital, reproductive medicine, 646000, luzhou sichuan, China
email a ：lddmemo@163.com
email b: eye99@163.com
* corresponding author
Objective: To analyze the impact of serum progesterone (P) levels on HCG Trigger Day on the Outcomes of fresh high-quality embryo transfer in GnRH antagonist cycles.
Methods: This retrospective study analyzed 380 patients undergoing fresh cycle high-quality embryo transfer with antagonist protocol at Southwest Medical University reproductive center (January 2019-December 2024).All the included patients were categorized into three groups based on serum P levels on HCG day:Group A (P ≤ 0.8 ng/mL), Group B (0.8＜P≤1.0 ng/mL), Group C(P >1.0 ng/mL). Based on the POSEIDON criteria, patients were stratified into subgroups for further analysis: expected poor ovarian responders (Group 3/4) and unexpected poor ovarian responders (Group 1/2), each divided by progesterone levels (≤0.8 vs >0.8 ng/mL) on HCG day. The reproductive outcomes were compared among the three groups and subgroups.Ordinal logistic regression analyzed factors influencing hCG-day P levels.
Results: The implantation (35.1% vs 30.1% vs 29.4%), clinical pregnancy (41.4% vs 41.9% vs 37.5%), ongoing pregnancy (88.6% vs 86.7% vs 74.3%), and live birth rates (34.3% vs 35.1% vs 29.2%) showed no significant differences among three groups(all P>0.05). MII rates differed significantly among groups (91.1% vs 87.6% vs 89.5%, P=0.03), whereas 2PN rates（76.9% vs 76.3% vs 76.2%）and blastocyst formation rates (64.2% vs 59.1% vs 64.9%) were showed no significant differences. In POSEIDON -defined expected poor ovarian responders, the live birth rate was lower in the group with HCG day P >0.8 ng/mL (11.8% vs 32.6%, P=0.03). In unexpected poor ovarian responders, no significant differences were observed in implantation, clinical pregnancy, ongoing pregnancy and live birth rates with increasing P levels (P>0.05). Ordered logistic regression indicated that the number of follicles ≥14 mm on HCG day influenced P levels (OR: 1.10, 95% CI: 1.01-1.20, P = 0.02).
Conclusion: In fresh embryo transfer and GnRH antagonist cycles, the number of follicles ≥14mm on HCG day independently predict progesterone elevation. Under the POSEIDON criteria, expected poor ovarian responders showed a significant decrease in live birth rates when P levels on HCG day exceeded 0.8 ng/mL.
Keywords: GnRH antagonist protocol ; fresh embryo transfer cycles ; progesterone levels on the day of hCG administration ; poor ovarian respose
During the ovulation induction process with the antagonist protocol, the gonadotropin releasing hormone antagonist (GnRH-ant) directly acts on the GnRH-ant receptors in the pituitary gland to inhibit the secretion of luteinizing hormone (LH) in order to prevent the premature elevation of progesterone. However, the incidence of elevated progesterone levels in the late follicular phase still reaches 5% to 38% [1,2]. Most previous studies have shown that the elevation of progesterone levels in the late follicular phase is negatively correlated with the pregnancy outcomes of fresh cycle embryo transfer [3-8]. It is speculated in the studies that this adverse effect may be related to the following two aspects. Firstly, the elevated progesterone levels interfere with the development and maturation of oocytes, affect their fertilization potential, and lead to a decrease in the formation rate of high-quality embryos [9-12]. Secondly, the elevation of progesterone in the late follicular phase impairs the endometrial receptivity and disrupts the synchrony between the endometrium and embryo development [13-16]. Due to many factors such as the differences in ovarian responses among the study populations, the laboratory detection methods for progesterone, and the research design schemes, there are significant differences in the threshold of elevated progesterone levels on the human chorionic gonadotropin (hCG) day among different studies, and the standards have not been unified yet. Therefore, exploring the causes of the elevation of progesterone levels during the ovulation induction process with the antagonist protocol, clarifying the thresholds of elevated progesterone levels on the hCG day for different populations with various ovarian responses, and implementing timely and effective intervention measures are of great significance for optimizing the clinical outcomes of fresh embryo transfer cycles.
Materials and Methods
I. Research Subjects
The clinical data of a total of 380 patients who received ovulation induction with the antagonist protocol in the Reproductive Center of the Affiliated Hospital of Southwest Medical University from January 2019 to December 2024 and underwent the transfer of 1 to 2 high-quality embryos in the fresh cycle were collected.
Inclusion Criteria
(1) Ovulation induction using the antagonist protocol; (2) Transfer of 1 to 2 high-quality embryos in the fresh cycle; (3) Induction of ovulation with human chorionic gonadotropin (hCG) triggering; (4) Luteinizing hormone (LH) < 10 mIU/mL and progesterone (P) < 2.0 ng/mL on the triggering day.
Exclusion Criteria
(1) Either spouse has abnormal chromosomal karyotype; (2) History of recurrent spontaneous abortion or failure to succeed after three or more embryo transfers; (3) Patients with untreated hydrosalpinx; (4) Uterine developmental malformation, intrauterine adhesion, endometrial polyp or submucous myoma, etc.; (5) Patients diagnosed with severe endometriosis; (6) Complicated with endocrine system diseases affecting pregnancy, including but not limited to polycystic ovary syndrome, abnormal prolactin level, thyroid dysfunction, etc.; (7) Patients requiring preimplantation genetic diagnosis or screening; (8) Patients with contraindications to assisted reproductive technology or pregnancy; (9) Cases with incomplete clinical data and lack of key research data.
Research Methods
A retrospective analysis was conducted on the clinical data of 380 patients who received ovulation induction with the antagonist protocol in the Reproductive Medicine Center of the Affiliated Hospital of Southwest Medical University from January 2019 to December 2024 and underwent the transfer of 1 to 2 high-quality embryos in the fresh cycle. Based on the previous literature reports [3,17] and the data situation of our center, the patients were grouped according to the progesterone (P) level on the hCG day: Group A (P ≤ 0.8 ng/mL on the hCG day), Group B (0.8 ng/mL < P ≤ 1.0 ng/mL on the hCG day), and Group C (P > 1.0 ng/mL on the hCG day). The baseline characteristics, ovulation induction parameters, and pregnancy outcomes among the groups were compared. Ordered logistic regression analysis was performed to analyze the influencing factors of the elevation of progesterone level on the hCG day. According to the previous references, the influence of the P level on the hCG day on the assisted reproductive outcome may be related to the ovarian reactivity of the population [18-20]. According to the Poseidon criteria and combined with the actual data situation, it was further divided into subgroups: subgroups with predicted low ovarian response according to the Poseidon criteria (POSEIDON Group 3/4) with P ≤ 0.8 ng/mL and P > 0.8 ng/mL on the hCG day, and subgroups with non-predicted low ovarian response according to the Poseidon criteria (POSEIDON Group 1/2) with P ≤ 0.8 ng/mL and P > 0.8 ng/mL on the hCG day. The assisted reproductive outcomes of each subgroup were compared respectively.
II. Review of Diagnosis and Treatment
Antagonist Ovulation Induction Protocol
On the 2nd to 3rd day of the menstrual cycle, the ovarian stimulation protocol was initiated with an individualized dosage of gonadotropin (Gn). The serum hormone levels were regularly monitored, and the number and diameter of follicles were evaluated by transvaginal ultrasound. Based on this, the dosage of gonadotropin (Gn) was adjusted. On the 5th day after the initiation of Gn or when the diameter of the dominant follicle reached 14 mm, a short-acting GnRH antagonist (Cetrotide 0.25 mg) was subcutaneously injected daily. When at least one follicle had a diameter ≥ 19 mm or three follicles had a diameter ≥ 18 mm, human chorionic gonadotropin (hCG 10,000 IU) or recombinant hCG (Elonva 250 μg) was injected. Oocyte retrieval was performed 34 to 37 hours later. On the 3rd day after oocyte retrieval, cleavage-stage embryo transfer was carried out, or blastocyst transfer was performed on the 5th day after oocyte retrieval. From the day of oocyte retrieval, intramuscular injection of progesterone at a dose of 60 mg/day was used for luteal support until a serum hCG test was conducted about 14 days after the transfer to determine whether pregnancy occurred.
In Vitro Fertilization, Embryo Culture and Morphological Scoring
Fertilization was completed within 6 hours after oocyte retrieval. In vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) was selected according to the results of semen analysis. On the 3rd day of embryo development, the embryos were evaluated according to the morphological scoring of cleavage-stage embryos. In our center, grade I to grade II embryos were considered high-quality cleavage-stage embryos. The embryos were continuously cultured until the 5th day, and evaluated using the Gardner blastocyst scoring system. Blastocysts with an expansion degree ≥ stage 3 and both the inner cell mass (ICM) and trophectoderm (TE) ratings above grade B (≥ 3BB) were defined as high-quality blastocysts.
Judgment of Pregnancy Outcomes
Quantitative detection of serum hCG was carried out 14 days after embryo transfer. If the value was lower than 5 IU/L, it was determined as non-pregnancy. If it was higher than 5 IU/L, an ultrasound examination was required on the 28th to 35th day after the transfer. If a gestational sac and primitive cardiac tube pulsation were found in the uterus or outside the uterus, it was considered a clinical pregnancy; otherwise, it was a biochemical pregnancy. If the pregnancy persisted for more than 12 weeks, it was a continued pregnancy. Termination of pregnancy before 28 weeks of gestation was defined as abortion, and the delivery of a live newborn after 28 weeks of gestation was defined as a live birth.
III. Observation Indicators of Outcomes
The main observation indicator of the outcome was the clinical pregnancy rate: the number of pregnancy (intrauterine and extrauterine) cycles / the number of transfer cycles × 100%. The secondary observation indicators were the metaphase II (MII) rate: the number of MII-stage oocytes / the total number of retrieved oocytes × 100%, the two-pronuclear (2PN) rate: the number of 2PN zygotes / the total number of zygotes × 100%, the blastocyst formation rate: the number of formed blastocysts / the total number of blastocysts cultured × 100%, the embryo implantation rate: the number of gestational sacs detected by ultrasound / the number of transferred embryos × 100%, the continued pregnancy rate: the number of cycles with pregnancy lasting more than 12 weeks / the number of clinical pregnancy cycles × 100%, and the live birth rate: the number of cycles with live birth / the number of transfer cycles × 100%.
IV. Statistical Methods
Statistical analysis was performed using SPSS 27.0 software and Zstats v1.0 software based on the R language. First, the normality and homogeneity of variance of the data were tested. The measurement data in this study did not meet the normal distribution and were expressed as the median (interquartile range) [M (P25, P75)]. The Mann-Whitney U test was used to evaluate the differences between two groups, and the Kruskal Wallis H test was used to evaluate the differences between more than two groups. Categorical variables were expressed as frequencies (%). The Pearson chi-square test or Fisher’s exact test was used to evaluate the differences between groups. Ordered logistic regression analysis was used to analyze the influencing factors of the elevation of progesterone level on the hCG day. The significance level was set at P < 0.05, and differences were considered statistically significant. When there were many multiple comparisons, the α division method was used to control the error rate, and the adjusted significance level α = 0.0167 (0.05/3).
Results
1.Comparison of Baseline Characteristics and Ovulation Induction Parameters of Patients in Each Group
As shown in Table 1, when comparing the baseline characteristics and ovulation induction parameters among the three groups with P ≤ 0.8 ng/mL on the hCG day (Group A), 0.8 ng/mL < P ≤ 1.0 ng/mL on the hCG day (Group B), and P > 1.0 ng/mL on the hCG day (Group C), there was a statistically significant difference only in the basal P level (P = 0.02), while there were no statistically significant differences in the other indicators (all P > 0.05), indicating that the groups were comparable.
Table 1Comparison of Baseline Characteristics and Ovarian Stimulation Parameters Among Groups A, B, and C
Continued Table 1 Comparison of Baseline Characteristics and Ovarian Stimulation Parameters Among Groups A, B, and C
| Group A (n=210) M (P25, P75) | Group B (n=74) M (P25, P75) | Group C (n=96) M (P25, P75) | H/χ² | P | |
| Gn starting dose (IU) | 225.00 (150.00,300.00) | 225.00 (150.00,300.00) | 225.00 (150.00,300.00) | 1.48 | 0.48 |
| Total Gn dose (IU) | 2356.25 (1706.25,2850.00) | 2250.00 (1800.00,2700.00) | 2250.00 (1734.38,2700.00) | 0.54 | 0.76 |
| Gn days (days) | 10.00 (9.00,11.00) | 10.00 (9.00,10.00) | 10.00 (9.00,11.00) | 2.12 | 0.35 |
| HCG day LH (mIU/ml) | 1.31 (0.77,2.02) | 1.73 (0.91,2.80) | 1.54 (0.93,2.60) | 5.50 | 0.06 |
| HCG day E2 (ng/ml) | 1941.82 (1369.63,2730.66) | 2268.26 (1709.17,3000.00) | 2439.36 (1639.79,3146.23) | 15.10 | <.01 |
| HCG day P (mIU/ml) | 0.52 (0.41,0.65) | 0.90 (0.84,0.94) | 1.24 (1.11,1.45) | 306.18 | <.01 |
| Fertilization method n(%) | 0.28 | ||||
| ICSI | 21 (10.00) | 5 (6.76) | 6 (6.25) | ||
| IVF | 187 (89.05) | 67 (90.54) | 86 (89.58) | ||
| IVF + RICSI | 2 (0.95) | 2 (2.70) | 4 (4.17) | ||
| Type of transferred embryo n(%) | 2.74 | 0.25 | |||
| Cleavage embryo | 153 (72.86) | 51 (68.92) | 61 (63.54) | ||
| Blastocyst | 57 (27.14) | 23 (31.08) | 35 (36.46) | ||
| Number of transferred embryos n(%) | 0.08 | 0.96 | |||
| 1 | 121 (57.62) | 44 (59.46) | 56 (58.33) | ||
| 2 | 89 (42.38) | 30 (40.54) | 40 (41.67) | ||
| Endometrial thickness on the transfer day (mm) | 10.60 (9.00,12.57) | 10.55 (9.10,12.10) | 10.90 (9.07,12.95) | 0.17 | 0.92 |
2.Comparison of Ovulation Induction Outcomes and Pregnancy Outcomes
As shown in Table 2, Table 3 and Table 4, there was a statistically significant difference in the MII rate (91.1% vs 87.6% vs 89.5%) among Group A, Group B and Group C (P = 0.03). Post-hoc comparison showed that the MII rate of Group A was significantly higher than that of Group B (91.10% vs 87.60%, P = 0.007). There were no statistically significant differences in the 2PN rate and blastocyst formation rate (P > 0.05). There were also no statistically significant differences in the embryo implantation rate, clinical pregnancy rate, continued pregnancy rate and live birth rate among the three groups (P > 0.05).
Table2Comparison of Embryo Laboratory Parameters Among Groups A, B, and C
| Group A (n=210) | Group B (n=74) | Group C (n=96) | c2 | P | |
| MII rate 2PN rate Blastocyst formation rate | 1733/1903(91.1%) 1238/1609(76.9%) 498/776(64.2%) | 681/777(87.6%) 482/632(76.3%) 194/328(59.1%) | 912/1019(89.5%) 661/868(76.2%) 301/464(64.9%) | 7.40 0.24 3.19 | 0.03 0.89 0.20 |
Table 3 Comparison of Pregnancy Outcomes Among Groups A, B, and C
| Group A (n=210) | Group B (n=74) | Group C (n=96) | c2 | P | |
| Embryo implantation rate | 105/299(35.1%) | 32/104(30.1%) | 40/136(29.4%) | 1.63 | 0.44 |
| Clinical pregnancy rate Continued pregnancy rate Live birth rate | 87/210(41.4%) 78/87(88.6%) 72/210(34.3%) | 31/74(41.9%) 26/31(86.7%) 26/74(35.1%) | 36/96(37.5%) 26/36(74.3%) 28/96(29.2%) | 0.49 4.12 0.94 | 0.78 0.13 0.62 |
Table 4 Post Hoc Analysis of MII Rates
| MII率 | χ² | P | |
| Group A | 1733/1903(91.1%) | 7.23 | 0.007 |
| Group B | 681/777(87.6%) | ||
| Group A | 1733/1903(91.1%) | 1.90 | 0.168 |
| Group C | 912/1019(89.5%) | ||
| Group B | 681/777(87.6%) | 1.51 | 0.219 |
| Group C | 912/1019(89.5%) |
3.Ordinal Logistic Regression Analysis of Factors Influencing the Elevation of Progesterone on the hCG Day
As shown in Table 5, the results of the ordinal logistic regression analysis of the factors influencing the elevation of progesterone on the hCG day indicated that the total dosage of Gn and the number of Gn days were not independent influencing factors for the elevation of progesterone on the hCG day in the fresh cycle of the antagonist protocol. The number of follicles with a diameter ≥ 14 mm on the hCG day was an independent influencing factor for the elevation of progesterone on the hCG day in the fresh cycle of the antagonist protocol (P = 0.02, OR: 1.10, 95% CI: 1.01 ~ 1.20).
Table 5 Ordinal Logistic Regression Analysis of Factors Influencing Progesterone Elevation on HCG Day
| Variables | β | S.E | Wald | P | OR (95%CI) |
| 1|2 | 1.05 | 0.08 | 13.76 | <.01 | 2.87 (2.47 ~ 3.33) |
| 2|3 | 1.95 | 0.10 | 19.53 | <.01 | 7.06 (5.80 ~ 8.59) |
| Total dosage of Gn | 0.00 | 0.00 | 0.21 | 0.84 | 1.00 (1.00 ~ 1.00) |
| Number of Gn days | -0.04 | 0.20 | -0.20 | 0.84 | 0.96 (0.65 ~ 1.42) |
| Number of follicles with diameter ≥ 14 mm on hCG day | 0.10 | 0.04 | 2.29 | 0.02 | 1.10 (1.01 ~ 1.20) |
Note: 1: P ≤ 0.8 ng/mL on the hCG day, 2: 0.8 ng/mL < P ≤ 1.0 ng/mL on the hCG day, 3: P > 1.0 ng/mL on the hCG day
4. Comparison of Pregnancy Outcomes Based on POSEIDON Criteria Grouping and Different Progesterone Levels on the hCG Day
As shown in Table 6, among the population with a predicted low response according to the POSEIDON criteria (POSEIDON Group 3/4), the live birth rate (11.8%) in the group with P > 0.8 ng/ml on the hCG day was significantly lower than that (32.6%) in the group with P ≤ 0.8 ng/ml on the hCG day, and the difference was statistically significant (P = 0.03). The embryo implantation rate, clinical pregnancy rate, and continued pregnancy rate showed a decreasing trend in the group with elevated progesterone levels on the hCG day, but there was no statistical difference (P > 0.05). Among the population with a non-predicted low response according to the POSEIDON criteria (POSEIDON Group 1/2), as the progesterone level on the hCG day increased, the embryo implantation rate, clinical pregnancy rate, and continued pregnancy rate showed a decreasing trend, but the differences were not statistically significant, and there was no statistical difference in the live birth rate (P > 0.05).
Table 6 Comparison of Pregnancy Outcomes by Progesterone Levels on HCG Day Across POSEIDON Stratification Groups
| HCG日P≤0.8 | HCG日P＞0.8 | c2 | P | |
| Implantation rate | ||||
| Population with non-predicted low response according to POSEIDON criteria | 86/232(37.1%) | 63/195(32.3%) | 1.06 | 0.30 |
| Population with predicted low response according to POSEIDON criteria | 20/68(29.4%) | 9/44(20.5%) | 1.12 | 0.29 |
| Clinical pregnancy rate | ||||
| Population with non-predicted low response according to POSEIDON criteria | 71/164(43.3%) | 58/136(42.6%) | 0.01 | 0.91 |
| Population with predicted low response according to POSEIDON criteria | 16/46(34.8%) | 9/34(26.5%) | 0.63 | 0.43 |
| Continued pregnancy rate | ||||
| Population with non-predicted low response according to POSEIDON criteria | 61/71(85.9%) | 46/58(79.3%) | 0.99 | 0.32 |
| Population with predicted low response according to POSEIDON criteria | 15/16(93.8%) | 7/9(77.8%) | 0.53 | |
| Live birth rate | ||||
| Population with non-predicted low response according to POSEIDON criteria | 57/164(34.8%) | 50/136(36.8%) | 0.13 | 0.72 |
| Population with predicted low response according to POSEIDON criteria | 15/46(32.6%) | 4/34(11.8%) | 4.69 | 0.03 |
Discussion
Most clinical studies and meta-analyses have suggested that the elevation of progesterone levels on the triggering day has a negative impact on clinical outcomes [3-8], which may be related to the following mechanisms: (1) The elevation of progesterone in the late follicular phase can affect the pregnancy outcome by altering the genetic expression of the endometrium, thus reducing the endometrial receptivity [13-15]; (2) High progesterone levels may trigger premature follicular atresia, affect the maturation process and quality of oocytes in that cycle, lead to a decrease in the fertilization rate and impairment of embryo developmental potential, resulting in negative pregnancy outcomes [9,10,21]. In addition, some studies have shown that high progesterone levels on the triggering day have no significant impact on the pregnancy outcomes of frozen embryo transfer cycles [2,22], suggesting that the quality of oocytes and embryos may not be related to the progesterone level on the triggering day. Currently, there is no unified conclusion on the correlation between the progesterone level on the triggering day and the quality of oocytes and embryos. The results of this study showed that the rate of mature oocytes in the group with P ≥ 0.8 ng/ml on the hCG day was significantly lower, indicating that high progesterone levels on the hCG day may affect the quality of oocytes. However, there were no significant differences in the 2PN rate and blastocyst formation rate. Since the processes of fertilization and embryo development are related to many factors such as sperm quality, in vitro fertilization technology, and in vitro embryo culture conditions, this may be the reason for the inconsistent results in various studies, which requires further exploration in the future.
Currently, most studies recommend that all embryos should be cryopreserved when the progesterone level on the triggering day exceeds 1.5 ng/mL [4,6,7]. Due to many factors such as the differences in ovarian responses among the study populations, the laboratory detection methods for progesterone, and the research design schemes, there are significant differences in the threshold of elevated progesterone levels among different studies, and the standards have not been unified yet. The results of this study showed that although the elevation of P on the hCG day was related to a decrease in the pregnancy rate, the difference was not statistically significant (P < 0.05), which was inconsistent with most studies. The possible reasons for this may be as follows: (1) Since the proportion of fresh embryo transfer cycles with P > 1.5 ng/ml on the hCG day included in this study in our center was only 6.1% (23 cases out of 380 cases), which is the threshold of elevated progesterone levels on the hCG day determined in most studies, due to the inability to cover a wider range of progesterone levels, it cannot more comprehensively reflect the impact of the P level on the hCG day on the pregnancy outcome. (2) The mechanism by which the elevation of progesterone levels in the late follicular phase affects the pregnancy outcome may be related to its impact on the quality of oocytes and embryos [9,10,21]. However, all the cycles included in this study involved the transfer of high-quality embryos, which may be one of the reasons for the lack of significant differences in the results. (3) The ovarian reactivity of the population was not taken into account in the initial analysis. Further analysis in this study found that among patients with a predicted low ovarian response according to the POSEIDON criteria, the live birth rate in the group with elevated progesterone levels (P > 0.8 ng/mL) on the hCG day was significantly lower; while among patients with a non-predicted low ovarian response, there were no significant differences in the clinical pregnancy rate, continued pregnancy rate, and live birth rate among groups with different progesterone levels. Some studies have shown that there are significant differences in the serum progesterone level thresholds among populations with different ovarian responses. In fresh cycle transfers of populations with low ovarian responses, slightly elevated progesterone levels on the triggering day may have an adverse impact on the pregnancy outcome, while populations with high ovarian responses may require a higher progesterone threshold [18-20]. Therefore, when defining the threshold of elevated progesterone levels, the population heterogeneity of ovarian responses should be fully considered. During the ovulation induction process in populations with low ovarian responses, it is necessary to focus on monitoring the changes in progesterone levels and to detect and implement interventions in a timely manner for abnormally elevated progesterone levels.
The results of this study showed that the progesterone level on the hCG day increased with the increase in the number of follicles with a diameter ≥ 14 mm on the hCG day, suggesting that the synchronous development of multiple follicles and the cumulative effect of hormone secretion may be one of the reasons for the elevation of progesterone levels on the hCG day. Some studies have found that high-dose Gn stimulation induces an increase in the expression of 3β-hydroxysteroid dehydrogenase (3β-HSD) in ovarian granulosa cells [23], resulting in a significant increase in the conversion of pregnenolone to progesterone. The imbalance between the synthesis and decomposition of high-dose progesterone leads to an increase in the serum progesterone level. However, this study showed that there was no significant correlation between the progesterone level on the hCG day and the dosage and duration of Gn. During the ovulation induction process, high-dose Gn stimulation will cause the synchronous development of multiple follicles. The interaction between the dosage and duration of Gn use and the development of multiple follicles on the progesterone level on the hCG day may be worthy of further study, in order to better guide the control of progesterone levels in fresh cycles.
In conclusion, during the ovulation induction process with the antagonist protocol, the simultaneous development of a large number of follicles is a predictive indicator for the elevation of progesterone levels on the hCG day. The elevation of progesterone levels on the hCG day may lead to adverse pregnancy outcomes by impairing the endometrial receptivity. Whether high progesterone levels affect the quality of oocytes and embryos remains controversial. The elevation of progesterone levels on the hCG day has a negative impact on the pregnancy outcomes of fresh transfer cycles, and its threshold level may be related to the ovarian reactivity of the population. Based on the POSEIDON classification criteria, the progesterone level on the hCG day should be closely monitored in populations with predicted low ovarian responses, while for populations with predicted high ovarian responses, the restricted range of progesterone levels for fresh cycle transfers can be appropriately relaxed.
References
[1] Hill M J, Royster G D, Healy M W, et al. Are good patient and embryo characteristics protective against the negative effect of elevated progesterone level on the day of oocyte maturation?[J]. Fertility and Sterility, 2015, 103(6): 1477-1484.
[2] Bosch E, Labarta E, Crespo J, et al. Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles[J]. Human Reproduction, 2010, 25(8): 2092-2100.
[3] Venetis C A, Kolibianakis E M, Bosdou J K, et al. Progesterone elevation and probability of pregnancy after IVF: a systematic review and meta-analysis of over 60 000 cycles[J]. Human Reproduction Update, 2013, 19(5): 433-457.
[4] Mascarenhas M, Kamath M S, Chandy A, et al. Progesterone/Estradiol Ratio as a Predictor in the ART Cycles with Premature Progesterone Elevation on the Day of hCG Trigger[J]. Journal of Reproduction & Infertility, 2015, 16(3): 155-161.
[5] Dong M, Sun L. Why Our Clinical Pregnancy Rates Have Improved Over the Past Two Years: Exploring Key Points of Gonadotropin-Releasing Hormone Antagonist Protocol in Fresh Embryo Transfer Cycles[J]. Fertility & Reproduction, 2023, 05(04): 402-402.
[6] Lee C I, Chen H H, Huang C C, et al. Early Progesterone Change Associated With Pregnancy Outcome After Fresh Embryo Transfer in Assisted Reproduction Technology Cycles With Progesterone Level of >1.5 ng/ml on Human Chorionic Gonadotropin Trigger Day[J]. Frontiers in Endocrinology, 2020, 11: 653.
[7] Racca A, Vanni V S, Somigliana E, et al. Is a freeze-all policy the optimal solution to circumvent the effect of late follicular elevated progesterone? A multicentric matched-control retrospective study analysing cumulative live birth rate in 942 non-elective freeze-all cycles[J]. Human Reproduction, 2021, 36(9): 2463-2472.
[8] Zhang J, Du M, Wu Y, et al. Effect of Serum Progesterone Level on the Day of Human Chorionic Gonadotropin on the Live Birth Rate of Fresh Cycle Transfer in the Antagonist Protocol [J]. National Medical Journal of China, 2022, 102(44): 3537-3542.
[9] Huang B, Ren X, Wu L, et al. Elevated Progesterone Levels on the Day of Oocyte Maturation May Affect Top Quality Embryo IVF Cycles[J]. PLOS ONE, 2016, 11(1).
[10] Wu X, Mao Y, Gao Y, et al. Progesterone rise on hCG day is negatively correlated with IVF-ET outcomes in natural cycles[J]. Clinica Chimica Acta, 2018, 478: 194-199.
[11] Vanni V S, Somigliana E, Reschini M, et al. Top quality blastocyst formation rates in relation to progesterone levels on the day of oocyte maturation in GnRH antagonist IVF/ICSI cycles[J]. PLOS ONE, 2017, 12(5).
[12] Racca A, Santos-Ribeiro S, De Munck N, et al. Impact of late-follicular phase elevated serum progesterone on cumulative live birth rates: is there a deleterious effect on embryo quality?[J]. Human Reproduction, 2018, 33(5): 860-868.
[13] Xiong Y, Wang J, Liu L, et al. Effects of high progesterone level on the day of human chorionic gonadotrophin administration in in vitro fertilization cycles on epigenetic modification of endometrium in the peri-implantation period[J]. Fertility and Sterility, 2017, 108(2): 269-276.
[14] Xiong Y, Hu L, Zhang T, et al. Effects of high progesterone in in-vitro fertilization cycle on DNA methylation and gene expression of adhesion molecules on endometrium during implantation window[J]. Journal of Assisted Reproduction and Genetics, 2020, 37(1): 33-43.
[15] Labarta E, Martinez-Conejero J A, Alama P, et al. Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis[J]. Human Reproduction, 2011, 26(7): 1813-1825.
[16] Li R, Qiao J, Wang L, et al. MicroRNA array and microarray evaluation of endometrial receptivity in patients with high serum progesterone levels on the day of hCG administration[J]. Reproductive Biology and Endocrinology, 2011, 9(1): 29.
[17] Zhang J, Du M, Wu Y, et al. Effect of serum progesterone levels on hCG trigger day on pregnancy outcomes in GnRH antagonist cycles[J]. Frontiers in Endocrinology, 2022, 13.
[18] Xu B, Li Z, Zhang H, et al. Serum progesterone level effects on the outcome of in vitro fertilization in patients with different ovarian response: an analysis of more than 10,000 cycles[J]. Fertility and Sterility, 2012, 97(6): 1321-1327.
[19] Wu Z, Dong Y, Ma Y, et al. Progesterone elevation on the day of hCG trigger has detrimental effect on live birth rate in low and intermediate ovarian responders, but not in high responders[J]. Scientific Reports, 2019, 9(1): 5127.
[20] Griesinger G, Mannaerts B, Andersen C Y, et al. Progesterone elevation does not compromise pregnancy rates in high responders: a pooled analysis of in vitro fertilization patients treated with recombinant follicle-stimulating hormone/gonadotropin-releasing hormone antagonist in six trials[J]. Fertility and Sterility, 2013, 100(6): 1622-1628.e3.
[21] Cao Y, Liu J, Zhang Y. Correlation Analysis between the Elevation of Serum Progesterone on the Triggering Day and the Rate of High-quality Embryos in Populations with Different Ovarian Responses [J]. Acta Academiae Medicinae Tianjinensis, 2019, 25(4): 385-390.
[22] Neves A R, Santos-Ribeiro S, García-Martínez S, et al. The effect of late-follicular phase progesterone elevation on embryo ploidy and cumulative live birth rates[J]. Reproductive BioMedicine Online, 2021, 43(6): 1063-1069.
[23] Oktem O, Akin N, Bildik G, et al. FSH Stimulation promotes progesterone synthesis and output from human granulosa cells without luteinization[J]. Human Reproduction, 2017, 32(3): 643-652.