Comparison of the pregnancy outcomes of progestin-primed vs. antagonist ovarian stimulation in patients with poor ovarian response: a retrospective study

Abstract

Objectives

Progestin-primed ovarian stimulation (PPOS) is an efficient controlled ovarian stimulation (COS) method. The study explored the pregnancy outcomes between PPOS and antagonist ovarian stimulation protocol (GnRH-ant) in infertile patients with poor ovarian response (POR).

Methods

This retrospective study included patients with POR who underwent COS at the Reproductive Medical Center of Shanxi Maternal and Child Health Hospital from January 2021 to April 2022. The cycles were grouped as the GnRH-ant group and the PPOS group. The primary outcome was the clinical pregnancy rate; the secondary outcomes included the biochemical pregnancy abortion rate and live birth rate.

Results

Frozen embryo transfer was used in all cycles in this study. The cycles were divided into the GnRH-ant (n = 236 cycles) and PPOS (n = 273 cycles) groups. Age, BMI, type of infertility, infertility duration, FSH, LH, PRL, E2, T, P, and the number of cycles in the hospital were similar between the two groups (all p > 0.05). No statistically significant differences were observed in the clinical pregnancy rate (primary outcome, 32.71% vs. 43.90%, p = 0.082), total Gn dose, total Gn days, ART mode (IVF or ICSI), AFC, MII follicles, 2PN embryos, fertility, cycle cancelation rate, biochemical pregnancy rate, abortion rate, or live birth rate between the two groups (all p > 0.05). The PPOS group exhibited a higher rate of high-quality embryos than the GnRH-ant group (50.12% vs. 42.90%, p = 0.045).

Conclusions

The PPOS protocol was comparable to the GnRH-ant protocol regarding induction parameters and cycle cancelation, biochemical pregnancy, clinical pregnancy, and abortion rates but might be associated with a higher proportion of high-quality embryos.

Keywords:

• High progesterone ovarian stimulation
• low ovarian response
• pregnancy outcome

Introduction

Assisted reproductive technology (ART) is one of the key factors in infertility treatment [1–3]. Controlled ovarian stimulation (COS) is an important component of ART that allows obtaining oocytes for in vitro fertilization (IVF) [1–3]. Still, COS can have difficulties overcoming poor ovarian function (POF) and yielding sufficient oocytes for IVF, leading to poor outcomes [4–6].

Poor ovarian response (POR) to ovarian stimulation is the most challenging and is usually related to advanced maternal age and abnormal ovarian reserve [7]. The incidence of POR in women undergoing ART with COS ranges from 9% to 24% (and up to 35% in some reports) [8, 9], and POR is associated with poor pregnancy outcomes [9]. The common COS agents (gonadotropin (Gn) and gonadotropin-releasing hormone agonist (GnRH-a)) appear to be less effective in POR [3], but several alternative strategies have been described, including growth hormone (GH) [10], double stimulation [11], and gonadotropin-releasing-hormone antagonist (GnRH-ant) [12]. Although these new strategies require confirmation, they appear to achieve better clinical outcomes, lower frequency of side effects, and a lower cost compared with aggressive COS with high dosages of Gn [13–15]. The GnRH antagonist protocols also appear effective in women with POR [16, 17]. Indeed, in poor responders classified Poseidon Group 4, the GnRH-ant protocol with maximum FSH dose and supplementary LH achieved better follicular output rates, follicle-to-oocyte index, number of day-2 embryos, and number of top-quality embryos than a milder protocol [18]. As reviewed by Shrestha et al. [17], the GnRH-ant protocol achieves good outcomes in poor responders.

High-progesterone ovarian stimulation protocols (HPOS, including progestin-primed ovarian stimulation (PPOS)) are more flexible and have recently emerged in clinical practice [19]. Their advantages lie in better control of LH levels, lower costs, and easier administration (i.e. oral, no injections) than conventional COS, while the ovulation induction effects and clinical pregnancy outcomes are similar to those of traditional COS [20, 21]. Moreover, PPOS is considered a feasible COS protocol in women >40 years of age [22]. However, the available literature evaluated the success or failure of COS on the oocyte and embryo outcomes, but the reported follow-up is often not long enough to report the effects of COS on birth rate and other pregnancy outcomes [20–22].

Therefore, this study aimed to explore the clinical pregnancy outcomes between PPOS and GnRH-ant in infertile patients with POR.

Methods

Study design and patients

This retrospective study included patients with POR who underwent IVF or intracytoplasmic sperm injection (ICSI) at the Reproductive Medical Center of Shanxi Maternal and Child Health Hospital from January 2021 to April 2022. The study was approved by the Medical Ethics Committee of the Hospital (IRB-KY-2021-001). The requirement for informed consent was waived due to the retrospective nature of this study.

The definition of POR was 1) older mothers (≥40 years old) or any other POR risk factors, 2) previous POR, with conventional stimulation regimen yielding ≤3 oocytes, and 3) abnormal ovarian reserve test results (i.e. AFC of 5-7 follicles or AMH at 0.5-1.1 ng/ml) [7].

This study used specialized data statistics software for human assisted reproductive technology from Wuhan Mutual Creation United Technology Co., Ltd. The screening process involved searching for IVF-assisted pregnancy patients with a total of ≤5 bilateral ovarian antral follicles determined by vaginal ultrasound within the system. Patients with infertility caused by abnormal endocrine, metabolic, or autoimmune diseases were excluded. Patients with hydrosalpinx, scar diverticulum, polyps, and other factors that may affect embryo implantation were also excluded. POR was diagnosed according to the criteria of the 2011 European Society of Human Reproduction and Embryology (ESHRE) consensus [7].

Grouping and COS procedure

The included cycles were divided into two groups according to the ovulation induction strategies accepted by the patients: the antagonist ovarian stimulation protocol (the GnRH-ant group) and the PPOS group. The specific plan is determined based on doctor recommendations and patient choices.

The patients in the GnRH-ant group were treated with Gn (FSH, Urofollitropin, Zhuhai Lizhu Medicine) at 150–300 U/day starting on the 2^nd to 4^th menstruation days. GnRH antagonists (Ganirelix acetate, Merck Serono, Switzerland) were added when the dominant follicles reached a diameter greater than 12 mm. Upon follicle development to approximately 18 mm in diameter, 5000 U of hCG were administered 36–38 h prior to oocyte retrieval. The patients in the PPOS group were intramuscularly injected with Gn (FSH, Urofollitropin, Zhuhai Lizhu Medicine) at 150-300 U/day, combined with oral medroxyprogesterone acetate (MPA, Pfizer, Italy) at 10 mg/d starting on the 2^nd to 4^th menstruation days until human chorionic gonadotropin (hCG) day. When the follicle developed to a diameter of about 18 mm, 5000 U of hCG were injected 36-38 h before oocyte retrieval.

Frozen embryo transfer (FET) was used in all cycles in this study. For the FET protocol with a natural cycle, the endometrium and follicles were monitored. The transfer was performed when the endometrial thickness was >8 mm 3 days after ovulation. If the endometrial thickness was insufficient, estradiol valerate was supplemented according to the situation, and luteal support was provided after transfer. Dydrogesterone was taken twice daily, one capsule each time, and blood was tested 10 days later.

For the artificial cycle, on the 2^nd to 4^th day of menstruation, 2 mg/day of estradiol valerate was given for 7 days, followed by 4 mg/day for 3 days. When the thickness of the endometrium reached ≥8 mm, dydrogesterone tablets were given three times a day, one capsule for three days after transfer, while continuing to take estradiol valerate until the blood test. After transfer, the corpus luteum was supported, and dydrogesterone tablets were given three times a day, one capsule each time, for 10 days before blood testing.

Data collection

The data were extracted from the medical records management system of the Reproductive Medicine Center of Shanxi Maternal and Child Health Hospital (Lianhe Science and Technology Co., Ltd.). They included age, body mass index (BMI), occupation, infertility type, years of infertility, assisted reproduction programs (IVF or ICSI), basic follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), estradiol (E2), testosterone (T), progesterone (P), total Gn, the total number of days of Gn, and the total number of cycles at the study hospital. A cycle was defined as oocyte collection, embryo transfer, and follow-up.

The effect of ovulation induction was observed, including antral follicle count (AFC), the number of mature follicles on hCG day, and the rates of mature follicles (MII), diprokaryotic embryos (2PN), transferable embryos, and high-quality embryos. The cycle cancelation rate was also recorded. The cycle cancelation rate was calculated as (number of cycles with unharvested oocytes + number of cycles without embryos to transfer)/the total number of cycles. High-quality embryos were defined as day 3 embryos having 7-8 cells with little difference in size and fragmentation <15%.

Outcomes

The primary outcome was the clinical pregnancy rate (the transfer cycle of clinical pregnancy sac observed under ultrasound/total transfer cycle). The secondary outcomes included the biochemical pregnancy rate (the transfer cycle of biochemical pregnancy/total transfer cycle), the abortion rate (number of abortion cycles/number of clinical pregnancy cycles), and the live birth rate (number of live births/number of clinical pregnancies. All patients were followed up on the 10^th, 12^th, 20^th, 28^th, 35^th, and 42^nd days after embryo transfer (ET) and the day of the child’s birth. Biochemical pregnancy was defined as hCG ≥40 mIU/ml. Clinical pregnancy was defined as a gestational sac seen under ultrasound.

Statistical analysis

Statistical analysis was performed using SPSS 21.0 (IBM Corp., Armonk, NY, USA). The continuous data conforming to the normal distribution were presented as mean ± standard deviation (SD) and analyzed using Student’s t-test. Those not conforming to the normal distribution were presented as median (range) and analyzed using the Mann-Whitney U-test. Categorical data were presented as n (%) and analyzed using the chi-square test. Two-sided P-values <0.05 were considered statistically significant.

Results

Characteristics of the patients

Out of 5197 cycles in 3188 patients, 829 cycles were included based on the sum of bilateral ovarian antral follicle numbers being ≤5; 201 cycles were excluded because of other ovulation induction regimens, 50 for incomplete data, 29 because of endocrine or immune factors, 13 for hydrosalpinx, and 27 for endometrial polyps. Therefore, 509 cycles were included: 273 cycles with PPOS and 236 with GnRH-ant (Figure 1).

Figure 1. Study flowchart.

Age, BMI, type of infertility, infertility duration, FSH, LH, PRL, E2, T, P, and the number of cycles in the hospital were similar between the two groups (all p > 0.05). Only the occupation was different, with more teachers and medical personnel in the PPOS group and more company employees in the GnRH-ant group (p < 0.001) (Table 1).

Table 1. Characteristics of the patients.

Characteristics	GnRH-ant (n = 236 cycles)	PPOS (n = 273 cycles)	P
Age, years	35.09 ± 5.80	35.96 ± 5.59	0.087
BMI, kg/cm^2	22.92 ± 3.63	23.62 ± 4.42	0.056
Occupation			<0.001
Wait for employment	65 (27.54)	78 (28.57)
Company employee	85 (36.02)	88 (32.23)
Teachers	18 (7.63)	29 (10.63)
Individual household	22 (9.32)	26 (9.52)
Medical personnel	14 (5.93)	21 (7.69)
Freelance work	10 (4.24)	10 (3.66)
Accountant	9 (3.81)	6 (2.20)
Others	13 (5.51)	16 (5.86)
Type of infertility			0.178
Primary infertility	130 (55.08)	125 (45.79)
Secondary infertility	106 (44.92)	148 (54.21)
Years of infertility, years	4.30 ± 3.62	4.63 ± 3.86	0.422
Sex hormones (baseline)
FSH, mIU/ml	12.92 ± 8.32	12.57 ± 7.81	0.352
LH, mIU/ml	4.35 ± 3.38	3.97 ± 2.69	0.161
PRL, ng/ml	14.41 ± 10.90	14.42 ± 14.20	0.995
E2, pg/ml	59.54 ± 23.20	60.50 ± 24.10	0.652
T, ng/ml	47.16 ± 18.08	45.16 ± 36.63	0.446
P, ng/ml	0.52 ± 0.22	0.53 ± 0.24	0.749
The total number of cycles in the hospital	2.88 ± 2.13	2.98 ± 2.45	0.625

The data are shown as n (%) or mean ± standard deviation.

BMI: body mass index; FSH: follicle-stimulating hormone; LH: luteinizing hormone; PRL: prolactin; E2: estradiol; T: testosterone; P: progesterone.

Ovulation induction effect and pregnancy outcomes

There were no statistically significant differences in total Gn dose, total Gn days, mode of ART (IVF or ICSI), AFC, MII follicles, 2PN embryos, fertility, cycle cancelation rate, biochemical pregnancy rate, clinical pregnancy rate, and abortion rate between the two groups (all p > 0.05). The rate of high-quality embryos was higher in the PPOS group than in the GnRH-ant group (50.12% vs. 42.90%, p = 0.045) (Table 2). In the GnRH-ant group, there were six cases of miscarriage and two cases of ectopic pregnancy, resulting in a live birth rate of 27/35 (77.14%). In the PPOS group, there were seven cases of miscarriage and four cases of ectopic pregnancy, resulting in a live birth rate of 43/54 (79.63%) (p = 0.780).

Table 2. Comparison of ovulation-promoting effects and pregnancy outcomes.

Characteristics	GnRH-ant group (n = 236 cycles)	PPOS group (n = 273 cycles)	P
Total Gn, U	2615.16 ± 1660.81	2359.99 ± 1339.98	0.056
Total days of Gn, days	10.06 ± 3.89	9.74 ± 3.51	0.331
Assisted reproduction program			0.527
IVF	73/236 (48.67)	85/273 (45.21)
ICSI	77/236 (51.33)	103/273 (54.79)
Antral follicle counting	4.03 ± 2.18	3.85 ± 1.697	0.268
Mature follicles (MII)	2.81 ± 1.39	2.55 ± 1.27	0.068
Number of diprokaryotic embryos (2PN)	340/422 (80.56)	353/479 (73.70)	0.083
Fertility	359/422 (85.07)	415/479 (86.64)	0.500
Rate of high-quality embryos	154/359 (42.90)	208/415 (50.12)	0.045
Cancelation rate of cycle	86/236 (36.44)	85/273 (31.13)	0.206
Pregnancy outcomes
Biochemical pregnancy rate	45/107 (42.06)	58/123 (47.15)	0.438
Clinical pregnancy rate	35/107 (32.71)	54/123 (43.90)	0.082
Abortion rate	6/35 (17.14)	7/54 (12.96)	0.585
Live birth rate	27/35 (77.14)	43/54 (79.63)	0.780

The data are shown as n (%) or mean ± standard deviation.

Gn: gonadotropin; IVF: in vitro fertilization; ICSI: intracytoplasmic sperm injection.

Discussion

The present study suggests that the pregnancy outcomes in the PPOS group were comparable to the GnRH-ant group. Still, the proportion of high-quality embryos appeared higher in the PPOS group. A higher yield of high-quality embryos could influence the pregnancy outcomes in some patients. Additional studies in larger sample sizes are required for confirmation.

A recent study by Turkgeldi et al. [23] compared the outcomes of the GnRH-ant and PPOS protocols and concluded that PPOS could be used in women with decreased ovarian reserve without compromising the number of retrieved oocytes. Although the definition of decreased ovarian reserve differs from the ESHRE criteria for POR [7], the study by Turkgledi et al. supports the present study [23]. Importantly, in the present study, the proportion of high-quality embryos was higher with the PPOS protocol than with the GnRH-ant protocol. All other retrieval and ET parameters were similar between the two groups.

In the present study, the clinical pregnancy rate was similar between the two groups. A previous study evaluated the outcomes of PPOS (63 cycles) and GnRH-ant (123 cycles) and reported that compared with the GnRH-ant protocol, PPOS was significantly more effective in improving the clinical pregnancy rate in women with POR [24]. This discrepancy can be due to many reasons, including the criteria for POR and the characteristics of the patients.

To the best of our knowledge, up to date, there is only one published study comparing GnRH-ant and HPOS in women with POR. Wu et al. [25] reported no outcome differences between the two groups. Still, POR was diagnosed according to the Bologna criteria, and the number of the highest-quality embryos obtained in the Wu study was higher. At the same time, the basal E2 was lower compared to the present study. The mean age of participants and duration of infertility were higher, suggesting that the study population differed from the present study. Hence, it is important to select the patients carefully to obtain homogeneous study populations and to compare the COS protocols among various patient populations. In this way, studies could reveal the most appropriate protocols for specific patient populations.

There is no published data available on the relationship between E2 and HPOS outcomes in POR, but a recent study reported that PPOS might be the reason for significantly lower E2 in women with polycystic ovarian syndrome [26]. Still, the effect of E2 on ART outcomes is under discussion, and the previous studies were conducted under fresh embryo transfer conditions. Some of them reported that the serum E2 concentrations on the trigger day have a positive correlation with the pregnancy outcomes [27], but others reported adverse effects [28] or no association at all [29]. In the present study, the baseline levels of E2 were not significantly different between the two groups, and frozen ET was performed for all cycles.

Despite the number of proposed strategies, no clear conclusion has been established yet on which COS protocol would be preferable for patients with POR [5, 6, 30]. While the GnRH-ant protocol has some economic advantages [31], PPOS might be a promising new protocol for treating women with POR and could yield better-quality embryos. Additional prospective randomized trials are needed to evaluate its effects.

The present study suggests that the pregnancy outcomes in the PPOS group were comparable to the GnRH-ant group, but the proportion of high-quality embryos appeared to be higher in the PPOS group. A higher yield of high-quality embryos could influence pregnancy outcomes in some patients. The fact that the two protocols appear to yield similar pregnancy outcomes is a result in itself. It suggests that the two protocols are possible in the study population, and the choice of a protocol over the other can, therefore, be made based on adverse effects and costs without compromising the pregnancy outcomes. Of course, the present study has limitations, and that apparent similitude must be confirmed in formal trials. The clinical significance of the higher yield of high-quality embryos with the GnRH-ant protocol is also worth exploring. High-quality embryos have a higher probability of implantation, which could affect the clinical pregnancy rates, and embryo quality is considered one of the most important factors influencing the success of IVF [32, 33]. Still, implantation is affected by many factors, including endometrial thickness, and embryo quality is only one factor affecting implantation [34]. Still, high-quality embryos could control one factor affecting implantation [35, 36].

This study had some limitations. This study was retrospective, limiting the data to those available in the patient charts. The limited study period also resulted in a relatively small number of patients/cycles that could be included. Retrospective studies can suffer from an information bias. In addition, the selection criteria introduce an inevitable selection bias that can limit the generalizability of the conclusions. Retrospective studies have a low level of evidence, and the results obtained here should be validated in future multicenter, large-sample prospective randomized controlled trials on the application value of COS in patients with POR using PPOS. At the study hospital, the treatment plans are always comprehensively discussed between the patient and the physician until a plan is mutually agreed upon. Various clinical, economic, and personal considerations are considered in the decision to propose a given strategy. Unfortunately, the exact and complete clinical reasoning is not always clearly indicated in the charts. Secondly, even though the follow-up was longer compared with other studies to evaluate the successful birth rate parameter, there were no statistically significant differences between the two groups. Thirdly, the two groups were similar in patient characteristics, except for occupation. Occupation was provided to give an idea of the socioeconomic status of the included patients, but the differences should not influence the results, especially since the differences in percentages were small. Finally, frozen embryo transfer was used in all cycles in this study, and the results (pregnancy rate and live birth rate) cannot be compared to established fresh transfer protocols.

In conclusion, the PPOS protocol was comparable to the GnRH-ant protocol regarding induction parameters and cycle cancelation, biochemical pregnancy, clinical pregnancy, and abortion rates but might be associated with a higher proportion of high-quality embryos.

Availability of data and material

All data generated or analyzed during this study are included in this published article.

Ethical statement

The study was approved by the Medical Ethics Committee of Shanxi Maternal and Child Health Hospital (IRB-KY-2021-001). The informed consent of the patients was waived due to the retrospective nature of this study.

Acknowledgments

Thanks to the Reproductive Medicine Center of Shanxi Maternal and Child Health Hospital for providing the data.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Shanxi Reproductive and Genetic Research Technology cultivation team under Grant (number: 2020TD19). The funder was not involved in the study design, collection, analysis, interpretation of data, writing the paper, or decision to submit it for publication.

Notes on contributors

Zuoping Shi

Zuoping Shi: Protocol/project development. Wenhui Zhao: Data collection or management. Xueqing Wu: Data analysis. Xingyu Bi: Manuscript writing/editing.

Wenhui Zhao

Zuoping Shi: Protocol/project development. Wenhui Zhao: Data collection or management. Xueqing Wu: Data analysis. Xingyu Bi: Manuscript writing/editing.

Xueqing Wu

Zuoping Shi: Protocol/project development. Wenhui Zhao: Data collection or management. Xueqing Wu: Data analysis. Xingyu Bi: Manuscript writing/editing.

Xingyu Bi

Zuoping Shi: Protocol/project development. Wenhui Zhao: Data collection or management. Xueqing Wu: Data analysis. Xingyu Bi: Manuscript writing/editing.