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. 2026 Jan 23;7:1719930. doi: 10.3389/frph.2025.1719930

Progestin-primed ovarian stimulation protocol in patients undergoing assisted reproductive technology

Shanqin Qi 1,†,‡, Haiyan Yu 1,2,†, Xiaojing Yang 1,3,†, Qinghan Shi 4, Liu Yang 5, Kehua Wang 6,*,‡
PMCID: PMC12876159  PMID: 41659361

Abstract

Purpose

To evaluate the effectiveness and safety of the novel protocol—progestin-primed ovarian stimulation (PPOS) protocol during controlled ovarian hyperstimulation (COH), in patients undergoing in vitro fertilization/intracytopalsmic sperm injection and embryo transfer (IVF/ICSI-ET).

Methods

By reviewing and analyzing published studies since PPOS protocol was firstly reported in 2015, we compared differences in ovarian stimulation characteristics, embryological features, pregnancy rates, and neonatal outcomes between PPOS protocol and conventional regimens employed in assisted reproductive technology (ART), and discussed the advantages and limitations of PPOS protocol.

Main finding

By adding exogenous progestin (P) during early follicular phase, PPOS scheme provide robust control over preovulatory luteinizing hormone (LH) surge and spontaneous ovulation, which promote oocyte maturation and recovery. Compared to various traditional protocols, PPOS achieved promising clinical pregnancy results, and equivalent rates of birth defect and congenital malformation. Moreover, it possessed significantly lower risk of ovarian hyperstimlation syndrome (OHSS).

Conclusion

Not inferior or comparable outcomes indicated that PPOS protocol is a competent alternative for ART with no obviously detrimental impact on oocyte development and embryo quality.

Keywords: embryo competence, in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI), oocyte quality, premature LH surge, reproductive outcome

1. Introduction

One of the premises of a successful in vitro fertilization/intracytoplasmic sperm injection and embryo transfer (IVF/ICSI-ET) treatment is high-quality oocytes and embryos. The suggested way to improve pregnancy outcomes is to facilitate the growth and maturation of follicles and ensure the generation of viable or high-quality embryos (1). The rise in the serum estradiol (E2) concentration with multi-follicular development results in the premature surge of the luteinizing hormone (LH) via positive feedback effects on the pituitary level to induce ovulation. This reduces the number of oocytes collected and disrupts the schedule of assisted reproductive technology (ART), leading to disappointing results for both clinicians and patients (2, 3). Gonadotropin-releasing hormone (GnRH) analog is extensively used to suppress untimely LH surges, however, due to the complexity of treatments, specific side effects, and ineffective blockade of GnRH analog (4–8), better approaches are urgently needed to control preovulatory LH surges.

Kuang and colleagues (9) successfully conducted luteal phase stimulation and showed that luteal phase endogenous progesterone blocks the LH surge. The same group (10) investigated the novel progestin-primed ovarian stimulation (PPOS) protocol to explore the effect of follicular phase exogenous progesterone in inhibiting untimely LH rise. The PPOS protocol showed similar outcomes to the traditional controlled ovarian stimulation (COS) regimens (10–16), and the several advantages of PPOS over the classical method, including oral administration, lower cost, and good compliance, make it a widely used approach (12, 17).

PPOS protocol simultaneously combines conventional COH medications including but not limited to gonadotropin (Gn), commonly known as human menopausal gonadotropin (hMG) and follicle-stimulating hormone (FSH) (17–19), or GnRH analog (20–22), or clomiphene citrate and letrozole (23–26), with progestin, such as medroxyprogesterone acetate (MPA) (10, 17, 21, 27–30), dydrogesterone (Duphaston, DYG) (18, 20, 29–31), or micronized progesterone (Utrogestan, MIP) (32, 33), from the natural or artificial menstruation cycle day (MC) 2–5 to human chorionic gonadotropin (hCG) administration day. The final stage of oocyte maturation is induced by GnRH agonist (GnRHa) alone or a co-trigger with low-dose hCG. After oocyte pick-up and fertilization by IVF or ICSI, cryopreservation of the whole embryo cohort and a delayed freeze-thaw embryo transfer (FET) are carried out sequentially (10, 18, 29).

In a natural cycle, as multiple follicles develop, estradiol is continuously produced and induces an LH surge in the late follicular phase leading to spontaneous ovulation (34). Progestin was originally used for contraception as it resists the aforementioned procedure. Later, it was found to be effective in preventing premature ovulation in COH (31, 35). When progestin is continuously given (starting from the early follicular phase), it can inhibit the LH peak and allow more oocytes maturation and retrieval by blocking the estradiol-induced positive feedback of GnRH pulse and Gn secretion through hypothalamus-pituitary-ovary (HPO) axis (36). However, early exposure of the endometrium to progestin leads to reduced receptivity and embryo-endometrium asynchrony; fresh embryo transfer is not feasible in this context and FET in a later cycle is required (35, 37, 38). Advancements in cryopreservation successfully separate the standard sequence of stimulation-retrieval-fertilization-transfer (12), which promoted the widespread acceptance of the PPOS scheme (17).

This article extensively reviewed studies and compared the efficacy and safety of PPOS protocol with conventional protocols. The comparative parameters include ovarian stimulation characteristics, embryonic features, pregnancy rates, and neonatal health risks in ART.

2. Materials and methods

2.1. Literature search

We mainly searched two databases, PubMed and the Cochrane Library, covering the period from 2015 to 2024. A combined search was carried out using MeSH terms and free-text keywords, including but not limited to “progestin-primed ovarian stimulation”, “PPOS”, “controlled ovarian hyperstimulation”, “COH”, “controlled ovarian stimulation”, “COS”, “in vitro fertilization”, “IVF”, “assisted reproductive technology”, “ART”. Relevant references were also manually searched. After deleting duplicates and reading through the entire text, we selected 29 articles on the clinical research of the PPOS protocol and extracted information regarding the mechanisms and results of PPOS.

2.2. Selection criteria

Inclusion criteria: (1) RCT or retrospective studies published in English; (2) undergoing IVF or ICSI; (3) study group is the PPOS regimen, control group is GnRH analog regimen, natural cycle, or micro-stimulation regimen; (4) research indicators involve COS data, IVF laboratory results, and pregnancy outcomes.

Exclusion criteria: (1) narrative reviews, conferences, etc.; (2) missing original data.

2.3. Risk assessment

Two authors (SQ and HY) assessed the risk of bias for each literature using the Cochrane bias risk tool, categorized into three levels: low risk, medium risk, and high risk. If there was a disagreement, it was discussed and decided with the third author (XY).

3. Results

3.1. Ovarian stimulation, oocyte performance, embryonic feature, and clinical outcome

3.1.1. Comparison with GnRHa short protocol

Kuang et al. (10), for the first time, conducted a prospective controlled study consisting of 300 normogonadotropic patients to compare the IVF/ICSI outcomes with PPOS and GnRHa short protocol. The number of retrieved oocytes through the PPOS protocol was similar to the GnRHa short protocol (9.9 ± 6.7 vs. 9.0 ± 6.0), however, PPOS resulted in higher hMG consumption and persisted LH suppression. Premature LH surge was 0.7% in the PPOS group. The implantation rate (IR, 31.9% vs. 27.7%), clinical pregnancy rate (CPR, 47.8% vs. 43.3%), and live birth rate (LBR, 42.6% vs. 35.5%) in the PPOS group were slightly higher than that of the controls but failed to reach a statistical significance. They concluded that MPA was a viable alternative for LH surge suppression in patients undergoing COH. Zhu et al. (33) replaced MPA with MIP and got similar results, i.e., comparable oocyte retrieval, mature oocyte rate, IR, and CPR. Wang et al. (17) verified the protocol in polycystic ovarian syndrome (PCOS) patients and achieved a higher fertilization rate (77.69 ± 16.59 vs. 70.54 ± 19.23) and ongoing pregnancy rate (OPR, 58.67% vs. 42.86%) in the PPOS group. Wen et al. (39) detected 12 elevated lipidomic components in follicular fluid (FF) in patients receiving PPOS, and this group showed a better clinical outcome compared with the patients on the short GnRHa protocol.

3.1.2. Comparison with GnRH antagonist protocol

The GnRH antagonist (GnRHant) protocol has gained steady popularity since the 1990s (40, 41). This protocol is flexible, swift, and includes reversible suppression of the pituitary, so the comparisons of the PPOS protocol with the GnRHant protocol are quite common. In a retrospective analysis, Huang et al. (42) concluded that among patients with poor ovarian response (POR), the PPOS group had significantly higher rates of metaphase II (MII) oocytes, fertilization, top-quality embryo, clinical pregnancy, and live birth compared with the antagonist group. Du et al. (43) applied PPOS in patients with POR diagnosed according to Poseidon standard, and found that the Gn dosage of PPOS protocol in Poseidon 1 group was higher than that of antagonist protocol, but the number of available embryos in Poseidon 2 groups was significantly increased, and other outcomes were similar. Yildiz et al. (11) performed a self-control study involving two COH cycles within 6 months per oocyte donor (a flexible PPOS cycle following a previous antagonist cycle) in which MPA was administered based on the same standard as the antagonist. More cumulus-oocyte complexes (COC) and more MII oocytes were collected from the flexible PPOS group than from the control. Recipients achieved identical rates of fertilization and pregnancy. This study was considered to be a high-quality analysis and support the effectiveness of the PPOS protocol in a systematic review (12). After that, the same team used flexible PPOS protocol in decreased ovarian reserve (DOR) patients, and achieved identical results as flexible antagonist scheme in terms of premature LH rate, number of retrieved eggs and MII eggs; They also concluded that fPPOS has less inhibition on pituitary and better response to GnRHa trigger in normal responders (22, 44, 45). Li et al. (46) implemented a prospective cohort study to explore the differences in apoptotic rates of granulosa cells (GCs) and hormone levels in FF between patients on the PPOS and the antagonist protocol. They obtained similar GCs apoptotic rates, FF hormonal profiles, ovarian response, and laboratory parameters, including MII oocyte rate, fertilization rate, and optimal-embryo rate. Several other studies (10, 13, 16, 19, 20) from different countries and centers also independently arrived at similar conclusions that the PPOS protocol is as effective as the antagonist protocol in providing COH.

In contrast, Beguería et al. (21) achieved an unexpectedly lower biochemical pregnancy rate (BPR), CPR, OPR, and LBR in the MPA group compared with the antagonist group in a prospective randomized controlled trial (RCT). They speculated that the primary reason for this discrepancy is that the recombinant FSH (rFSH) administered in their study was hCG free, while the hMG used in some studies (47) contained microdose hCG, which improved LH activity. They also triggered ovulation with GnRHa alone, which may be less effective than co-trigger with GnRHa and low-dose hCG (21). Notably, ovarian stimulation, laboratory features, and recipients' baselines were all comparable between the two groups. The inferior pregnancy rates may be because of uncontrolled confounders or the protocol itself and need to be further analyzed. Caetano et al. (48) recovered less oocytes (mean number 9 vs. 11) and slightly higher CPR (58.4% vs. 54.9%, p = 0.735) in the progestin (MPA or DYG) group compared with the GnRHant group. The authors declared that the oocyte collection difference might be attributed to the baseline heterogeneity. The GnRHant group showed lower baseline FSH and more antral follicle count (AFC), indicating better ovarian reserve. No significant differences were observed in gonadotropin dose and duration, fertilization rate, and blastocyst formation rate, and the LH blockade was credible (< 1%).

3.1.3. Comparison with GnRHa long protocol

Chen et al. (13) performed a self-controlled, retrospective study to investigate the pregnancy rate of PPOS protocol in aged infertile women who had a failed previous cycle with GnRHa long protocol. They found significantly higher oocyte utilization rate (54.5% vs. 46.9%) and optimal embryo rate (59.9% vs. 45.6%) and correspondingly increased CPR (22.58% vs. 12.70%) after FET in the MPA group.

3.1.4. Comparison with GnRHa ultra-long protocol

Yang et al. (14) compared the effect of PPOS with GnRHant and GnRHa ultra-long protocol in endometrioma patients undergoing IVF/ICSI. In this study, BPR, CPR, and LBR were significantly lower in the MPA group than that in the ultra-long group (OR 2.3, 95% CI 1.1–4.9, OR 2.4, 95% CI 1.1–5.3, OR 2.6, 95% CI 1.3–5.1, respectively) but were all similar to the GnRHant group. Oocyte collection, endometrial thickness, and OPR were equivalent in all arms. Noticeably, demographic data were balanced between PPOS and GnRHant groups. But the ultra-long group had a significantly lower age of patients (30 vs. 34) and partners (31 vs. 34), and more AFC (11 vs. 5), these may be the contributing factors to the discrepancy in pregnancy rates.

3.1.5. Comparison with mild stimulation protocol

Mild stimulation has been proved to generate high-quality oocytes and fewer aneuploid embryos due to less intervention to the ovary. This was especially important for aged or diminished ovarian reserve (DOR) patients, therefore, someone (49) chose it as control while validating the PPOS protocol. Peng et al. (50) investigated the embryological characteristics between the two regimens in women aged above 40. They found a significantly lower spontaneous LH surge rate (2.1% vs. 12.3%) and a higher percentage of top-quality embryos (50.08% vs. 33.29%) with the adjuvant DYG. Tu et al. (15) also gained similar outcomes of more oocyte retrieval (p < 0.001) and top-quality embryos (p = 0.038) and a lower incidence of untimely LH rise (0.7% vs. 8.3%, p = 0.001) in DOR patients.

3.1.6. Comparison with the natural cycle

Chen et al. (16) investigated the inhibitory capacity of the natural cycle and PPOS protocol on the LH peak. Employing mild stimulation (MPA 10 mg/d from MC 3, hMG 75–150 U when FSH was ≤ 8 U/L) in this study, the MPA group achieved statistically lower incidence of spontaneous ovulation (2% vs. 10.8%) and premature LH surge (1% vs. 50%), and significantly more recovered oocytes and viable embryos. The authors certificated the robust inhibition of MPA on LH surge, with no side effects on oocyte quality and embryo competence.

3.2. Incidence of premature LH surge and OHSS risk

Several studies showed stronger control of the PPOS scheme over premature LH surge regardless of the progestin type. Kuang et al. (10) reduced the spontaneous LH surge rate to 0.7% with MPA, which is significantly lower than the reported 0.34% – 38% in the GnRHant group. Zhu et al. (18) compared Duphaston (20 mg/d) vs. Utrogestan (100 mg/d), while Yu et al. (31) compared Duphaston (20 mg/d) vs. MPA (10 mg/d) respectively, in similarly designed prospective studies in normal ovulatory patients. Similar results were obtained: no premature LH surge, no moderate or severe ovarian hyperstimulation syndrome (OHSS), and similar laboratory data and pregnancy rates in each study. In a Japanese study (20), no patient had a spontaneous LH peak, while one patient developed moderate OHSS in PPOS and GnRHant groups, respectively. As the primary endpoint of a prospective RCT in POR patients performed by Chen et al. (51), the premature LH surge was zero in the PPOS group vs. 5.88% in the antagonist group and neither group showed moderate or severe OHSS. Xiao et al. (52) established the reduced risk of mild-moderate OHSS (0 vs. 6.67%) in the MPA group, with no harmful effect on clinical results in PCOS patients compared with the GnRHant group. In a comparison of DYG and antagonist in another PCOS cohort (19), the results were consistent with Zhu et al. (18) and Yu et al. (31). A systematic review (53) also summarized PPOS protocol to result in a lower frequency of OHSS (RR 0.52, 95% CI 0.36–0.75) and equivalent pregnancy rates when compared with the controls.

3.3. Neonatal outcomes

After years of application, the safety of mild stimulation and GnRHa short protocol have been verified (48, 54, 55). Zhang et al. (56) enrolled 4,596 newborns in a retrospective study to investigate the potential impact of PPOS and the two conventional protocols on fetal development and calculated no difference in neonatal outcomes or congenital malformations among the three arms. Wang et al. (57) investigated 1,589 infants from either the PPOS regimen or GnRHa short protocol and confirmed similar birth characteristics and live-birth defects rate. Liang et al. (58) investigated infants delivered by mothers with advanced endometriosis who underwent ART with either PPOS, GnRHant protocol, or GnRHa long protocol and failed to exhibit any difference in neonatal outcomes. No adverse effect of progestin on embryonic development potential was established.

3.4. Cost-effectiveness

Longer duration and higher dosage of Gn are common profiles in PPOS protocol than others except for GnRHa downregulation protocol due to its stable control of the pituitary (10, 15, 20, 33, 50, 53). The PPOS protocol is still more economical during COH because of the lower price of progestin than GnRH analog. A study (20) calculated a total cost savings of 176.5 dollars in inhibiting premature LH peak with DYG over antagonist per patient. Mathieu et al. (59) stated that the PPOS scheme could save 209 euros per aspirated cycle. However, the cryopreservation of embryos and freeze-thaw procedure necessitated for PPOS will increase the overall cost, which makes it less cost-effective in that sense (60). Overall, this protocol may be especially applicable for those who attempt fertility preservation, preimplantation genetic diagnosis, or oocyte donors, or those with endometrial polyps and need treatment before transfer (61).

4. Discussion

Premature LH surge occurs in 3% – 10% of IVF cycles, it compromises oocyte yield and leads to embryo-endometrium asynchrony and hence increases cycle cancelation rate (2, 3, 38, 62). Conventional protocols employ GnRHa or antagonist to prohibit the premature LH rise, however, the GnRHa protocol is prone to high OHSS risk, hypo-oestrogenic symptoms, and ovarian cysts (4, 63), while the antagonist protocol is associated with decreased oocytes yield, increased cancellation rate, and incomplete LH surge blockade (5, 6, 41, 62), especially for those with advanced age or DOR (7, 8). Besides, both increase the complexity and cost of treatment. So, specialists come up with the novel use of progestin.

Progestin has been used for contraception for at least 50 years, it blocks the E2-induced LH surge to inhibit ovulation (64). Based on this, experts explored its application in preventing preovulation (10, 31, 35). High concentration of progestin can suppress the hypothalamic GnRH pulse, thus reducing the pulsatile secretion of LH (65). Follicular phase administration of progestin generates a decrease in the frequency and amplitude of LH pulses, as well as a reduction in plasma concentration (66). It is assumed that three stages constitute the GnRH surge: initiation, transmission, and release in a natural cycle (65). The adjuvant progestin in the stages of signal initiation and transmission can prohibit the surge, however, it will not work if given during the late stage of signal transmission, i.e., the onset of GnRH/LH surge (67). So the role of progestin in stimulating or blocking an LH surge depends on its administration time (18). Therefore, it is scheduled during the early follicular phase in PPOS protocol, or when the E2 level is less than 50 – 70 pg/mL (10).

GnRH-ant causes rapid suppression of LH by competing for GnRH receptors (68), but endogenous estrogen can induce some GnRH release, so a premature LH surge may still occur (51). In the PPOS protocol, the application of progesterone precedes the estrogen surge, inhibiting hypothalamic GnRH pulses through negative feedback and thereby indirectly and moderately controlling the pituitary, maintaining a stable low level of LH throughout the COH process and ensuring oocyte maturation and quality (51, 69, 70). However, accurately comparing different studies on premature LH surge is challenging. Firstly, there is a lack of a precise definition: some consider an increase in LH levels over 10 (59, 71, 72) or 15 (51, 73) as premature, while others only intervene when LH levels exceed 20 (16). Secondly, there are differences between protocols, for example, even within antagonist protocols, the starting time, dosage, and frequency of antagonists vary.

In terms of laboratory results and pregnancy outcomes, most studies suggest that PPOS is comparable to conventional regimens, including rates of aneuploidy, number of oocytes retrieved, number of top-quality embryos, CPR, LBR, and miscarriage rate (12, 74–76). Previous studies have suggested that LH accumulation during the follicular phase may impair GCs, reduce the developmental potential and maturity of oocytes, leading to suboptimal oocytes and embryos (77–79). The PPOS protocol can antagonize LH surges by reducing the frequency of LH pulses and increasing the concentration of E2 and P in follicular fluid, which provide a suitable internal environment for oocyte maturation (80, 81). Carter et al. (82) observed not only no effect of exogenous progestin on in vitro oocyte maturation and blastogenesis but progestin also enhanced fertilization and cleavage rate. Aparicio et al. (83) reported a positive correlation between exogenous P and oocyte quality.

Of course, experts currently have concerns about this new scheme. Some believe that progesterone may cause the developmental arrest of oocytes in the GV stage, reducing the blastocyst rate. Salehnia and Zavareh (84) suggested that progestin will reduce oocyte maturity rate if the concentration of adjuvant P increased from 10 to 100 µmol/L. Silva and Knight (85) supported this view and reported a 40% decrease in bovine blastocyst rate with the addition of progestin. Progesterone receptors are expressed in granulosa cells, and progesterone exerts its effects on oocytes through them (86). Some scholars (87) have pointed out that high levels of P before ovulation disrupt the mitochondrial OXPHOS pathway, damaging granulosa cell function and consequently harming oocyte quality. The administration of antioxidants can reverse this effect. Therefore, for patients at risk of oxidative stress, such as those who are obese or elderly, PPOS may not be the best option (86). Thus the impact of the PPOS scheme on oocyte and embryo development requires more in-depth exploration through both in vivo and in vitro studies.

OHSS is one of the common complications in IVF, usually mild to moderate (88). Due to the development of multiple follicles, several corpora lutea formed when exogenous hCG was used to induce the final maturation of oocytes, which stimulates the ovaries to produce a large amount of vascular endothelial growth factor (VEGF) and other vasoactive substances, increasing vascular permeability, which causes fluid accumulation outside the blood vessels (89, 90). The endogenous and exogenous hCG after embryo transfer exacerbate this pathology, and in severe cases, it can be life-threatening. Unlike the pituitary-suppressing effect of the long GnRHa protocol, the PPOS regimen is allowed to use GnRHa to trigger the final maturation of oocytes. The advantage of GnRHa is that it simultaneously triggers LH and FSH surges, mimicking the endocrine characteristics of the natural cycle, thereby promoting oocyte maturation and cumulus expansion (91). In addition, the short-term LH/FSH surge by GnRHa trigger reduces luteal VEGF secretion, preventing OHSS (92). It has been reported that in IVF cycles, the OHSS rate triggered by HCG is around 16% – 30%, whereas GnRHa significantly reduces this proportion (93). Therefore, PPOS combined with GnRHa trigger is an ideal choice for reducing the risk of OHSS and maintaining pregnancy potential. At the same time, the inherent freeze-all strategy of the PPOS protocol separates the sequential processes of ovarian stimulation and embryo transfer, which effectively reduces the incidence of OHSS (90), making it a suitable choice for populations at high risk of OHSS, such as those with PCOS.

Compared with conventional GnRH analog regimen (11, 21, 46, 94, 95), natural cycle (16, 61), or mild stimulation cycle (16, 27, 57, 63), whether they were in poor (13, 16, 30, 44, 45, 96), normal (10, 18, 66, 97), or high responders (17, 52, 94, 97), RCT or not (53, 98), prospective and retrospective (10, 21, 53, 96, 99), or whether the primary measurement were ovarian stimulation characteristics (85, 98, 99), endocrinological profiles (46, 51, 65–67), embryological features (16, 27, 84), clinical results (28, 43, 52, 57), neonatal outcomes (56–58), or incidence of preovulatory LH surge and OHSS (12, 19, 35, 51, 65), PPOS has achieved encouraging results. In summary, there are mainly two viewpoints: one advocates that the PPOS scheme shows no significant statistical difference from the control group, and is even superior to the control group in aspects such as the suppression of the early LH peak and the prevention of OHSS. The other viewpoint suggests that the advantages of PPOS are not universal, as patients who are older or have endometriosis may not benefit significantly.

This article suffers from some limitations. Firstly, the efficacy of different types and doses of progestin, as well as modifications of the PPOS protocol, were not discussed. Secondly, differences in type and initial dosage of Gn, ovulation trigger agent, the threshold of premature LH surge, etc., may affect the evaluation power and needs to be refined. Well-designed and more comprehensive future studies are warranted to investigate the strengths and weaknesses of the PPOS protocol.

5. Conclusion

In conclusion, the PPOS protocol is not inferior when compared with the controls and is an effective and safe choice for ART. In the future, the benefits and drawbacks of this program, as well as the target population, need to be supported by more high-quality clinical research.

Acknowledgments

The authors would like to thank all the colleagues who helped with literature retrieval and analysis.

Funding Statement

The author(s) declared that financial support was received for this work and/or its publication. This study was supported by Tai'an Science and Technology Innovation Development Project (2024NS130).

Edited by: Shevach Friedler, Barzilai Medical Center, Israel

Reviewed by: Shahar Kol, Independent Researcher, Haifa, Israel

Muhjah Falah, University of Kerbala, Iraq

Abbreviations 2PN, 2 pronuclei; AFC, antral follicle count; ART, assisted reproductive technology; BR, biochemical pregnancy; CA, corifollitropin alfa; CCPR, cumulative clinical pregnancy rate; CLBR, cumulative live birth rate; CMA, chlormadinone acetate; COC, cumulus oocyte complexes; COS, controlled ovarian stimulation; CPR, clinical pregnancy rate; DOR, deminished ovarian reserve; DYG, dydrogesterone; E2, estrodiol; FET, frozen-thawed embryo transfer; FF, follicular fluid; fPPOS, flexible progestin-primed ovarian stimulation; GCs, granulosa cells; Gn, gonadotropin; GnRH, gonadotropin-releasing hormone; GnRHa, GnRH agonist; GnRHant, GnRH antagonist; hCG, human chorionic gonadotropin; hMG, human menopausal gonadotropin; HPO, hypothalamus-pituitary-ovary; IR, implantation rate; IVF/ICSI-ET, in vitro fertilization/ intracytoplasmic sperm injection and embryo transfer; LBR, live birth rate; LH, luteinizing hormone; LPS, luteal phase stimulation; MC, menstruation cycle day; MII, metaphase II; MIP, micronized progesterone (Utrogestan); MPA, medroxyprogesterone acetate; N, no; No. number; NOR, normal ovarian response; OHSS, ovarian hyperstimulation syndrome; OPR, ongoing pregnancy rate; OPU, oocyte pick-up; P, progesterone; PCOS, polycystic ovarian syndrome; POR, poor ovarian response; PPOS, Progestin-primed ovarian stimulation; RCT, randomized controlled trial; rFSH, recombinant follicle stimulating hormone; VEGF, vascular endothelial growth factor; Y, yes.

Author contributions

SQ: Writing – original draft, Conceptualization, Methodology. HY: Methodology, Writing – original draft. XY: Writing – original draft, Methodology. QS: Writing – original draft, Funding acquisition. LY: Writing – original draft, Data curation. KW: Writing – review & editing, Supervision.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/frph.2025.1719930/full#supplementary-material

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References

  • 1.Pirtea P, de Ziegler D, Poulain M, Ayoubi JM. New twists in ovarian stimulation and their practical implications. Front Med (Lausanne). (2019) 6:197. 10.3389/fmed.2019.00197 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Messinis IE. Ovarian feedback, mechanism of action and possible clinical implications. Hum Reprod Update. (2006) 12(5):557–71. 10.1093/humupd/dml020 [DOI] [PubMed] [Google Scholar]
  • 3.Papanikolaou EG, Kolibianakis EM, Pozzobon C, Tank P, Tournaye H, Bourgain C, et al. Progesterone rise on the day of human chorionic gonadotropin administration impairs pregnancy outcome in day 3 single-embryo transfer, while has no effect on day 5 single blastocyst transfer. Fertil Steril. (2009) 91(3):949–52. 10.1016/j.fertnstert.2006.12.064 [DOI] [PubMed] [Google Scholar]
  • 4.Mehta RH, Anand Kumar TC. Can GnRH agonists act directly on the ovary and contribute to cyst formation? Hum Reprod. (2000) 15(3):505–7. 10.1093/humrep/15.3.505 [DOI] [PubMed] [Google Scholar]
  • 5.Lambalk CB, Banga FR, Huirne JA, Toftager M, Pinborg A, Homburg R, et al. GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type. Hum Reprod Update. (2017) 23(5):560–79. 10.1093/humupd/dmx017 [DOI] [PubMed] [Google Scholar]
  • 6.Kahyaoğlu S, Yılmaz B, Işık AZ. Pharmacokinetic, pharmacodynamic, and clinical aspects of ovulation induction agents: a review of the literature. J Turk Ger Gynecol Assoc. (2017) 18(1):48–55. 10.4274/jtgga.2016.0107 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Bosch E, Valencia I, Escudero E, Crespo J, Simón C, Remohí J, et al. Premature luteinization during gonadotropin-releasing hormone antagonist cycles and its relationship with in vitro fertilization outcome. Fertil Steril. (2003) 80(6):1444–9. 10.1016/j.fertnstert.2003.07.002 [DOI] [PubMed] [Google Scholar]
  • 8.Reichman DE, Zakarin L, Chao K, Meyer L, Davis OK, Rosenwaks Z. Diminished ovarian reserve is the predominant risk factor for gonadotropin-releasing hormone antagonist failure resulting in breakthrough luteinizing hormone surges in in vitro fertilization cycles. Fertil Steril. (2014) 102(1):99–102. 10.1016/j.fertnstert.2014.04.010 [DOI] [PubMed] [Google Scholar]
  • 9.Kuang Y, Hong Q, Chen Q, Lyu Q, Ai A, Fu Y, et al. Luteal-phase ovarian stimulation is feasible for producing competent oocytes in women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment, with optimal pregnancy outcomes in frozen-thawed embryo transfer cycles. Fertil Steril. (2014) 101(1):105–11. 10.1016/j.fertnstert.2013.09.007 [DOI] [PubMed] [Google Scholar]
  • 10.Kuang Y, Chen Q, Fu Y, Wang Y, Hong Q, Lyu Q, et al. Medroxyprogesterone acetate is an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Fertil Steril. (2015) 104(1):62–70.e3. 10.1016/j.fertnstert.2015.03.022 [DOI] [PubMed] [Google Scholar]
  • 11.Yildiz S, Turkgeldi E, Angun B, Eraslan A, Urman B, Ata B. Comparison of a novel flexible progestin primed ovarian stimulation protocol and the flexible gonadotropin-releasing hormone antagonist protocol for assisted reproductive technology. Fertil Steril. (2019) 112(4):677–83. 10.1016/j.fertnstert.2019.06.009 [DOI] [PubMed] [Google Scholar]
  • 12.Ata B, Capuzzo M, Turkgeldi E, Yildiz S, La Marca A. Progestins for pituitary suppression during ovarian stimulation for ART: a comprehensive and systematic review including meta-analyses. Hum Reprod Update. (2021) 27(1):48–66. 10.1093/humupd/dmaa040 [DOI] [PubMed] [Google Scholar]
  • 13.Chen Y-m, Qi Q-r, Xie Q-z, Yang Y-f, Xia Y, Zhou X-d. Effect of progestin-primed ovarian stimulation protocol on outcomes of aged infertile women who failed to get pregnant in the first IVF/ICSI cycle: a self-controlled study. Curr Med Sci. (2018) 38(3):513–8. 10.1007/s11596-018-1908-z [DOI] [PubMed] [Google Scholar]
  • 14.Yang A-M, Feng T-F, Han Y, Zhao Z-M, Wang W, Wang Y-Z, et al. Progestin-primed ovarian stimulation protocol for patients with endometrioma. Front Endocrinol (Lausanne). (2022) 13:798434. 10.3389/fendo.2022.798434 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Tu X, You B, Jing M, Lin C, Zhang R. Progestin-primed ovarian stimulation versus mild stimulation protocol in advanced age women with diminished ovarian reserve undergoing their first in vitro fertilization cycle: a retrospective cohort study. Front Endocrinol (Lausanne). (2022) 12:801026. 10.3389/fendo.2021.801026 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Chen Q, Wang Y, Sun L, Zhang S, Chai W, Hong Q, et al. Controlled ovulation of the dominant follicle using progestin in minimal stimulation in poor responders. Reprod Biol Endocrinol. (2017) 15(1):71. 10.1186/s12958-017-0291-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Wang Y, Chen Q, Wang N, Chen H, Lyu Q, Kuang Y. Controlled ovarian stimulation using medroxyprogesterone acetate and hMG in patients with polycystic ovary syndrome treated for IVF. Medicine (Baltimore). (2016) 95(9):e2939. 10.1097/md.0000000000002939 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Zhu X, Ye H, Fu Y. Duphaston and human menopausal gonadotropin protocol in normally ovulatory women undergoing controlled ovarian hyperstimulation during in vitro fertilization/intracytoplasmic sperm injection treatments in combination with embryo cryopreservation. Fertil Steril. (2017) 108(3):505–12.e2. 10.1016/j.fertnstert.2017.06.017 [DOI] [PubMed] [Google Scholar]
  • 19.Huang T-C, Huang M-Z, Seow K-M, Yang I-J, Pan S-P, Chen M-J, et al. Progestin primed ovarian stimulation using corifollitropin alfa in PCOS women effectively prevents LH surge and reduces injection burden compared to GnRH antagonist protocol. Sci Rep. (2021) 11(1):22732. 10.1038/s41598-021-02227-w [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Iwami N, Kawamata M, Ozawa N, Yamamoto T, Watanabe E, Moriwaka O, et al. New trial of progestin-primed ovarian stimulation using dydrogesterone versus a typical GnRH antagonist regimen in assisted reproductive technology. Arch Gynecol Obstet. (2018) 298(3):663–71. 10.1007/s00404-018-4856-8 [DOI] [PubMed] [Google Scholar]
  • 21.Beguería R, García D, Vassena R, Rodríguez A. Medroxyprogesterone acetate versus ganirelix in oocyte donation: a randomized controlled trial. Hum Reprod. (2019) 34(5):872–80. 10.1093/humrep/dez034 [DOI] [PubMed] [Google Scholar]
  • 22.Kalafat E, Turkgeldi E, Yıldız S, Dizdar M, Keles I, Ata B. Outcomes of a GnRH agonist trigger following a GnRH antagonist or flexible progestin-primed ovarian stimulation cycle. Front Endocrinol. (2022) 13:837880. 10.3389/fendo.2022.837880 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Ye H, Tian H, He W, Lyu Q, Kuang Y, Chen Q, et al. Progestin-primed milder stimulation with clomiphene citrate yields fewer oocytes and suboptimal pregnancy outcomes compared with the standard progestin-primed ovarian stimulation in infertile women with polycystic ovarian syndrome. Reprod Biol Endocrinol. (2018) 16(1):53. 10.1186/s12958-018-0373-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Lin Y, Chen Q, Zhu J, Teng Y, Huang X, Chen X. Progestin-primed ovarian stimulation with clomiphene citrate supplementation may be more feasible for young women with diminished ovarian reserve compared with standard progestin-primed ovarian stimulation: a retrospective study. Drug Des Devel Ther. (2021) 15:5087–97. 10.2147/dddt.S338748 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Jiang X, Jiang S, Diao H, Deng K, Zhang C. Progestin-primed ovarian stimulation protocol with or without letrozole for patients with normal ovarian reserve: a retrospective cohort study. J Clin Pharm Ther. (2021) 47(4):469–76. 10.1111/jcpt.13567 [DOI] [PubMed] [Google Scholar]
  • 26.Liu Y, Chen Q, Yu S, Wang Y, He W, Chang HY-N, et al. Progestin-primed ovarian stimulation with or without clomiphene citrate supplementation in normal ovulatory women undergoing in vitro fertilization/intracytoplasmic sperm injection: a prospective randomized controlled trial. Clin Endocrinol. (2018) 88(3):442–52. 10.1111/cen.13532 [DOI] [PubMed] [Google Scholar]
  • 27.Cai R, Zheng B, Lin Q, Deng J, Zeng X, Lin W, et al. A meta-analysis of the efficacy of progestin-primed ovarian stimulation with medroxyprogesterone acetate in ovulation induction in poor ovarian responders. J Gynecol Obstet Hum Reprod. (2021) 50(7):102049. 10.1016/j.jogoh.2020.102049 [DOI] [PubMed] [Google Scholar]
  • 28.Dong J, Wang Y, Chai WR, Hong QQ, Wang NL, Sun LH, et al. The pregnancy outcome of progestin-primed ovarian stimulation using 4 versus 10 mg of medroxyprogesterone acetate per day in infertile women undergoing in vitro fertilisation: a randomised controlled trial. BJOG. (2017) 124(7):1048–55. 10.1111/1471-0528.14622 [DOI] [PubMed] [Google Scholar]
  • 29.Huang J, Xie Q, Lin J, Lu X, Zhu J, Gao H, et al. Progestin-primed ovarian stimulation with dydrogesterone versus medroxyprogesterone acetate in women with polycystic ovarian syndrome for in vitro fertilization: a retrospective cohort study. Drug Des Devel Ther. (2019) 13:4461–70. 10.2147/DDDT.S230129 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Zhang J, Du M, Li Z, Liu W, Ren B, Zhang Y, et al. Comparison of dydrogesterone and medroxyprogesterone in the progestin-primed ovarian stimulation protocol for patients with poor ovarian response. Front Endocrinol. (2021) 12:708704. 10.3389/fendo.2021.708704 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Yu S, Long H, Chang HY-n, Liu Y, Gao H, Zhu J, et al. New application of dydrogesterone as a part of a progestin-primed ovarian stimulation protocol for IVF: a randomized controlled trial including 516 first IVF/ICSI cycles. Hum Reprod. (2018) 33(2):229–37. 10.1093/humrep/dex367 [DOI] [PubMed] [Google Scholar]
  • 32.Zhu X, Ye H, Fu Y. Use of utrogestan during controlled ovarian hyperstimulation in normally ovulating women undergoing in vitro fertilization or intracytoplasmic sperm injection treatments in combination with a “freeze all” strategy: a randomized controlled dose-finding study of 100 mg versus 200 mg. Fertil Steril. (2017) 107(2):379–86.e4. 10.1016/j.fertnstert.2016.10.030 [DOI] [PubMed] [Google Scholar]
  • 33.Zhu X, Zhang X, Fu Y. Utrogestan as an effective oral alternative for preventing premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. Medicine (Baltimore). (2015) 94(21):e909. 10.1097/md.0000000000000909 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Messinis IE, Messini CI, Dafopoulos K. Novel aspects of the endocrinology of the menstrual cycle. Reprod Biomed Online. (2014) 28(6):714–22. 10.1016/j.rbmo.2014.02.003 [DOI] [PubMed] [Google Scholar]
  • 35.Massin N. New stimulation regimens: endogenous and exogenous progesterone use to block the LH surge during ovarian stimulation for IVF. Hum Reprod Update. (2017) 23(2):211–20. 10.1093/humupd/dmw047 [DOI] [PubMed] [Google Scholar]
  • 36.La Marca A, Capuzzo M. Use of progestins to inhibit spontaneous ovulation during ovarian stimulation: the beginning of a new era? Reprod Biomed Online. (2019) 39(2):321–31. 10.1016/j.rbmo.2019.03.212 [DOI] [PubMed] [Google Scholar]
  • 37.Maheshwari A, Pandey S, Shetty A, Hamilton M, Bhattacharya S. Obstetric and perinatal outcomes in singleton pregnancies resulting from the transfer of frozen thawed versus fresh embryos generated through in vitro fertilization treatment: a systematic review and meta-analysis. Fertil Steril. (2012) 98(2):368–77.e1-9. 10.1016/j.fertnstert.2012.05.019 [DOI] [PubMed] [Google Scholar]
  • 38.Labarta E, Martínez-Conejero JA, Alamá P, Horcajadas JA, Pellicer A, Simón C, et al. Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. (2011) 26(7):1813–25. 10.1093/humrep/der126 [DOI] [PubMed] [Google Scholar]
  • 39.Wen X, Kuang Y, Zhou L, Yu B, Chen Q, Fu Y, et al. Lipidomic components alterations of human follicular fluid reveal the relevance of improving clinical outcomes in women using progestin-primed ovarian stimulation compared to short-term protocol. Med Sci Monit. (2018) 24:3357–65. 10.12659/msm.906602 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Nakano R, Mizuno T, Kotsuji F, Katayama K, Wshio M, Tojo S. “Triggering” of ovulation after infusion of synthetic luteinizing hormone releasing factor (LRF). Acta Obstet Gynecol Scand. (1973) 52(3):269–72. 10.3109/00016347309158325 [DOI] [PubMed] [Google Scholar]
  • 41.Hall JE, Brodie TD, Badger TM, Rivier J, Vale W, Conn PM, et al. Evidence of differential control of FSH and LH secretion by gonadotropin-releasing hormone (GnRH) from the use of a GnRH antagonist. J Clin Endocrinol Metab. (1988) 67(3):524–31. 10.1210/jcem-67-3-524 [DOI] [PubMed] [Google Scholar]
  • 42.Huang P, Tang M, Qin A. Progestin-primed ovarian stimulation is a feasible method for poor ovarian responders undergoing in IVF/ICSI compared to a GnRH antagonist protocol: a retrospective study. J Gynecol Obstet Hum Reprod. (2019) 48(2):99–102. 10.1016/j.jogoh.2018.10.008 [DOI] [PubMed] [Google Scholar]
  • 43.Du M, Zhang J, Li Z, Liu X, Li J, Liu W, et al. Comparison of the cumulative live birth rates of progestin-primed ovarian stimulation and flexible GnRH antagonist protocols in patients with low prognosis. Front Endocrinol. (2021) 12:705264. 10.3389/fendo.2021.705264 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Turkgeldi E, Yildiz S, Cekic SG, Shakerian B, Keles I, Ata B. Effectiveness of the flexible progestin primed ovarian stimulation protocol compared to the flexible GnRH antagonist protocol in women with decreased ovarian reserve. Hum Fertil. (2020) 25(2):306–12. 10.1080/14647273.2020.1794060 [DOI] [PubMed] [Google Scholar]
  • 45.Kalafat E, Dizdar M, Turkgeldi E, Yildiz S, Keles I, Ata B. The comparison of fixed and flexible progestin primed ovarian stimulation on mature oocyte yield in women at risk of premature ovarian insufficiency. Front Endocrinol. (2022) 12:797227. 10.3389/fendo.2021.797227 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Li X, Zhang X, Cai J, Pang J, Sun P, Chen J, et al. Granulosa cells apoptosis and follicular fluid hormones: comparison of progestin-primed ovarian stimulation versus GnRH antagonist protocols. Gynecol Endocrinol. (2020) 37(7):609–13. 10.1080/09513590.2020.1822802 [DOI] [PubMed] [Google Scholar]
  • 47.Rao CV. Differential properties of human chorionic gonadotrophin and human luteinizing hormone binding to plasma membranes of bovine corpora lutea. Acta Endocrinol (Copenh). (1979) 90(4):696–710. 10.1530/acta.0.0900696 [DOI] [PubMed] [Google Scholar]
  • 48.Caetano JPJ, Calazans LC, Amorim LVC, Pereira LMR, Xavier E, Campos ALM, et al. Progestin-primed ovarian stimulation is a non-inferior alternative to the GnRH antagonist protocol in patients undergoing assisted reproductive techniques: a retrospective study. JBRA Assist Reprod. (2022) 26(1):38–43. 10.5935/1518-0557.20210057 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Gianaroli L, Magli MC, Cavallini G, Crippa A, Capoti A, Resta S, et al. Predicting aneuploidy in human oocytes: key factors which affect the meiotic process. Hum Reprod. (2010) 25(9):2374–86. 10.1093/humrep/deq123 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Peng Q, Cao X, Wang J, Wang L, Xu J, Ji X, et al. Progestin-primed ovarian stimulation vs mild stimulation in women with advanced age above 40: a retrospective cohort study. Reprod Biol Endocrinol. (2019) 17(1):91. 10.1186/s12958-019-0518-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Chen Q, Chai W, Wang Y, Cai R, Zhang S, Lu X, et al. Progestin vs. gonadotropin-releasing hormone antagonist for the prevention of premature luteinizing hormone surges in poor responders undergoing in vitro fertilization treatment: a randomized controlled trial. Front Endocrinol. (2019) 10:796. 10.3389/fendo.2019.00796 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Xiao Z-n, Peng J-l, Yang J, Xu W-m. Flexible GnRH antagonist protocol versus progestin-primed ovarian stimulation (PPOS) protocol in patients with polycystic ovary syndrome: comparison of clinical outcomes and ovarian response. Curr Med Sci. (2019) 39(3):431–6. 10.1007/s11596-019-2055-x [DOI] [PubMed] [Google Scholar]
  • 53.Cui L, Lin Y, Wang F, Chen C. Effectiveness of progesterone-primed ovarian stimulation in assisted reproductive technology: a systematic review and meta-analysis. Arch Gynecol Obstet. (2021) 303(3):615–30. 10.1007/s00404-020-05939-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Bergh T, Ericson A, Hillensjö T, Nygren KG, Wennerholm UB. Deliveries and children born after in-vitro fertilisation in Sweden 1982–95: a retrospective cohort study. Lancet. (1999) 354(9190):1579–85. 10.1016/S0140-6736(99)04345-7 [DOI] [PubMed] [Google Scholar]
  • 55.Westergaard HB, Johansen AM, Erb K, Andersen AN. Danish national in-vitro fertilization registry 1994 and 1995: a controlled study of births, malformations and cytogenetic findings. Hum Reprod. (1999) 14(7):1896–902. 10.1093/humrep/14.7.1896 [DOI] [PubMed] [Google Scholar]
  • 56.Zhang J, Mao X, Wang Y, Chen Q, Lu X, Hong Q, et al. Neonatal outcomes and congenital malformations in children born after human menopausal gonadotropin and medroxyprogesterone acetate treatment cycles. Arch Gynecol Obstet. (2017) 296(6):1207–17. 10.1007/s00404-017-4537-z [DOI] [PubMed] [Google Scholar]
  • 57.Wang N, Lin J, Zhu Q, Fan Y, Wang Y, Fu Y, et al. Comparison of neonatal outcomes and live-birth defects after progestin-primed ovarian stimulation versus conventional ovarian stimulation for in vitro fertilization. Medicine (Baltimore). (2018) 97(34):e11906. 10.1097/md.0000000000011906 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Liang Z, Wang Y, Kuang Y. Live-birth outcomes and congenital malformations after progestin-primed ovarian stimulation in maternal endometriosis. Drug Des Devel Ther. (2020) 14:5459–67. 10.2147/DDDT.S263138 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Mathieu d’Argent E, Ferrier C, Zacharopoulou C, Ahdad-Yata N, Boudy A-S, Cantalloube A, et al. Outcomes of fertility preservation in women with endometriosis: comparison of progestin-primed ovarian stimulation versus antagonist protocols. J Ovarian Res. (2020) 13(1):18. 10.1186/s13048-020-00620-z [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Evans MB, Parikh T, DeCherney AH, Csokmay JM, Healy MW, Hill MJ. Evaluation of the cost-effectiveness of ovulation suppression with progestins compared with GnRH analogs in assisted reproduction cycles. Reprod Biomed Online. (2019) 38(5):691–8. 10.1016/j.rbmo.2018.12.044 [DOI] [PubMed] [Google Scholar]
  • 61.Guan S, Feng Y, Huang Y, Huang J. Progestin-primed ovarian stimulation protocol for patients in assisted reproductive technology: a meta-analysis of randomized controlled trials. Front Endocrinol. (2021) 12:702558. 10.3389/fendo.2021.702558 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev. (2016) 4(4):Cd001750. 10.1002/14651858.CD001750.pub4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Toftager M, Bogstad J, Bryndorf T, Løssl K, Roskær J, Holland T, et al. Risk of severe ovarian hyperstimulation syndrome in GnRH antagonist versus GnRH agonist protocol: RCT including 1050 first IVF/ICSI cycles. Hum Reprod. (2016) 31(6):1253–64. 10.1093/humrep/dew051 [DOI] [PubMed] [Google Scholar]
  • 64.Heikinheimo O, Gordon K, Williams RF, Hodgen GD. Inhibition of ovulation by progestin analogs (agonists vs antagonists): preliminary evidence for different sites and mechanisms of actions. Contraception. (1996) 53(1):55–64. 10.1016/0010-7824(95)00255-3 [DOI] [PubMed] [Google Scholar]
  • 65.Richter TA, Robinson JE, Lozano JM, Evans NP. Progesterone can block the preovulatory gonadotropin-releasing hormone/luteinising hormone surge in the ewe by a direct inhibitory action on oestradiol-responsive cells within the hypothalamus. J Neuroendocrinol. (2005) 17(3):161–9. 10.1111/j.1365-2826.2005.01287.x [DOI] [PubMed] [Google Scholar]
  • 66.Soules MR, Steiner RA, Clifton DK, Cohen NL, Aksel S, Bremner WJ. Progesterone modulation of pulsatile luteinizing hormone secretion in normal women. J Clin Endocrinol Metab. (1984) 58(2):378–83. 10.1210/jcem-58-2-378 [DOI] [PubMed] [Google Scholar]
  • 67.Harris TG, Dye S, Robinson JE, Skinner DC, Evans NP. Progesterone can block transmission of the estradiol-induced signal for luteinizing hormone surge generation during a specific period of time immediately after activation of the gonadotropin-releasing hormone surge-generating system. Endocrinology. (1999) 140(2):827–34. 10.1210/endo.140.2.6490 [DOI] [PubMed] [Google Scholar]
  • 68.He W, Li X, Adekunbi D, Liu Y, Long H, Wang L, et al. Hypothalamic effects of progesterone on regulation of the pulsatile and surge release of luteinising hormone in female rats. Sci Rep. (2017) 7(1):8096. 10.1038/s41598-017-08805-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Wang M, Zheng L, Ma S, Xu Y, Zhang J, Fu L. A comparison of the effects of progestin-primed ovarian stimulation protocol and gonadotropin-releasing hormone antagonist protocol in assisted reproductive technology: a systematic review and meta-analysis. J Assist Reprod Genet. (2025) 42(10):3217–29. 10.1007/s10815-025-03612-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Zhang W, Xie D, Zhang H, Huang J, Xiao X, Wang B, et al. Cumulative live birth rates after the first ART cycle using flexible GnRH antagonist protocol vs. standard long GnRH agonist protocol: a retrospective cohort study in women of different ages and various ovarian reserve. Front Endocrinol (Lausanne). (2020) 11:287. 10.3389/fendo.2020.00287 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Kao T-C, Hsieh Y-C, Yang I-J, Wu M-Y, Chen M-J, Yang J-H, et al. Progestin-primed ovarian stimulation versus GnRH antagonist protocol in poor responders: risk of premature LH surge and outcome of oocyte retrieval. J Formos Med Assoc. (2023) 122(1):29–35. 10.1016/j.jfma.2022.08.023 [DOI] [PubMed] [Google Scholar]
  • 72.Cai H, Shi Z, Liu D, Bai H, Zhou H, Xue X, et al. Flexible progestin-primed ovarian stimulation versus a GnRH antagonist protocol in predicted suboptimal responders undergoing freeze-all cycles: a randomized non-inferiority trial. Hum Reprod. (2025) 40(2):319–27. 10.1093/humrep/deae286 [DOI] [PubMed] [Google Scholar]
  • 73.Zhao W, Sun P, Li T, Li Y, Liang X, Li J. Outcomes and cost-effectiveness comparisons of progestin-primed ovarian stimulation, GnRH antagonist protocol, and luteal phase stimulation for fertility preservation. Int J Gynaecol Obstet. (2023) 163(2):645–50. 10.1002/ijgo.14903 [DOI] [PubMed] [Google Scholar]
  • 74.La Marca A, Capuzzo M, Sacchi S, Imbrogno MG, Spinella F, Varricchio MT, et al. Comparison of euploidy rates of blastocysts in women treated with progestins or GnRH antagonist to prevent the luteinizing hormone surge during ovarian stimulation. Hum Reprod. (2020) 35(6):1325–31. 10.1093/humrep/deaa068 [DOI] [PubMed] [Google Scholar]
  • 75.Vidal MDM, Martínez F, Rodríguez I, Polyzos NP. Ovarian response and embryo ploidy following oral micronized progesterone-primed ovarian stimulation versus GnRH antagonist protocol. A prospective study with repeated ovarian stimulation cycles. Hum Reprod. (2024) 39(5):1098–104. 10.1093/humrep/deae047 [DOI] [PubMed] [Google Scholar]
  • 76.Yang L, Luo K, Lu G, Lin G, Gong F. Euploidy rates among preimplantation genetic testing for aneuploidy cycles with oral dydrogesterone primed ovarian stimulation or GnRH antagonist protocol. Reprod Biomed Online. (2022) 45(4):721–6. 10.1016/j.rbmo.2022.03.003 [DOI] [PubMed] [Google Scholar]
  • 77.Qiao J, Feng HL. Extra- and intra-ovarian factors in polycystic ovary syndrome: impact on oocyte maturation and embryo developmental competence. Hum Reprod Update. (2011) 17(1):17–33. 10.1093/humupd/dmq032 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Franks S, Stark J, Hardy K. Follicle dynamics and anovulation in polycystic ovary syndrome. Hum Reprod Update. (2008) 14(4):367–78. 10.1093/humupd/dmn015 [DOI] [PubMed] [Google Scholar]
  • 79.Yang L, Liang F, Yuan Y, Luo X, Wang Q, Yao L, et al. Efficacy of progestin-primed ovarian stimulation in women with polycystic ovary syndrome undergoing in vitro fertilization: a systematic review and meta-analysis. Front Endocrinol (Lausanne). (2023) 14:1224858. 10.3389/fendo.2023.1224858 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Richter TA, Robinson JE, Evans NP. Progesterone blocks the estradiol-stimulated luteinizing hormone surge by disrupting activation in response to a stimulatory estradiol signal in the ewe. Biol Reprod. (2002) 67(1):119–25. 10.1095/biolreprod67.1.119 [DOI] [PubMed] [Google Scholar]
  • 81.Borman SM, Chaffin CL, Schwinof KM, Stouffer RL, Zelinski-Wooten MB. Progesterone promotes oocyte maturation, but not ovulation, in nonhuman primate follicles without a gonadotropin surge. Biol Reprod. (2004) 71(1):366–73. 10.1095/biolreprod.103.023390 [DOI] [PubMed] [Google Scholar]
  • 82.Carter F, Rings F, Mamo S, Holker M, Kuzmany A, Besenfelder U, et al. Effect of elevated circulating progesterone concentration on bovine blastocyst development and global transcriptome following endoscopic transfer of in vitro produced embryos to the bovine oviduct. Biol Reprod. (2010) 83(5):707–19. 10.1095/biolreprod.109.082354 [DOI] [PubMed] [Google Scholar]
  • 83.Aparicio IM, Garcia-Herreros M, O’Shea LC, Hensey C, Lonergan P, Fair T. Expression, regulation, and function of progesterone receptors in bovine cumulus oocyte complexes during in vitro maturation. Biol Reprod. (2011) 84(5):910–21. 10.1095/biolreprod.110.087411 [DOI] [PubMed] [Google Scholar]
  • 84.Salehnia M, Zavareh S. The effects of progesterone on oocyte maturation and embryo development. Int J Fertil Steril. (2013) 7(2):74–81. [PMC free article] [PubMed] [Google Scholar]
  • 85.Silva CC, Knight PG. Effects of androgens, progesterone and their antagonists on the developmental competence of in vitro matured bovine oocytes. J Reprod Fertil. (2000) 119(2):261–9. 10.1530/reprod/119.2.261 [DOI] [PubMed] [Google Scholar]
  • 86.Handa M, Takiuchi T, Kawaguchi S, Hon C-C, Moody J, Okazaki Y, et al. Adverse effects of progestin-primed ovarian stimulation: combination of clinical study and single-cell analysis. Reprod BioMed Online. (2025) 51(2);104833. 10.1016/j.rbmo.2025.104833 [DOI] [PubMed] [Google Scholar]
  • 87.Lan Y, Zhang S, Gong F, Lu C, Lin G, Hu L. The mitochondrial DNA copy number of cumulus granulosa cells may be related to the maturity of oocyte cytoplasm. Hum Reprod. (2020) 35(5):1120–9. 10.1093/humrep/deaa085 [DOI] [PubMed] [Google Scholar]
  • 88.Practice Committee of the American Society for Reproductive Medicine. Prevention of moderate and severe ovarian hyperstimulation syndrome: a guideline. Fertil Steril. (2024) 121(2):230–45. 10.1016/j.fertnstert.2023.11.013 [DOI] [PubMed] [Google Scholar]
  • 89.Schirmer DA, 3rd, Kulkarni AD, Zhang Y, Kawwass JF, Boulet SL, Kissin DM. Ovarian hyperstimulation syndrome after assisted reproductive technologies: trends, predictors, and pregnancy outcomes. Fertil Steril. (2020) 114(3):567–78. 10.1016/j.fertnstert.2020.04.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.Leathersich S, Roche C, Hart R. Minimising OHSS in women with PCOS. Front Endocrinol (Lausanne). (2025) 16:1507857. 10.3389/fendo.2025.1507857 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Fusi FM, Arnoldi M, Bosisio C, Lombardo G, Ferrario M, Zanga L, et al. Ovulation induction and luteal support with GnRH agonist in patients at high risk for hyperstimulation syndrome. Gynecol Endocrinol. (2015) 31(9):693–7. 10.3109/09513590.2015.1025379 [DOI] [PubMed] [Google Scholar]
  • 92.Castillo JC, Haahr T, Martínez-Moya M, Humaidan P. Gonadotropin-releasing hormone agonist for ovulation trigger—OHSS prevention and use of modified luteal phase support for fresh embryo transfer. Ups J Med Sci. (2020) 125(2):131–7. 10.1080/03009734.2020.1736696 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 93.Castillo JC, Dolz M, Bienvenido E, Abad L, Casañ EM, Bonilla-Musoles F. Cycles triggered with GnRH agonist: exploring low-dose HCG for luteal support. Reprod Biomed Online. (2010) 20(2):175–81. 10.1016/j.rbmo.2009.11.018 [DOI] [PubMed] [Google Scholar]
  • 94.Wang N, Zhu Q, Ma M, Liang Z, Tao Y, Wang Y, et al. Comparison of a progestin-primed ovarian stimulation protocol with a flexible GnRH antagonist protocol in patients with polycystic ovary syndrome who are participating in an IVF programme: study protocol for a randomised controlled trial. BMJ Open. (2020) 10(12):e038153. 10.1136/bmjopen-2020-038153 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Shen X, Gao H, Chen Q, Cai R, Lyu Q, Wang Y, et al. Effect of switching from a progestin-primed ovarian stimulation protocol to a modified ultra-long protocol among women who had 1 progestin-primed ovarian stimulation (PPOS) failure verses those who had 2 PPOS failures. Med Sci Monit. (2020) 26:e918705. 10.12659/msm.918705 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.Wang Y, Kuang Y, Chen Q, Cai R. Gonadotropin-releasing hormone antagonist versus progestin for the prevention of premature luteinising hormone surges in poor responders undergoing in vitro fertilisation treatment: study protocol for a randomised controlled trial. Trials. (2018) 19(1):455. 10.1186/s13063-018-2850-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Zhu J, Zhang J, Yang J, Li D, Wang C, Elizur SE, et al. A comprehensive evaluation of progestin-primed ovarian stimulation protocol in patients with or without PCOS undergoing in vitro fertilization. Reprod Biol. (2021) 21(4):100540. 10.1016/j.repbio.2021.100540 [DOI] [PubMed] [Google Scholar]
  • 98.Guo Y-c, Chen P-y, Li T-t, Jia L, Sun P, Zhu W-s, et al. Different progestin-primed ovarian stimulation protocols in infertile women undergoing in vitro fertilization/intracytoplasmic sperm injection: an analysis of 1188 cycles. Arch Gynecol Obstet. (2019) 299(4):1201–12. 10.1007/s00404-019-05065-4 [DOI] [PubMed] [Google Scholar]
  • 99.Dong M, Sun L, Huang L, Wang F, Zhang X, Liu F. Fixed gonadotropin-releasing hormone antagonist protocol versus flexible progestin-primed ovarian stimulation protocol in patients with asynchronous follicular development during controlled ovulation stimulation: a retrospective study. Front Endocrinol. (2021) 12:690575. 10.3389/fendo.2021.690575 [DOI] [PMC free article] [PubMed] [Google Scholar]

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