Different Methods for Inducing Final Oocyte Maturation When Employing Progesterone-Primed Ovarian Stimulation Protocols

Different Methods for Inducing Final Oocyte Maturation When Employing Progesterone-Primed Ovarian Stimulation Protocols | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Different Methods for Inducing Final Oocyte Maturation When Employing Progesterone-Primed Ovarian Stimulation Protocols Yen-Ju Sung, Liang-Hsuan Chen, Tzu-Hsuan Chin, Shang-Yu Huang, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1002007/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Evidently, when undergoing GnRH-antagonist protocols, dual trigger has proven to produce not just better quality and quantity of oocytes but also pregnancy outcome. However, not much comparative studies have been published when PPOS protocol is used for ovarian stimulation. Can the same positive outcomes be expected after the patients have been exposed to the high level of progesterone required for PPOS protocols? Methods In this retrospective cohort study, patients undergoing PPOS protocols were separated into three groups based on the method employed for triggering final follicular maturation, which included: (a) human chorionic gonadotropin (hCG); (b) Gonadotropin-releasing hormone-agonist (GnRH-agonist); or (c)dual trigger (GnRH-agonist + hCG). Either in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI) was utilized for fertilization. Assessment comprised of their dynamic hormone profiles, embryonic analysis, and clinical outcomes. Results Of the 344 recruited patients, those fulfilling the Bologna criteria as poor ovarian responders and showing Estradiol (E2)<1000 pg/ml on the day of triggering had higher oocyte maturation rate (82% vs 58%, p 6500 pg/ml on the day of triggering, none of the three triggering methods demonstrated a significant advantage regarding the number of oocytes, percentage of matured oocytes, and rate of oocytes at fertilization or cleavage stages. Conclusions Implementing dual trigger for stimulating final follicular maturation in patients undergoing PPOS protocols is debatable. For poor ovarian response (POR) patients, dual trigger appeared to yield higher percentage of matured oocytes. In contrast, for hyper-responders, methods of triggering oocyte maturation did not affect the percentage of matured oocytes or the qualities of the embryos. For this group of patients, therefore, the agent used should be one that would reduce the risks of ovarian hyper-stimulation syndrome (OHSS). Obstetrics & Gynecology progestin primed ovarian stimulation final follicular maturation human chorionic gonadotropin dual trigger embryo quality mature oocyte Background Infertility afflicts about 10% of the female population, with etiologies encompassing tubal, uterine, ovulatory, or unexplained origins [ 1 ]. Whatever the cause, assisted-reproductive technology has become an essential part of the treatment, and the world’s first In vitro fertilization(IVF) baby was born in 1978 [ 2 ]. More than forty years have passed since then, and with progressive maturation of techniques and continuous development of numerous pharmaceutical agents, IVF treatments have grown to become more tailored to each individual patient for optimal effects. Suppressing the luteining hormone (LH) surge is an important part of the IVF cycle and can be clinically overcome with Gonadotropin-releasing hormone-agonist (GnRH-agonist) and Gonadotropin-releasing hormone-antagonist (GnRH-antagonist) [ 3 ]. Through downregulating the gonadotropins during the process of ovarian stimulation, GnRH agonist provides the additional benefit of synchronizing the size and growth of the antral follicles. On the other hand, GnRH-antagonists induce direct inhibitory effect, which has the advantages of faster onsets and less flare-ups [ 4 ]. Such downregulation is later observed in other pathways. Research has shown that progesterone secreted from the corpus luteum has the ability to inhibit the pulsatile secretion of GnRH and thus LH, which in turn blocks the positive feedback loop of Estradiol (E2) [ 5 ]. Therefore, when high concentration of exogeneous progesterone is supplied during controlled-ovarian stimulation, LH surge can be adequately suppressed. Such usage was first documented in 2015 when medroxyprogesterone (MPA) was implemented for LH suppression [ 6 ]. Studies that followed also consistently demonstrated this effect. Thus, the term progesterone-primed ovarian stimulation protocols (PPOS) was coined [ 7 ]. However, when using PPOS protocols, all of the retrieved embryos need to be cryopreserved because fresh embryo transfer is not an option after the endometrium has been exposed to high level of progesterone required for PPOS protocol. The endometrium would have reached the receptive period too early, resulting in embryo-endometrium asynchrony [ 8 ]. Fortunately, with the significant improvement of cryopreservation, high pregnancy rate can still be achieved with thawed embryos [ 9 ]. Therefore, currently, PPOS protocols have been deemed suitable for patients seeking fertility preservation, oocyte donation, or alternative options for avoiding ovarian hyperstimulation syndrome (OHSS) [ 7 ]. During the process of ovarian stimulation, opportune triggering of final follicular maturation is a crucial step, and, previously, human chorionic gonadotropin (hCG) was used as a surrogate of LH to produce such effect. After about 30 years, GnRH-agonists became an alternative agent for triggering final follicular maturation during GnRH-antagonist protocols with the goal of reducing risks of OHSS [ 10 ]. This concept was indeed proven by later researches, with many of them demonstrating less occurrences of OHSS with GnRH-agonist when compared with hCG; however, lower live birth and ongoing pregnancy rate (pregnancy beyond 12 weeks) and higher early miscarriage (less than 12 weeks) rate were observed with GnRH-agonist [ 11 ]. This may be attributed to defective luteal phase and decreased endometrial receptivity resulted from GnRH-agonist trigger [ 12 ]. Hence, the concept of “dual trigger” emerged, which combined a bolus of GnRH-agonist and a bolus of hCG at the time of triggering, and has been proven advantageous. In a retrospective study, when dual trigger was used for normal responders, the results showed higher implantation, clinical pregnancy, and live-birth rates when compared with hCG alone [ 13 ]. Similarly, in a randomized controlled trial, when dual trigger was used for normal responders, more MII oocytes and blastocysts were retrieved when compared with hCG trigger alone; in addition, the blastocysts obtained with dual trigger also showed higher quality [ 14 ]. In patients with diminished ovarian reserve, the use of dual trigger has also produced higher live birth rate, clinical pregnancy rate, and fertilization rate [ 15 , 16 ]. Such positive results could also be seen in patients with poor ovarian reserve, with dual trigger demonstrating higher number of oocytes and number of mature oocytes [ 17 ]. When GnRH-agonist was employed for hyper-responders, higher number of oocytes and matured oocytes were obtained when compared with triggering with hCG only. Moreover, it has the additional benefit of lowering the risks for OHSS [ 18 , 19 ]. However, not much have been published for using dual triggers for hyper-responders. Evidently, when undergoing GnRH-antagonist protocols, dual trigger has proven to produce not just better quality and quantity of oocytes but also pregnancy outcome [ 14 ]. However, not much comparative studies have been published when PPOS protocol is used for ovarian stimulation. Can the same positive outcomes be expected after the patients have been exposed to the high level of progesterone required for PPOS protocols? Theoretically, with high level of progesterone, FSH and LH secretions are inhibited [ 5 ]. During luteal phase stimulation, ovarian stimulation required a longer stimulation and a higher dose of total gonadotropin. These differences are not clinically significant [ 20 ]. Hence, when triggering with dual trigger or GnRH-agonist only, the secretions of endogenous FSH and LH may also be affected. This study aims to discuss whether different triggering methods used for final follicular maturation in PPOS protocols can affect the quality and quantity of the embryos retrieved. Materials And Methods Study population This retrospective study included patients undergoing PPOS protocols in the Reproductive Center of Chang Gung Memorial Hospital (Linkou branch) from January 2017 to December 2020. The inclusion criteria were patients enrolled for PPOS protocols with age between 20~45 years old, body mass index (BMI) less than 30 kg/m 2 , and normal thyroid stimulating hormone (TSH) and prolactin levels. Patients with endocrine disorders, systemic diseases, or Mullerian malformations were excluded from this study. The study was reviewed and approved by the institutional review board of the Human Investigation and Ethical Committee of Chang Gung Medical Foundation (Project no. 202100501B0; May. 4, 2021) Definition of study group The patients were assigned to three different final follicular maturation trigger modalities: (a) hCG (recombinant-hCG 500 µg ; Ovidrel®; Merck Serono S.p.A.); (b) GnRH agonist (Triptorelin 0.2mg; Decapeptyl®; Ferring GmbH ) (c) Dual trigger (Triptorelin 0.2mg + recombinant -hCG 500 µg or 250µg) Poor responders were defined according to the Bologna criteria [21] while high ovarian responders were patients demonstrating an E2 level greater than 6,500 pg/mL on the day of triggering. Clinical protocols The regime used for ovarian stimulation was tailored individually to each patient, depending on her age, BMI, hormone levels, number of antral follicles, and previous response to stimulation. In general, on menstrual cycle day 2 or day 3 of the treatment cycles, the stimulation protocol was initiated by daily injection of recombinant-follicle-stimulating hormone (r-FSH) (Follitropin alfa; Gonal-F®, Merck Serono, SA, Geneva, Switzerland), r-FSH combined with recombinant-luteining hormone (r-LH) (Follitropin alfa + Lutropin alfa; Pergoveris®, Merck Serono, SA, Geneva, Switzerland), or human menopause gonadotrophin (HMG ; Menopur®, Ferring, Kiel, Germany) at a dose of 150-225 IU/day or long-acting r-FSH 100-150 µg (Corifollitropin alfa, Elonva®, Germany) in the three groups. An additional daily dose of progestin (Medroxyprogesterone 10mg once per day or Dydrogesterone 10mg twice per day) could be administered flexibly starting on menstrual cycle day 3 or menstrual cycle day 5 to7 when E2 was greater than 200 ng/mL or when the leading follicle reached 10 mm by transvaginal ultrasonography scanning, till the day of triggering. The process for inducing final oocyte maturation would be initiated as soon as follicles were observed to be around 18mm under sonography. The specific method selected would be based on patient’s clinical status and the clinician’s personal preference. Transvaginal retrieval of oocytes would be performed 36 hours after triggering. Based on the results of semen analysis, the matured oocytes were inseminated either by conventional insemination or intracytoplasmic sperm injection (ICSI). Basal ovarian reserve parameters, including serum FSH, LH and E2 levels, were measured on menstrual cycle day 2 to day 3. During treatment, serum LH and E2 levels were recorded on menstrual cycle days 7 to day 9, which corresponded to day 2 to day 4 of progestin supplementation, and the day of triggering. Primary and secondary outcome measures The primary endpoints of the study were number of oocytes retrieved and the proportion of matured oocytes. Secondary outcomes included fertilization rates and the percentage of embryos at the cleavage stage. Rate of matured oocyte was calculated from dividing the number of matured oocytes by the total number of oocytes retrieved. Fertilization rate was obtained from dividing the number of fertilized oocytes by the number of matured oocytes inseminated. Cleavage stage embryo was defined as an embryo presenting with two divided cells on day 2 or day 3 after inseminating. The percentage of cleavage embryo was calculated from dividing the number of cleavage stage embryos by the total number of oocytes fertilized. Statistical analysis All data was analyzed with Statistical Package for Social Sciences (SPSS) version 22.0 (SPSS Inc., Chicago, IL). When comparisons were made among the three groups, one-way ANOVA was utilized while Turkey HDS test was applied to identify the group causing the differences. Meanwhile, the Kruskal-Wallis test was used for intergroup comparisons of parameters without normal distributions, and the Mann-Whitney U test was applied to identify the group causing the difference. The X 2 test was applied for comparing the qualitative data. A p value <0.05 was considered statistically significant. Results This study included a total of 344 patients undergoing PPOS protocol who were separated into three groups based on the method used for final follicular maturation: 21 patients in the hCG group, 16 patients in the GnRH-agonist group, and 297 patients in the dual trigger (hCG + GnRH-agonist) group. Patients’ baseline characteristics, including BMI, duration of infertility, previous infertility history, antral follicle count (AFC), anti-mullerian hormone (AMH) level, and basal hormone profile, are shown in Table 1. Patients in the GnRH-agonist group were generally younger and had significantly higher AMH levels. The stimulation parameters and cycle outcomes of the three groups are presented in Table 1. Duration required for stimulation in the hCG group was longer than that of the dual trigger group (11.9±2.93 vs 10.02±1.71, p<0.05). Meanwhile, patients in the GnRH agonist group had significantly higher number of follicles on day of trigger, E2 level on the day of adding progestin, E2 level on the day of triggering, number of retrieved oocytes, and number of mature oocytes when compared with the other two groups. However, if the inclusion criteria was adjusted to only incorporate patients with E2 <1000 pg/mL on the day of triggering and classified as POR based on the Bologna criteria[21], 11 patients would be placed in the hCG group while 70 patients would be in the dual trigger group. The baseline characteristics of this new grouping of patients are shown in Table 2. There were no significant differences between the groups. The stimulation parameters and cycle outcomes of the two groups are presented in Table 2. Patients in the dual trigger group had significantly higher percentage of oocyte maturity when compared with that of the hCG group (0.82±.26 vs 0.58±0.50, p6500 pg/mL on the trigger day, 7 patients would be placed in the GnRH-agonist group while 10 patients were placed in the dual trigger group. There were no significant differences, may it be the baseline characteristics, stimulation parameters, or cycle outcomes, between the two groups. These results are shown in Table 3. Discussion This study categorized the patients into three separate groups differentiated by the method used for final oocyte maturation. Based on their own expertise, the clinicians would choose the most optimal regime for each patient by evaluating her baseline characteristics and responses to treatment. According to their experiences, hCG injections would be employed for patients with low E2 levels (usually 3500 pg/mL) on the day of triggering and risks for developing OHSS[ 22 ], GnRH-agonist would be used. GnRH agonist trigger for final oocyte maturation significantly reduces the risk of ovarian hyperstimulation syndrome (OHSS) in in vitro fertilization (IVF) cycles [ 11 ]. For patients falling within the middle of the spectrum, dual trigger was the main modality used, with a few exceptions that would be explained later. Therefore, upon initial assessment, it could be expected that the baseline parameters of the patients among the three groups were distinctive. However, after redefining the inclusion criteria and comparing the patients by evaluating the hCG versus dual trigger group and GnRH agonist versus dual trigger group, the baseline characteristics of the study population showed no statistical differences. After eliminating the numerous confounding factors associated with different baseline characteristics, we could further analyze the data by the two new established categories: “hCG versus dual trigger” and “GnRH agonist versus dual trigger”. In the “hCG versus dual trigger group”, if dual trigger was prescribed for POR patients with E2 <1000 pg/mL on the day of triggering, statistically higher rate of oocyte maturation was found. This observation was also previously described in GnRH-antagonist cycles, where the authors believed hCG and GnRH-agonist together could incite more oocyte maturation [ 6 , 14 ]. GnRH-agonist has the ability to stimulate excretion of endogenous FSH and LH. LH has long been established as an important hormone for inciting final maturation of the oocytes; nonetheless, recent studies have also demonstrated the role of FSH in in vitro maturation of oocytes while animal studies have revealed the ability of FSH to induce ovulation, independently of the LH surge. It is theorized that FSH surge prompts the formation of more LH receptor on the luteinized granulosa cells, which then promotes the maturation of oocytes and expansion of cumulus cells [ 23 – 26 ]. For the “GnRH-agonist versus dual trigger group”, if patients had E2>6500 pg/mL on the day of triggering, use of either method for triggering did not show any statistically differences in the outcomes. Presumably, for these hyper-responders or patients with PPOS, utilizing hCG with higher efficacy or affinity would not make a significant difference in the final outcome. Therefore, for these patients, physicians should focus on lowering the risks of developing OHSS or other complications instead. In our study, none of the patients were found to have OHSS. The PPOS protocol used in this study included the standard method (on menstrual day 3 till day of triggering )[ 6 ] and the flexible method (on menstrual cycle day 5 to day 7 or E2>200 or follicle >10mm till day of triggering ) [ 27 ]. Current studies have not concluded on the prognostic effects of either method. A comparison of flexible PPOS with GnRH antagonist protocol in women who donated oocytes showed no significant differences in the final outcomes [ 27 ]. The choice of progestin supplementation used for our PPOS protocols included Medroxyprogesterone 10mg once per day and Dydrogesterone 10 mg twice per day, with neither showing a significant advantage or disadvantage in the final outcomes in current studies [ 7 , 28 , 29 ]. With molecular structure more similar to the natural progesterone hormone, Dydrogesterone is widely used for hormone replacement, therapy, menstrual disorder treatment, endometriosis treatment, luteal support in pregnancy and threaten abortion [ 28 ]. However, use of Medroxyprogesterone is contraindicated in pregnancy [ 30 ] and breast cancer [ 31 ]. Dydrogesterone, meanwhile, appears to have fewer side effects and can be used for pregnant patients and those with history of breast cancer. However, its pricing is generally higher, and some studies have mentioned a higher rate of premature LH surge associated with its usage [ 29 ]. Researches and analysis focused on comparing live births resulted from PPOS protocols with those of GnRH-agonist have not revealed higher rates of congenital malformation, preterm labor, low body weight, and others [ 32 ]. This is the first retrospective study discussing whether different methods for triggering follicular maturation could produce different outcomes. We hypothesized that with the higher concentration of progesterone required for PPOS cycles, it could have various effects on the agents used for triggering. Hence, different agents used for follicular maturation could possibly produce distinctive outcomes from those obtained from GnRH-antagonist cycle. Surprisingly, for POR patients, similar results were seen while not much comparisons could be made for hyper-responders due to lack of published research so far. A major limitation to our study is the non-randomized grouping of the patients. Since all of the patients were categorized into the three study groups based on the physicians’ clinical experiences, this created many differences in baseline parameters and other characteristics. For instance, most patients in the hCG group had limited number of embryos, so the retrieved follicles were all cryopreserved on Day 2 or day 3. We would not observe any blastocyst stage for that group of patients. In addition, during PPOS cycles, there were no standardization on the timing and type of medications prescribed, which could potentially affect the final results. Thirdly, due to the chemical structure of dydrogesterone, we could not accurately measure and monitor the levels of progesterone in the blood with the current diagnostic tests when using PPOS cycles [ 33 ]. Such data would have been helpful to include in the results. Lastly, longer study duration could have provided even more accurate analysis regarding the clinical pregnancy and live birth rates. Conclusion During PPOS cycles, if patients present with E2<1000 pg/mL on the day of triggering, employing dual trigger appears to have higher oocyte maturation rate (82% vs 58%, p6500 pg/mL on the day of trigger, using dual trigger or GnRH agonist for final maturation did not exhibit significant differences in oocyte number, percentage of matured oocyte, fertilization rate, and the number of cleavage embryos. Therefore, the type of triggering agent used should be guided by aiming to lower the risks of developing OHSS. Abbreviations AMH : anti-mullerian hormone ; AFC : antral follicle count BMI : body mass index E2 : Estradiol ; GnRH-agonist : Gonadotropin-releasing hormone-agonist ; GnRH-antagonist : Gonadotropin-releasing hormone-antagonist ; hCG: human chorionic gonadotropin ; IVF: In vitro fertilization ; ICSI : intracytoplasmic sperm injection ; LH : luteining hormone ; MPA : medroxyprogesterone ; OHSS : ovarian hyperstimulation syndrome ; PPOS: progesterone-primed ovarian stimulation protocols ; POR : poor ovarian response ; r-FSH : recombinant-follicle-stimulating hormone ; r-LH : luteining hormone ; SPSS : Statistical Package for Social Sciences ; TSH : thyroid stimulating hormone Declarations Financial Disclosure: All authors have no conflict of interest to be declared. Ethics approval and consent to participate This study was reviewed and approved by the institutional review board of the Human Investigation and Ethical Committee of Chang Gung Medical Foundation (Project no. 202100501B0; May. 4, 2021). Since this was a retrospective study, it had been granted an exemption from informed consent by IRB committee (review board of the Human Investigation and Ethical Committee of Chang Gung Medical Foundation). All methods were carried out in accordance with relevant guidelines and regulations of Chang Gung Medical Hospital and Taiwan. Consent for publication Not applicable Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interest The authors declared that they have no competing interest Funding The study was supported by Chang Kung memorial hospital. No financial support was required. This study did not receive funding from any private or public sectors Authors’ contribution H.M.W designed the study. Y.J.S and L.H.C performed the data collection and analysis. Y.J.S drafted the manuscript under the supervision of H.M.W. Y.J.S, L.H.C, T.H.C, S.Y.H, H.T.Y, C.L.C, H.Y.H, H.S.W, Y.K.S, H.M.W were involved in hypothesis generation, subjects recruitment, data management, result interpretation . All authors read and approved the final manuscript. Acknowledgements: Not applicable Author’s information Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Kwei-Shan, Tao-Yuan, Taiwan. References Vander Borght, M. and C. Wyns, Fertility and infertility: Definition and epidemiology. Clinical biochemistry, 2018. 62 : p. 2-10. Fishel, S., First in vitro fertilization baby—this is how it happened. Fertility and sterility, 2018. 110 (1): p. 5-11. 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Tables Table 1. IVF cycle characteristics, endocrine parameters, and outcomes in different study groups hCG GnRH-agonist Dual trigger a p Value No of patients 21 16 297 Age (years) 37.52 ± 5.58 33.56 ± 3.91 37.64 ± 4.76 <0.05* BMI (kg/m 2 ) 24.02 ± 5.32 22.37 ± 3.24 22.48 ± 3.63 0.187 AMH (ng/ml) 2.29 ± 2.51 8.12 ± 4.00 2.74 ± 2.66 <0.05* Infertility years 3.73 ± 3.41 3.73 ± 2.78 3.83 ± 3.15 0.987 Primary infertility 65% (13/20) 81% (13/16) 61% (177/288) Male factor 12% (2/17) 40% (6/15) 13% (36/280) Basal FSH(IU/L) 7.99 ± 4.79 6.25 ± 2.24 9.22 ± 7.48 0.227 Basal LH(IU/L) 4.99 ± 3.40 6.32 ± 2.61 4.79 ± 3.92 0.297 Basal E2(pg/ml) 46.09 ± 46.20 31.19 ± 13.29 45.52 ± 76.64 0.761 Day of stimulation 11.19 ± 2.93 10.63 ± 0.96 10.02 ± 1.71 <0.05* Total follicles on day of triggering 6.52 ± 5.05 14.88 ± 3.63 8.10 ± 4.48 <0.05* E2 on the day of progestin (pg/ml) 675.36 ± 691.33 2079.57 ± 1215.99 672.93 ± 803.54 <0.05* LH on the day of progestin (IU/L) 5.26 ± 3.83 8.18 ± 6.55 5.39 ± 5.09 0.101 E2 on the day of triggering (pg/ml) 1282.19 ± 1481.59 6180.63 ± 3338.36 1944.61 ± 1892.78 <0.05* LH on the day of triggering (IU/L) 4.34 ± 4.55 3.42 ± 2.08 4.52 ± 4.53 0.624 Retrieved oocytes 8.48 ± 10.42 27.38 ± 10.95 11.23 ± 10.68 <0.05* Mature oocytes 7.55 ± 9.82 21.00 ± 8.43 9.02 ± 9.34 <0.05* Oocyte maturity rate 0.72 ± 0.36 0.79 ± 0.20 0.80 ± 0.20 0.399 No of 2PN 4.29 ± 6.73 16.00 ± 6.61 6.43 ± 6.63 <0.05* No of blastocyst 2 ± 4.57 9.87 ± 5.10 3.13 ± 4.11 <0.05* Data are expressed in mean ± SD or frequency (%) BMI= body mass index; AMH= anti-Müllerian hormone; ICSI=intracytoplasmic sperm injection FSH= follicle stimulating hormone; LH= luteining hormone; E2= estradiol; 2PN= 2-pronuclear zygote Dual trigger a : GnRH-agonist + hCG Ｍatured oocytes were inseminated either by conventional insemination or ICSI Table 2. POR patient characteristics, endocrine parameters, and outcomes in different study groups hCG Dual trigger a p Value No of patients 11 70 Age (years) 40.73±4.74 40.61±3.90 0.269 BMI (kg/m 2 ) 25.97±6.39 23.54±4.16 0.102 AMH (ng/ml) 0.71±0.40 0.62±0.49 0.591 Infertility years 4.27±3.88 4.42±3.66 0.865 Primary infertility 58%(7/12) 64%(76/119) Male factor 20%(2/10) 11%(12/106) Basal FSH (IU/L) 9.96±5.59 13.30±12.10 0.574 Basal LH (IU/L) 4.58±4.46 4.62±3.52 0.579 Basal E2 (pg/ml) 34.79±30.86 44.02±48.01 0.773 Days of stimulation 12.45±3.20 9.73±2.16 0.110 Total follicles on day of triggering 2.55±1.29 3.54±1.85 0.169 E2 on the day of progestin (pg/ml) 180.75±214.56 203.01±181.84 0.692 LH l on the day of progestin (IU/L) 6.54±5.11 7.25±7.20 0.806 E2 on the day of triggering (pg/ml) 384.73±191.85 391.47±243.48 0.143 LH on the day of triggering (IU/L) 6.09±6.01 7.64±7.36 0.884 Retrieved oocytes 1.36±1.50 1.97±1.20 0.619 Mature oocytes 1.00±1.55 1.56±1.07 0.313 Oocyte maturity rate 0.58±0.50 % 0.82±0.26 % P<0.05* No of 2PN by ICSI 0.9±1.60 1.15±1.06 0.594 Fertilization rate by ICSI 0.88±0.25 % 0.71±0.42 % 0.954 Cleavage stage rate 1±0 % 0.94±0.22 % 0.354 No of blastocyst 0±0 0.20±0.60 P<0.05* Data are expressed in mean ± SD or frequency (%) BMI= body mass index; AMH= anti-Müllerian hormone; ICSI=intracytoplasmic sperm injection FSH= follicle stimulating hormone; LH= luteining hormone; E2= estradiol; 2PN= 2-pronuclear zygote Dual trigger a : GnRH-agonist + hCG Table 3. Hyper-responder patient characteristics, endocrine parameters, and outcomes in different study groups GnRH-agonist Dual trigger a p Value No of patients 7 10 Age (years) 34.14±4.41 34.30±4.19 0.718 BMI (kg/m 2 ) 21.26±3.03 21.73±3.27 0.761 AMH (ng/ml) 6.47±3.23 8.13±3.09 0.236 Infertility years 3.57±3.46 2.60±0.97 0.087 Primary infertility 86% (6/7) 60% (6/10) Male factor 43% (3/7) 10% (1/10) Basal FSH (IU/L) 5.64±2.20 6.21±1.72 0.525 Basal LH (IU/L) 6.34±4.00 7.26±5.46 0.642 Basal E2 (pg/ml) 35.96±11.38 42.89±21.82 0.066 Days of stimulation 10.86±0.69 10.60±1.43 0.215 Total follicle on day of triggering 14.71±3.15 11.70±3.06 0.969 E2 on the day of progestin (pg/ml) 2336.86±754.29 3275.20±1497.92 0.226 LH on the day of progestin (IU/L) 10.64±7.56 7.87±9.43 0.893 E2 on the day of triggering (pg/ml) 9043.43±2558.62 8651.20±1992.62 0.634 LH on the day of triggering (IU/L) 3.81±1.35 3.81±2.68 0.055 Retrieved oocytes 28.00±11.66 36.40±15.62 0.188 Mature oocytes 22.71±10.42 30.70±16.49 0.187 Oocyte maturity rate 0.82±0.20 0.83±0.17 0.655 No of 2PN by ICSI 15.29±7.25 19.9±9.16 0.594 Fertilization rate by ICSI 0.73±0.17 0.71±0.20 0.702 Cleavage stage rate 0.93±0.12 0.98±0.04 0.164 No of blastocyst 9.43±4.47 10.80±4.57 0.674 Data are expressed in mean ± SD or frequency (%) BMI= body mass index; AMH= anti-Müllerian hormone; ICSI=intracytoplasmic sperm injection FSH= follicle stimulating hormone; LH= luteining hormone; E2= estradiol; 2PN= 2-pronuclear zygote Dual trigger a : GnRH-agonist + hCG Additional Declarations No competing interests reported. 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Linkou","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Liang-Hsuan","middleName":"","lastName":"Chen","suffix":""},{"id":60990322,"identity":"d7eb5477-9287-4ba2-97ad-41adf85c8555","order_by":2,"name":"Tzu-Hsuan Chin","email":"","orcid":"","institution":"Chang Gung Memorial Hospital at Linkou","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Tzu-Hsuan","middleName":"","lastName":"Chin","suffix":""},{"id":60990324,"identity":"88ac4d53-881c-459e-aadc-1504411fd004","order_by":3,"name":"Shang-Yu Huang","email":"","orcid":"","institution":"Chang Gung Memorial Hospital at Linkou","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shang-Yu","middleName":"","lastName":"Huang","suffix":""},{"id":60990326,"identity":"5b54785b-02e8-4e90-affe-d96eec8cc298","order_by":4,"name":"Hsing-Tse Yu","email":"","orcid":"","institution":"Chang Gung Memorial Hospital at Linkou","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hsing-Tse","middleName":"","lastName":"Yu","suffix":""},{"id":60990327,"identity":"f5a7f709-2814-4bac-81cf-8acec9dd1b8e","order_by":5,"name":"Chia-Lin Chang","email":"","orcid":"","institution":"Chang Gung Memorial Hospital at Linkou","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chia-Lin","middleName":"","lastName":"Chang","suffix":""},{"id":60990328,"identity":"061f6b34-1005-440a-a425-0eedd726227e","order_by":6,"name":"Hong-Yuan Huang","email":"","orcid":"","institution":"Chang Gung Memorial Hospital at Linkou","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hong-Yuan","middleName":"","lastName":"Huang","suffix":""},{"id":60990330,"identity":"6a5de665-7109-4054-8ee8-0580110f9f11","order_by":7,"name":"Hsin-Shih Wang","email":"","orcid":"","institution":"Chang Gung Memorial Hospital at Linkou","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hsin-Shih","middleName":"","lastName":"Wang","suffix":""},{"id":60990333,"identity":"3f33c058-b2d9-4a99-9e03-98d63d5812f9","order_by":8,"name":"Yung-Kuei Soong","email":"","orcid":"","institution":"Chang Gung Memorial Hospital at Linkou","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yung-Kuei","middleName":"","lastName":"Soong","suffix":""},{"id":60990335,"identity":"c6036c28-6339-428d-bfc4-24eec35d01df","order_by":9,"name":"Hsien-Ming Wu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIie3RIQvCQBTA8QcHsxxaXZB9hScLIiz4UVxZGrokxpksgnUfQxmYbxxsZWISBlcEwbRgNAh6ThDTOZvg/TnuXbgfFw5Ap/vF2GMFAC15Jl8QBDDDF/kk2WOTBFld0sy2CTsjd+Ms28cBOGNr0ErbKmLmo2ESSbLJ/YmIwOuvGTGUBJmPnKJwNwX1BAWO3ZAYhZLsSuRXSeKoNinkKyDJqt1IK2LBB2IWJSYLvNlR7huCoodISO+iIs2db58vU6+znGcnQacOWvPZEVXkLYrPD+I178sah2pYYX2i0+l0/9EdpdJPyy/K58AAAAAASUVORK5CYII=","orcid":"","institution":"Chang Gung Memorial Hospital at Linkou","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Hsien-Ming","middleName":"","lastName":"Wu","suffix":""}],"badges":[],"createdAt":"2021-10-21 04:14:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1002007/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1002007/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":20383405,"identity":"84f737a5-efc2-436e-99a3-e737077ade51","added_by":"auto","created_at":"2022-04-15 11:59:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":414948,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1002007/v1/824d1c57-216a-4061-851c-f9e3cc135074.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eDifferent Methods for Inducing Final Oocyte Maturation When Employing Progesterone-Primed Ovarian Stimulation Protocols\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eInfertility afflicts about 10% of the female population, with etiologies encompassing tubal, uterine, ovulatory, or unexplained origins [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Whatever the cause, assisted-reproductive technology has become an essential part of the treatment, and the world\u0026rsquo;s first In vitro fertilization(IVF) baby was born in 1978 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. More than forty years have passed since then, and with progressive maturation of techniques and continuous development of numerous pharmaceutical agents, IVF treatments have grown to become more tailored to each individual patient for optimal effects.\u003c/p\u003e \u003cp\u003eSuppressing the luteining hormone (LH) surge is an important part of the IVF cycle and can be clinically overcome with Gonadotropin-releasing hormone-agonist (GnRH-agonist) and Gonadotropin-releasing hormone-antagonist (GnRH-antagonist) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Through downregulating the gonadotropins during the process of ovarian stimulation, GnRH agonist provides the additional benefit of synchronizing the size and growth of the antral follicles. On the other hand, GnRH-antagonists induce direct inhibitory effect, which has the advantages of faster onsets and less flare-ups [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSuch downregulation is later observed in other pathways. Research has shown that progesterone secreted from the corpus luteum has the ability to inhibit the pulsatile secretion of GnRH and thus LH, which in turn blocks the positive feedback loop of Estradiol (E2) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Therefore, when high concentration of exogeneous progesterone is supplied during controlled-ovarian stimulation, LH surge can be adequately suppressed. Such usage was first documented in 2015 when medroxyprogesterone (MPA) was implemented for LH suppression [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Studies that followed also consistently demonstrated this effect. Thus, the term progesterone-primed ovarian stimulation protocols (PPOS) was coined [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, when using PPOS protocols, all of the retrieved embryos need to be cryopreserved because fresh embryo transfer is not an option after the endometrium has been exposed to high level of progesterone required for PPOS protocol. The endometrium would have reached the receptive period too early, resulting in embryo-endometrium asynchrony [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Fortunately, with the significant improvement of cryopreservation, high pregnancy rate can still be achieved with thawed embryos [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Therefore, currently, PPOS protocols have been deemed suitable for patients seeking fertility preservation, oocyte donation, or alternative options for avoiding ovarian hyperstimulation syndrome (OHSS) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDuring the process of ovarian stimulation, opportune triggering of final follicular maturation is a crucial step, and, previously, human chorionic gonadotropin (hCG) was used as a surrogate of LH to produce such effect. After about 30 years, GnRH-agonists became an alternative agent for triggering final follicular maturation during GnRH-antagonist protocols with the goal of reducing risks of OHSS [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This concept was indeed proven by later researches, with many of them demonstrating less occurrences of OHSS with GnRH-agonist when compared with hCG; however, lower live birth and ongoing pregnancy rate (pregnancy beyond 12 weeks) and higher early miscarriage (less than 12 weeks) rate were observed with GnRH-agonist [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This may be attributed to defective luteal phase and decreased endometrial receptivity resulted from GnRH-agonist trigger [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHence, the concept of \u0026ldquo;dual trigger\u0026rdquo; emerged, which combined a bolus of GnRH-agonist and a bolus of hCG at the time of triggering, and has been proven advantageous. In a retrospective study, when dual trigger was used for normal responders, the results showed higher implantation, clinical pregnancy, and live-birth rates when compared with hCG alone [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Similarly, in a randomized controlled trial, when dual trigger was used for normal responders, more MII oocytes and blastocysts were retrieved when compared with hCG trigger alone; in addition, the blastocysts obtained with dual trigger also showed higher quality [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In patients with diminished ovarian reserve, the use of dual trigger has also produced higher live birth rate, clinical pregnancy rate, and fertilization rate [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Such positive results could also be seen in patients with poor ovarian reserve, with dual trigger demonstrating higher number of oocytes and number of mature oocytes [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. When GnRH-agonist was employed for hyper-responders, higher number of oocytes and matured oocytes were obtained when compared with triggering with hCG only. Moreover, it has the additional benefit of lowering the risks for OHSS [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. However, not much have been published for using dual triggers for hyper-responders.\u003c/p\u003e \u003cp\u003eEvidently, when undergoing GnRH-antagonist protocols, dual trigger has proven to produce not just better quality and quantity of oocytes but also pregnancy outcome [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, not much comparative studies have been published when PPOS protocol is used for ovarian stimulation. Can the same positive outcomes be expected after the patients have been exposed to the high level of progesterone required for PPOS protocols?\u003c/p\u003e \u003cp\u003eTheoretically, with high level of progesterone, FSH and LH secretions are inhibited [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. During luteal phase stimulation, ovarian stimulation required a longer stimulation and a higher dose of total gonadotropin. These differences are not clinically significant [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Hence, when triggering with dual trigger or GnRH-agonist only, the secretions of endogenous FSH and LH may also be affected. This study aims to discuss whether different triggering methods used for final follicular maturation in PPOS protocols can affect the quality and quantity of the embryos retrieved.\u003c/p\u003e"},{"header":"Materials And Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective study included patients undergoing PPOS protocols in the Reproductive Center of Chang Gung Memorial Hospital (Linkou branch) from January 2017 to December 2020.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe inclusion criteria were patients enrolled for PPOS protocols with age between 20~45 years old, body mass index (BMI) less than 30 kg/m\u003csup\u003e2\u003c/sup\u003e, and normal thyroid stimulating hormone (TSH) and prolactin levels. \u0026nbsp;Patients with endocrine disorders, systemic diseases, or Mullerian malformations were excluded from this study. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study was reviewed and approved by the institutional review board of the Human Investigation and Ethical Committee of Chang Gung Medical Foundation (Project no. 202100501B0; May. 4, 2021)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinition of study group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patients were assigned to three different final follicular maturation trigger modalities: (a) hCG (recombinant-hCG 500 \u0026micro;g ; Ovidrel\u0026reg;; Merck Serono S.p.A.); (b) GnRH agonist (Triptorelin 0.2mg; Decapeptyl\u0026reg;; Ferring GmbH )\u0026nbsp;(c) Dual trigger (Triptorelin 0.2mg + recombinant -hCG 500 \u0026micro;g or 250\u0026micro;g)\u003c/p\u003e\n\u003cp\u003ePoor responders were defined according to the Bologna criteria\u0026nbsp;[21]\u0026nbsp;while high ovarian responders were patients demonstrating an E2\u0026nbsp;level greater than 6,500 pg/mL on the day of triggering.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical protocols\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe regime used for ovarian stimulation was tailored individually to each patient, depending on her age, BMI, hormone levels, number of antral follicles, and previous response to stimulation. \u0026nbsp;In general, on menstrual cycle day 2 or day 3 of the treatment cycles, the stimulation protocol was initiated by daily injection of recombinant-follicle-stimulating hormone (r-FSH) (Follitropin alfa; Gonal-F\u0026reg;, Merck Serono, SA, Geneva, Switzerland), r-FSH combined with recombinant-luteining hormone (r-LH) (Follitropin alfa + Lutropin alfa; Pergoveris\u0026reg;, Merck Serono, SA, Geneva, Switzerland), or human menopause gonadotrophin (HMG ; Menopur\u0026reg;, Ferring, Kiel, Germany) at a dose of 150-225 IU/day or long-acting r-FSH 100-150 \u0026micro;g (Corifollitropin alfa, Elonva\u0026reg;, Germany) in the three groups.\u0026nbsp; \u0026nbsp;An additional daily dose of progestin (Medroxyprogesterone 10mg once per day or Dydrogesterone 10mg twice per day) could be administered flexibly starting on menstrual cycle day 3 or menstrual cycle day 5 to7 when E2 was greater than 200 ng/mL or when the leading follicle reached 10 mm by transvaginal ultrasonography scanning, till the day of triggering. The process for inducing final oocyte maturation would be initiated as soon as follicles were observed to be around 18mm under sonography. \u0026nbsp;The specific method selected would be based on patient\u0026rsquo;s clinical status and the clinician\u0026rsquo;s personal preference. \u0026nbsp;Transvaginal retrieval of oocytes would be performed 36 hours after triggering. \u0026nbsp;Based on the results of semen analysis, the matured oocytes were inseminated either by conventional insemination or intracytoplasmic sperm injection (ICSI). \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBasal ovarian reserve parameters, including serum FSH, LH and E2 levels, were measured on menstrual cycle day 2 to day 3. During treatment, serum LH and E2 levels were recorded on menstrual cycle days 7 to day 9, which corresponded to day 2 to day 4 of progestin supplementation, and the day of triggering.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary and secondary outcome measures\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoints of the study were number of oocytes retrieved and the proportion of matured oocytes. \u0026nbsp;Secondary outcomes included fertilization rates and the percentage of embryos at the cleavage stage. \u0026nbsp;Rate of matured oocyte was calculated from dividing the number of matured oocytes by the total number of oocytes retrieved. \u0026nbsp;Fertilization rate was obtained from dividing the number of fertilized oocytes by the number of matured oocytes inseminated. \u0026nbsp;Cleavage stage embryo was defined as an embryo presenting with two divided cells on day 2 or day 3 after inseminating. \u0026nbsp;The percentage of cleavage embryo was calculated from dividing the number of cleavage stage embryos by the total number of oocytes fertilized.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data was analyzed with Statistical Package for Social Sciences (SPSS) version 22.0 (SPSS Inc., Chicago, IL). \u0026nbsp;When comparisons were made among the three groups, one-way ANOVA was utilized while Turkey HDS test was applied to identify the group causing the differences.\u0026nbsp;\u0026nbsp;Meanwhile, the Kruskal-Wallis test was used for intergroup comparisons of parameters without normal distributions, and the Mann-Whitney U test was applied to identify the group causing the difference. \u0026nbsp; The X\u003csup\u003e2\u003c/sup\u003e test was applied for comparing the qualitative data. \u0026nbsp;A p value \u0026lt;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThis study included a total of 344 patients undergoing PPOS protocol who were separated into three groups based on the method used for final follicular maturation: 21 patients in the hCG group, 16 patients in the GnRH-agonist group, and 297 patients in the dual trigger (hCG + GnRH-agonist) group. \u0026nbsp;Patients\u0026rsquo; baseline characteristics, including BMI, duration of infertility, previous infertility history, antral follicle count (AFC), anti-mullerian hormone (AMH) level, and basal hormone profile, are shown in Table 1. \u0026nbsp;Patients in the GnRH-agonist group were generally younger and had significantly higher AMH levels.\u003c/p\u003e\n\u003cp\u003eThe stimulation parameters and cycle outcomes of the three groups are presented in Table 1. \u0026nbsp;Duration required for stimulation in the hCG group was longer than that of the dual trigger group (11.9\u0026plusmn;2.93 vs 10.02\u0026plusmn;1.71, p\u0026lt;0.05). \u0026nbsp; Meanwhile, patients in the GnRH agonist group had significantly higher number of follicles on day of trigger, E2 level on the day of adding progestin, E2 level on the day of triggering, number of retrieved oocytes, and number of mature oocytes when compared with the other two groups.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHowever, if the inclusion criteria was adjusted to only incorporate patients with E2 \u0026lt;1000 pg/mL on the day of triggering and classified as POR based on the Bologna criteria[21], 11 patients would be placed in the hCG group while 70 patients would be in the dual trigger group.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe baseline characteristics of this new grouping of patients are shown in Table 2. \u0026nbsp; There were no significant differences between the groups. \u0026nbsp;The stimulation parameters and cycle outcomes of the two groups are presented in Table 2. \u0026nbsp; Patients in the dual trigger group had significantly higher percentage of oocyte maturity when compared with that of the hCG group (0.82\u0026plusmn;.26 vs 0.58\u0026plusmn;0.50, p\u0026lt;0.05).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhen analyzing the other end of the spectrum, where the inclusion criteria was changed to incorporate only patients with E2\u0026gt;6500 pg/mL on the trigger day, 7 patients would be placed in the GnRH-agonist group while 10 patients were placed in the dual trigger group. \u0026nbsp;There were no significant differences, may it be the baseline characteristics, stimulation parameters, or cycle outcomes, between the two groups. \u0026nbsp;These results are shown in Table 3.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study categorized the patients into three separate groups differentiated by the method used for final oocyte maturation. Based on their own expertise, the clinicians would choose the most optimal regime for each patient by evaluating her baseline characteristics and responses to treatment. According to their experiences, hCG injections would be employed for patients with low E2 levels (usually \u0026lt;1500 pg/mL) on the day of triggering. On the other hand, if patients have high E2 (usually \u0026gt;3500 pg/mL) on the day of triggering and risks for developing OHSS[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], GnRH-agonist would be used. GnRH agonist trigger for final oocyte maturation significantly reduces the risk of ovarian hyperstimulation syndrome (OHSS) in \u003cem\u003ein vitro\u003c/em\u003e fertilization (IVF) cycles [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFor patients falling within the middle of the spectrum, dual trigger was the main modality used, with a few exceptions that would be explained later. Therefore, upon initial assessment, it could be expected that the baseline parameters of the patients among the three groups were distinctive. However, after redefining the inclusion criteria and comparing the patients by evaluating the hCG versus dual trigger group and GnRH agonist versus dual trigger group, the baseline characteristics of the study population showed no statistical differences.\u003c/p\u003e \u003cp\u003eAfter eliminating the numerous confounding factors associated with different baseline characteristics, we could further analyze the data by the two new established categories: \u0026ldquo;hCG versus dual trigger\u0026rdquo; and \u0026ldquo;GnRH agonist versus dual trigger\u0026rdquo;. In the \u0026ldquo;hCG versus dual trigger group\u0026rdquo;, if dual trigger was prescribed for POR patients with E2 \u0026lt;1000 pg/mL on the day of triggering, statistically higher rate of oocyte maturation was found. This observation was also previously described in GnRH-antagonist cycles, where the authors believed hCG and GnRH-agonist together could incite more oocyte maturation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. GnRH-agonist has the ability to stimulate excretion of endogenous FSH and LH. LH has long been established as an important hormone for inciting final maturation of the oocytes; nonetheless, recent studies have also demonstrated the role of FSH in \u003cem\u003ein vitro\u003c/em\u003e maturation of oocytes while animal studies have revealed the ability of FSH to induce ovulation, independently of the LH surge. It is theorized that FSH surge prompts the formation of more LH receptor on the luteinized granulosa cells, which then promotes the maturation of oocytes and expansion of cumulus cells [\u003cspan additionalcitationids=\"CR24 CR25\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFor the \u0026ldquo;GnRH-agonist versus dual trigger group\u0026rdquo;, if patients had E2\u0026gt;6500 pg/mL on the day of triggering, use of either method for triggering did not show any statistically differences in the outcomes. Presumably, for these hyper-responders or patients with PPOS, utilizing hCG with higher efficacy or affinity would not make a significant difference in the final outcome. Therefore, for these patients, physicians should focus on lowering the risks of developing OHSS or other complications instead. In our study, none of the patients were found to have OHSS.\u003c/p\u003e \u003cp\u003eThe PPOS protocol used in this study included the standard method (on menstrual day 3 till day of triggering )[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] and the flexible method (on menstrual cycle day 5 to day 7 or E2\u0026gt;200 or follicle \u0026gt;10mm till day of triggering ) [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Current studies have not concluded on the prognostic effects of either method. A comparison of flexible PPOS with GnRH antagonist protocol in women who donated oocytes showed no significant differences in the final outcomes [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe choice of progestin supplementation used for our PPOS protocols included Medroxyprogesterone 10mg once per day and Dydrogesterone 10 mg twice per day, with neither showing a significant advantage or disadvantage in the final outcomes in current studies [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWith molecular structure more similar to the natural progesterone hormone, Dydrogesterone is widely used for hormone replacement, therapy, menstrual disorder treatment, endometriosis treatment, luteal support in pregnancy and threaten abortion [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, use of Medroxyprogesterone is contraindicated in pregnancy [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] and breast cancer [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Dydrogesterone, meanwhile, appears to have fewer side effects and can be used for pregnant patients and those with history of breast cancer. However, its pricing is generally higher, and some studies have mentioned a higher rate of premature LH surge associated with its usage [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eResearches and analysis focused on comparing live births resulted from PPOS protocols with those of GnRH-agonist have not revealed higher rates of congenital malformation, preterm labor, low body weight, and others [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis is the first retrospective study discussing whether different methods for triggering follicular maturation could produce different outcomes. We hypothesized that with the higher concentration of progesterone required for PPOS cycles, it could have various effects on the agents used for triggering. Hence, different agents used for follicular maturation could possibly produce distinctive outcomes from those obtained from GnRH-antagonist cycle. Surprisingly, for POR patients, similar results were seen while not much comparisons could be made for hyper-responders due to lack of published research so far.\u003c/p\u003e \u003cp\u003eA major limitation to our study is the non-randomized grouping of the patients. Since all of the patients were categorized into the three study groups based on the physicians\u0026rsquo; clinical experiences, this created many differences in baseline parameters and other characteristics. For instance, most patients in the hCG group had limited number of embryos, so the retrieved follicles were all cryopreserved on Day 2 or day 3. We would not observe any blastocyst stage for that group of patients. In addition, during PPOS cycles, there were no standardization on the timing and type of medications prescribed, which could potentially affect the final results. Thirdly, due to the chemical structure of dydrogesterone, we could not accurately measure and monitor the levels of progesterone in the blood with the current diagnostic tests when using PPOS cycles [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Such data would have been helpful to include in the results. Lastly, longer study duration could have provided even more accurate analysis regarding the clinical pregnancy and live birth rates.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eDuring PPOS cycles, if patients present with E2\u0026lt;1000 pg/mL on the day of triggering, employing dual trigger appears to have higher oocyte maturation rate (82% vs 58%, p\u0026lt;0.05) when compared with that from hCG. For patients with E2 \u0026gt;6500 pg/mL on the day of trigger, using dual trigger or GnRH agonist for final maturation did not exhibit significant differences in oocyte number, percentage of matured oocyte, fertilization rate, and the number of cleavage embryos. Therefore, the type of triggering agent used should be guided by aiming to lower the risks of developing OHSS.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAMH : anti-mullerian hormone \u0026nbsp;; AFC : antral follicle count BMI : body mass index E2 : Estradiol ; GnRH-agonist : Gonadotropin-releasing hormone-agonist \u0026nbsp;; GnRH-antagonist : Gonadotropin-releasing hormone-antagonist ; hCG: human chorionic gonadotropin ; IVF: In vitro fertilization ; ICSI : intracytoplasmic sperm injection ; LH : luteining hormone ; MPA : medroxyprogesterone ; OHSS : ovarian hyperstimulation syndrome ; PPOS: progesterone-primed ovarian stimulation protocols ; POR : poor ovarian response ; r-FSH : recombinant-follicle-stimulating hormone \u0026nbsp;; r-LH : luteining hormone ; SPSS : Statistical Package for Social Sciences ; TSH : thyroid stimulating hormone\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFinancial Disclosure:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eAll authors have no conflict of interest to be declared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was reviewed and approved by the institutional review board of the Human Investigation and Ethical Committee of Chang Gung Medical Foundation (Project no. 202100501B0; May. 4, 2021). \u0026nbsp;Since this was a retrospective study, it had been granted an exemption from informed consent by IRB committee (review board of the Human Investigation and Ethical Committee of Chang Gung Medical Foundation). All methods were carried out in accordance with relevant guidelines and regulations of Chang Gung Medical Hospital and Taiwan.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declared that they have no competing interest\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was supported by Chang Kung memorial hospital. \u0026nbsp; No financial support was required. \u0026nbsp; This study did not receive funding from any private or public sectors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eH.M.W designed the study. Y.J.S and L.H.C performed the data collection and analysis. Y.J.S drafted the manuscript under the supervision of H.M.W. Y.J.S, L.H.C, T.H.C, S.Y.H, H.T.Y, C.L.C, H.Y.H, H.S.W, Y.K.S, H.M.W were involved in hypothesis generation, subjects recruitment, data management, result interpretation . All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Obstetrics and Gynecology, Chang Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Kwei-Shan, Tao-Yuan, Taiwan.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eVander Borght, M. and C. 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Shapiro, and C.-C. Chang, \u003cem\u003eVitrification of the human embryo: a more efficient and safer in vitro fertilization treatment.\u003c/em\u003e Fertility and sterility, 2020. \u003cstrong\u003e113\u003c/strong\u003e(2): p. 241-247.\u003c/li\u003e\n\u003cli\u003eGONEN, Y., et al., \u003cem\u003eUse of gonadotropin-releasing hormone agonist to trigger follicular maturation for in vitro fertilization.\u003c/em\u003e The Journal of Clinical Endocrinology \u0026amp; Metabolism, 1990. \u003cstrong\u003e71\u003c/strong\u003e(4): p. 918-922.\u003c/li\u003e\n\u003cli\u003eYoussef, M.A., et al., \u003cem\u003eGonadotropin‐releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles.\u003c/em\u003e Cochrane Database of Systematic Reviews, 2011(1).\u003c/li\u003e\n\u003cli\u003eEngmann, L. and C. Benadiva. \u003cem\u003eOvarian hyperstimulation syndrome prevention strategies: luteal support strategies to optimize pregnancy success in cycles with gonadotropin-releasing hormone agonist ovulatory trigger\u003c/em\u003e. in \u003cem\u003eSeminars in reproductive medicine\u003c/em\u003e. 2010. \u0026copy; Thieme Medical Publishers.\u003c/li\u003e\n\u003cli\u003eLin, M.-H., et al., \u003cem\u003eDual trigger with combination of gonadotropin-releasing hormone agonist and human chorionic gonadotropin significantly improves the live-birth rate for normal responders in GnRH-antagonist cycles.\u003c/em\u003e Fertility and sterility, 2013. \u003cstrong\u003e100\u003c/strong\u003e(5): p. 1296-1302.\u003c/li\u003e\n\u003cli\u003eHaas, J., et al., \u003cem\u003eGnRH agonist and hCG (dual trigger) versus hCG trigger for final follicular maturation: a double-blinded, randomized controlled study.\u003c/em\u003e Human Reproduction, 2020. \u003cstrong\u003e35\u003c/strong\u003e(7): p. 1648-1654.\u003c/li\u003e\n\u003cli\u003eLin, M.-H., et al., \u003cem\u003eDual trigger with gonadotropin releasing hormone agonist and human chorionic gonadotropin significantly improves live birth rate for women with diminished ovarian reserve.\u003c/em\u003e Reproductive Biology and Endocrinology, 2019. \u003cstrong\u003e17\u003c/strong\u003e(1): p. 1-7.\u003c/li\u003e\n\u003cli\u003eChern, C.-U., et al., \u003cem\u003eDual-trigger improves the outcomes of in vitro fertilization cycles in older patients with diminished ovarian reserve: A retrospective cohort study.\u003c/em\u003e Plos one, 2020. \u003cstrong\u003e15\u003c/strong\u003e(7): p. e0235707.\u003c/li\u003e\n\u003cli\u003eZhang, J., et al., \u003cem\u003eDual trigger of final oocyte maturation in poor ovarian responders undergoing IVF/ICSI cycles.\u003c/em\u003e Reproductive biomedicine online, 2017. \u003cstrong\u003e35\u003c/strong\u003e(6): p. 701-707.\u003c/li\u003e\n\u003cli\u003eTannus, S., et al., \u003cem\u003eReproductive outcomes after a single dose of gonadotropin-releasing hormone agonist compared with human chorionic gonadotropin for the induction of final oocyte maturation in hyper-responder women aged 35\u0026ndash;40 years.\u003c/em\u003e Fertility and sterility, 2017. \u003cstrong\u003e107\u003c/strong\u003e(6): p. 1323-1328. e2.\u003c/li\u003e\n\u003cli\u003eTan, J., et al., \u003cem\u003eGnRH triggering may improve euploidy and live birth rate in hyper-responders: a retrospective cohort study.\u003c/em\u003e Journal of Assisted Reproduction and Genetics, 2020. \u003cstrong\u003e37\u003c/strong\u003e(8): p. 1939-1948.\u003c/li\u003e\n\u003cli\u003eBoots, C., et al., \u003cem\u003eOvarian stimulation in the luteal phase: systematic review and meta-analysis.\u003c/em\u003e Journal of assisted reproduction and genetics, 2016. \u003cstrong\u003e33\u003c/strong\u003e(8): p. 971-980.\u003c/li\u003e\n\u003cli\u003eFerraretti, A., et al., \u003cem\u003eESHRE consensus on the definition of \u0026lsquo;poor response\u0026apos;to ovarian stimulation for in vitro fertilization: the Bologna criteria.\u003c/em\u003e Human reproduction, 2011. \u003cstrong\u003e26\u003c/strong\u003e(7): p. 1616-1624.\u003c/li\u003e\n\u003cli\u003eD\u0026apos;Angelo, A., et al., \u003cem\u003eValue of the serum estradiol level for preventing ovarian hyperstimulation syndrome: a retrospective case control study.\u003c/em\u003e Fertility and sterility, 2004. \u003cstrong\u003e81\u003c/strong\u003e(2): p. 332-336.\u003c/li\u003e\n\u003cli\u003eZelinski-Wooten, M., et al., \u003cem\u003eEndocrinology: Follicle stimulating hormone alone supports follicle growth and oocyte development in gonadotrophin-releasing hormone antagonist-treated monkeys.\u003c/em\u003e Human Reproduction, 1995. \u003cstrong\u003e10\u003c/strong\u003e(7): p. 1658-1666.\u003c/li\u003e\n\u003cli\u003eAndersen, C.Y., et al., \u003cem\u003eFSH-induced resumption of meiosis in mouse oocytes: effect of different isoforms.\u003c/em\u003e Molecular Human Reproduction, 1999. \u003cstrong\u003e5\u003c/strong\u003e(8): p. 726-731.\u003c/li\u003e\n\u003cli\u003eStrickland, S. and W. Beers, \u003cem\u003eStudies on the role of plasminogen activator in ovulation. In vitro response of granulosa cells to gonadotropins, cyclic nucleotides, and prostaglandins.\u003c/em\u003e Journal of Biological Chemistry, 1976. \u003cstrong\u003e251\u003c/strong\u003e(18): p. 5694-5702.\u003c/li\u003e\n\u003cli\u003eEppig, J.J., \u003cem\u003eFSH stimulates hyaluronic acid synthesis by oocyte\u0026ndash;cumulus cell complexes from mouse preovulatory follicles.\u003c/em\u003e Nature, 1979. \u003cstrong\u003e281\u003c/strong\u003e(5731): p. 483-484.\u003c/li\u003e\n\u003cli\u003eYildiz, S., et al., \u003cem\u003eComparison of a novel flexible progestin primed ovarian stimulation protocol and the flexible gonadotropin-releasing hormone antagonist protocol for assisted reproductive technology.\u003c/em\u003e Fertility and sterility, 2019. \u003cstrong\u003e112\u003c/strong\u003e(4): p. 677-683.\u003c/li\u003e\n\u003cli\u003eYu, S., et al., \u003cem\u003eNew 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.\u003c/em\u003e Human Reproduction, 2018. \u003cstrong\u003e33\u003c/strong\u003e(2): p. 229-237.\u003c/li\u003e\n\u003cli\u003eHuang, J., et al., \u003cem\u003eProgestin-primed ovarian stimulation with dydrogesterone versus medroxyprogesterone acetate in women with polycystic ovarian syndrome for in vitro fertilization: a retrospective cohort study.\u003c/em\u003e Drug design, development and therapy, 2019. \u003cstrong\u003e13\u003c/strong\u003e: p. 4461.\u003c/li\u003e\n\u003cli\u003eKatz, Z., et al., \u003cem\u003eTeratogenicity of progestogens given during the first trimester of pregnancy.\u003c/em\u003e Obstetrics and gynecology, 1985. \u003cstrong\u003e65\u003c/strong\u003e(6): p. 775-780.\u003c/li\u003e\n\u003cli\u003eRuan, X. and A.O. Mueck, \u003cem\u003eThe choice of progestogen for HRT in menopausal women: breast cancer risk is a major issue.\u003c/em\u003e Hormone Molecular Biology and Clinical Investigation, 2019. \u003cstrong\u003e37\u003c/strong\u003e(1).\u003c/li\u003e\n\u003cli\u003eZolfaroli, I., et al., \u003cem\u003eImpact of progestin ovarian stimulation on newborn outcomes: a meta-analysis.\u003c/em\u003e Journal of assisted reproduction and genetics, 2020: p. 1-10.\u003c/li\u003e\n\u003cli\u003eAbdel-Hamid, M., et al., \u003cem\u003eDetermination of dydrogesterone in human plasma by tandem mass spectrometry: Application to therapeutic drug monitoring of dydrogesterone in gynecological disorders.\u003c/em\u003e Chromatographia, 2006. \u003cstrong\u003e64\u003c/strong\u003e(5): p. 287-292.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;IVF cycle characteristics, endocrine parameters, and outcomes in different study groups\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.91304347826087%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e\u003cstrong\u003ehCG\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGnRH-agonist\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.956521739130434%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDual trigger\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.565217391304348%\"\u003e\n \u003cp\u003e\u003cstrong\u003ep Value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.91304347826087%\"\u003e\n \u003cp\u003eNo of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.956521739130434%\"\u003e\n \u003cp\u003e297\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.565217391304348%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.91304347826087%\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e37.52\u0026nbsp;\u0026plusmn; 5.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e33.56 \u0026plusmn; 3.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.956521739130434%\"\u003e\n \u003cp\u003e37.64 \u0026plusmn; 4.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.565217391304348%\"\u003e\n \u003cp\u003e\u0026lt;0.05*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.91304347826087%\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e24.02\u0026nbsp;\u0026plusmn; 5.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e22.37 \u0026plusmn; 3.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.956521739130434%\"\u003e\n \u003cp\u003e22.48\u0026nbsp;\u0026plusmn; 3.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.565217391304348%\"\u003e\n \u003cp\u003e0.187\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.91304347826087%\"\u003e\n \u003cp\u003eAMH (ng/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e2.29\u0026nbsp;\u0026plusmn; 2.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e8.12 \u0026plusmn; 4.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.956521739130434%\"\u003e\n \u003cp\u003e2.74\u0026nbsp;\u0026plusmn; 2.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.565217391304348%\"\u003e\n \u003cp\u003e\u0026lt;0.05*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.91304347826087%\"\u003e\n \u003cp\u003eInfertility years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e3.73\u0026nbsp;\u0026plusmn; 3.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e3.73 \u0026plusmn; 2.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.956521739130434%\"\u003e\n \u003cp\u003e3.83\u0026nbsp;\u0026plusmn; 3.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.565217391304348%\"\u003e\n \u003cp\u003e0.987\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.91304347826087%\"\u003e\n \u003cp\u003ePrimary infertility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e65% (13/20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e81% (13/16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.956521739130434%\"\u003e\n \u003cp\u003e61% (177/288)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.565217391304348%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.91304347826087%\"\u003e\n \u003cp\u003eMale factor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e12% (2/17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e40% (6/15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.956521739130434%\"\u003e\n \u003cp\u003e13% (36/280)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.565217391304348%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.91304347826087%\"\u003e\n \u003cp\u003eBasal FSH(IU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e7.99 \u0026plusmn; 4.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e6.25 \u0026plusmn; 2.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.956521739130434%\"\u003e\n \u003cp\u003e9.22 \u0026plusmn; 7.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.565217391304348%\"\u003e\n \u003cp\u003e0.227\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.91304347826087%\"\u003e\n \u003cp\u003eBasal LH(IU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e4.99 \u0026plusmn; 3.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e6.32 \u0026plusmn; 2.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.956521739130434%\"\u003e\n \u003cp\u003e4.79 \u0026plusmn; 3.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.565217391304348%\"\u003e\n \u003cp\u003e0.297\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"21.91304347826087%\"\u003e\n \u003cp\u003eBasal E2(pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e46.09 \u0026plusmn; 46.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.782608695652176%\"\u003e\n \u003cp\u003e31.19 \u0026plusmn; 13.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.956521739130434%\"\u003e\n \u003cp\u003e45.52 \u0026plusmn; 76.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"21.565217391304348%\"\u003e\n \u003cp\u003e0.761\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eDay of stimulation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e11.19\u0026nbsp;\u0026plusmn; 2.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e10.63 \u0026plusmn; 0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e10.02\u0026nbsp;\u0026plusmn; 1.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e\u0026lt;0.05*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eTotal follicles on day of triggering\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e6.52 \u0026plusmn; 5.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e14.88 \u0026plusmn; 3.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e8.10\u0026nbsp;\u0026plusmn; 4.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e\u0026lt;0.05*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eE2 on the day of progestin (pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e675.36\u0026nbsp;\u0026plusmn; 691.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e2079.57 \u0026plusmn; 1215.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e672.93\u0026nbsp;\u0026plusmn; 803.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e\u0026lt;0.05*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eLH on the day of progestin (IU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e5.26\u0026nbsp;\u0026plusmn; 3.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e8.18 \u0026plusmn; 6.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e5.39\u0026nbsp;\u0026plusmn; 5.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e0.101\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eE2 on the day of triggering (pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e1282.19\u0026nbsp;\u0026plusmn; 1481.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e6180.63 \u0026plusmn; 3338.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e1944.61\u0026nbsp;\u0026plusmn; 1892.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e\u0026lt;0.05*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eLH on the day of triggering (IU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e4.34\u0026nbsp;\u0026plusmn; 4.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e3.42 \u0026plusmn; 2.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e4.52\u0026nbsp;\u0026plusmn; 4.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e0.624\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eRetrieved oocytes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e8.48\u0026nbsp;\u0026plusmn; 10.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e27.38 \u0026plusmn; 10.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e11.23\u0026nbsp;\u0026plusmn; 10.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e\u0026lt;0.05*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eMature oocytes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e7.55\u0026nbsp;\u0026plusmn; 9.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e21.00 \u0026plusmn; 8.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e9.02\u0026nbsp;\u0026plusmn; 9.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e\u0026lt;0.05*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eOocyte maturity rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e0.72\u0026nbsp;\u0026plusmn; 0.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e0.79 \u0026plusmn; 0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e0.80\u0026nbsp;\u0026plusmn; 0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e0.399\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eNo of 2PN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e4.29 \u0026plusmn; 6.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e16.00 \u0026plusmn; 6.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e6.43 \u0026plusmn; 6.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e\u0026lt;0.05*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"25%\"\u003e\n \u003cp\u003eNo of blastocyst\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e2 \u0026plusmn; 4.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e9.87 \u0026plusmn; 5.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e3.13 \u0026plusmn; 4.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.75%\"\u003e\n \u003cp\u003e\u0026lt;0.05*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are expressed in\u0026nbsp;mean \u0026plusmn; SD or frequency (%)\u003c/p\u003e\n\u003cp\u003eBMI= body mass index; AMH= anti-Müllerian hormone; ICSI=intracytoplasmic sperm injection\u003c/p\u003e\n\u003cp\u003eFSH= follicle stimulating hormone; LH= luteining hormone; E2= estradiol; 2PN= 2-pronuclear zygote\u003c/p\u003e\n\u003cp\u003eDual trigger\u003csup\u003ea\u0026nbsp;\u003c/sup\u003e: GnRH-agonist + hCG\u003c/p\u003e\n\u003cp\u003eＭatured oocytes were inseminated either by conventional insemination or ICSI\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;POR patient characteristics, endocrine parameters, and outcomes in different study groups\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e\u003cstrong\u003ehCG\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDual trigger\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e\u003cstrong\u003ep Value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eNo of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e40.73\u0026plusmn;4.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e40.61\u0026plusmn;3.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.269\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e25.97\u0026plusmn;6.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e23.54\u0026plusmn;4.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.102\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eAMH (ng/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e0.71\u0026plusmn;0.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e0.62\u0026plusmn;0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.591\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eInfertility years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e4.27\u0026plusmn;3.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e4.42\u0026plusmn;3.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.865\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003ePrimary infertility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e58%(7/12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e64%(76/119)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eMale factor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e20%(2/10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e11%(12/106)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eBasal FSH (IU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e9.96\u0026plusmn;5.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e13.30\u0026plusmn;12.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.574\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eBasal LH (IU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e4.58\u0026plusmn;4.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e4.62\u0026plusmn;3.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.579\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eBasal E2 (pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e34.79\u0026plusmn;30.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e44.02\u0026plusmn;48.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.773\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eDays of stimulation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e12.45\u0026plusmn;3.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e9.73\u0026plusmn;2.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.110\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eTotal follicles on day of triggering\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e2.55\u0026plusmn;1.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e3.54\u0026plusmn;1.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.169\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eE2 on the day of progestin (pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e180.75\u0026plusmn;214.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e203.01\u0026plusmn;181.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.692\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eLH l on the day of progestin (IU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e6.54\u0026plusmn;5.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e7.25\u0026plusmn;7.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.806\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eE2 on the day of triggering (pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e384.73\u0026plusmn;191.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e391.47\u0026plusmn;243.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.143\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eLH on the day of triggering (IU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e6.09\u0026plusmn;6.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e7.64\u0026plusmn;7.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.884\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eRetrieved oocytes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e1.36\u0026plusmn;1.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e1.97\u0026plusmn;1.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.619\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eMature oocytes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e1.00\u0026plusmn;1.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e1.56\u0026plusmn;1.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.313\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eOocyte maturity rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e0.58\u0026plusmn;0.50 %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e0.82\u0026plusmn;0.26 %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003eP\u0026lt;0.05*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eNo of 2PN by ICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e0.9\u0026plusmn;1.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e1.15\u0026plusmn;1.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.594\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eFertilization rate by ICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e0.88\u0026plusmn;0.25 %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e0.71\u0026plusmn;0.42 %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.954\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eCleavage stage rate\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e1\u0026plusmn;0 %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e0.94\u0026plusmn;0.22 %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003e0.354\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"30.042918454935624%\"\u003e\n \u003cp\u003eNo of blastocyst\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e0\u0026plusmn;0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"24.678111587982833%\"\u003e\n \u003cp\u003e0.20\u0026plusmn;0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"20.600858369098713%\"\u003e\n \u003cp\u003eP\u0026lt;0.05*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are expressed in\u0026nbsp;mean \u0026plusmn; SD or frequency (%)\u003c/p\u003e\n\u003cp\u003eBMI= body mass index; AMH= anti-Müllerian hormone; ICSI=intracytoplasmic sperm injection\u003c/p\u003e\n\u003cp\u003eFSH= follicle stimulating hormone; LH= luteining hormone; E2= estradiol; 2PN= 2-pronuclear zygote\u003c/p\u003e\n\u003cp\u003eDual trigger\u003csup\u003ea\u0026nbsp;\u003c/sup\u003e: GnRH-agonist + hCG\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u0026nbsp;Hyper-responder patient characteristics, endocrine parameters, and outcomes in different study groups\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e\u003cstrong\u003eGnRH-agonist\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e\u003cstrong\u003eDual trigger\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e\u003cstrong\u003ep Value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eNo of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e34.14\u0026plusmn;4.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e34.30\u0026plusmn;4.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.718\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e21.26\u0026plusmn;3.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e21.73\u0026plusmn;3.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.761\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eAMH (ng/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e6.47\u0026plusmn;3.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e8.13\u0026plusmn;3.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.236\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eInfertility years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e3.57\u0026plusmn;3.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e2.60\u0026plusmn;0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.087\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003ePrimary infertility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e86% (6/7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e60% (6/10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eMale factor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e43% (3/7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e10% (1/10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eBasal FSH (IU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e5.64\u0026plusmn;2.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e6.21\u0026plusmn;1.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.525\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eBasal LH (IU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e6.34\u0026plusmn;4.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e7.26\u0026plusmn;5.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.642\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eBasal E2 (pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e35.96\u0026plusmn;11.38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e42.89\u0026plusmn;21.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.066\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eDays of stimulation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e10.86\u0026plusmn;0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e10.60\u0026plusmn;1.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.215\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eTotal follicle on day of triggering\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e14.71\u0026plusmn;3.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e11.70\u0026plusmn;3.06\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.969\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eE2 on the day of progestin (pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e2336.86\u0026plusmn;754.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e3275.20\u0026plusmn;1497.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.226\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eLH on the day of progestin (IU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e10.64\u0026plusmn;7.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e7.87\u0026plusmn;9.43\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.893\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eE2 on the day of triggering (pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e9043.43\u0026plusmn;2558.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e8651.20\u0026plusmn;1992.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.634\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eLH on the day of triggering (IU/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e3.81\u0026plusmn;1.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e3.81\u0026plusmn;2.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.055\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eRetrieved oocytes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e28.00\u0026plusmn;11.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e36.40\u0026plusmn;15.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.188\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eMature oocytes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e22.71\u0026plusmn;10.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e30.70\u0026plusmn;16.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.187\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eOocyte maturity rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e0.82\u0026plusmn;0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e0.83\u0026plusmn;0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.655\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eNo of 2PN by ICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e15.29\u0026plusmn;7.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e19.9\u0026plusmn;9.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.594\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eFertilization rate by ICSI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e0.73\u0026plusmn;0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e0.71\u0026plusmn;0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.702\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eCleavage stage rate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e0.93\u0026plusmn;0.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e0.98\u0026plusmn;0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.164\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"33.83297644539615%\"\u003e\n \u003cp\u003eNo of blastocyst\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e9.43\u0026plusmn;4.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"23.98286937901499%\"\u003e\n \u003cp\u003e10.80\u0026plusmn;4.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"18.201284796573876%\"\u003e\n \u003cp\u003e0.674\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eData are expressed in\u0026nbsp;mean \u0026plusmn; SD or frequency (%)\u003c/p\u003e\n\u003cp\u003eBMI= body mass index; AMH= anti-Müllerian hormone; ICSI=intracytoplasmic sperm injection\u003c/p\u003e\n\u003cp\u003eFSH= follicle stimulating hormone; LH= luteining hormone; E2= estradiol; 2PN= 2-pronuclear zygote\u003c/p\u003e\n\u003cp\u003eDual trigger\u003csup\u003ea\u003c/sup\u003e: GnRH-agonist + hCG\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"progestin primed ovarian stimulation, final follicular maturation, human chorionic gonadotropin, dual trigger, embryo quality, mature oocyte","lastPublishedDoi":"10.21203/rs.3.rs-1002007/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1002007/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eEvidently, when undergoing GnRH-antagonist protocols, dual trigger has proven to produce not just better quality and quantity of oocytes but also pregnancy outcome. However, not much comparative studies have been published when PPOS protocol is used for ovarian stimulation. Can the same positive outcomes be expected after the patients have been exposed to the high level of progesterone required for PPOS protocols?\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this retrospective cohort study, patients undergoing PPOS protocols were separated into three groups based on the method employed for triggering final follicular maturation, which included: (a) human chorionic gonadotropin (hCG); (b) Gonadotropin-releasing hormone-agonist (GnRH-agonist); or (c)dual trigger (GnRH-agonist + hCG). Either \u003cem\u003ein vitro\u003c/em\u003e fertilization or intracytoplasmic sperm injection (IVF/ICSI) was utilized for fertilization. Assessment comprised of their dynamic hormone profiles, embryonic analysis, and clinical outcomes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf the 344 recruited patients, those fulfilling the Bologna criteria as poor ovarian responders and showing Estradiol (E2)\u0026lt;1000 pg/ml on the day of triggering had higher oocyte maturation rate (82% vs 58%, p\u0026lt;0.05) when triggered with dual trigger (GnRH-agonist + hCG) than hCG alone. For the patients with E2\u0026gt; 6500 pg/ml on the day of triggering, none of the three triggering methods demonstrated a significant advantage regarding the number of oocytes, percentage of matured oocytes, and rate of oocytes at fertilization or cleavage stages.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eImplementing dual trigger for stimulating final follicular maturation in patients undergoing PPOS protocols is debatable. For poor ovarian response (POR) patients, dual trigger appeared to yield higher percentage of matured oocytes. In contrast, for hyper-responders, methods of triggering oocyte maturation did not affect the percentage of matured oocytes or the qualities of the embryos. For this group of patients, therefore, the agent used should be one that would reduce the risks of ovarian hyper-stimulation syndrome (OHSS).\u003c/p\u003e","manuscriptTitle":"Different Methods for Inducing Final Oocyte Maturation When Employing Progesterone-Primed Ovarian Stimulation Protocols","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-11-08 15:15:12","doi":"10.21203/rs.3.rs-1002007/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"73d1f8d2-9bf7-4288-bc31-8ae123f3febf","owner":[],"postedDate":"November 8th, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":8364116,"name":"Obstetrics \u0026 Gynecology"}],"tags":[],"updatedAt":"2022-04-15T11:59:20+00:00","versionOfRecord":[],"versionCreatedAt":"2021-11-08 15:15:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1002007","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1002007","identity":"rs-1002007","version":["v1"]},"buildId":"rHA-KDH7Qsr4HCuvH75dn","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}