Initiating Dose of hMG in Clomiphene plus hMG regimen in aged patients with poor ovarian response: More is better?

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NINGYU SUN, Ping Yin, Hua Yan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2620256/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 Object: This study was to investigate the effect of different human Menotrophin (hMG) initiation doses on in vitro fertilization (IVF) outcomes in aged poor ovarian response(POR) patients undergoing ovulation induction with Clomiphene Citrate (CC) combined with hMG; Method: The clinical data of 142 POR patients more than 40 years old were collected and were divided into 3 groups according to the initiation dose of hMG (Group A=75IU, Group B=150IU, Group C=225IU). The baseline characteristics and IVF outcomes were compared; Results: We found that with the increase of hMG initiation dose, the average number of oocytes retrieved increased, pair-to-pair comparison showed that the the average number of oocytes retrieved in Group Awas significantly lower than that in the Group B and Group C( P <0.05). Compared with Group B, the fertilization rate and oocyte utilization rate of patients in Group C were significantly lower ( P 0.05). Conclusions: For aged POR patients receiving CC combined with hMG, increasing hMG cannot improve patients' IVF outcomes and Pregnancy outcomes. 150IU of hMG initiation dose may be the bette r choice for aged POR patients. in vitro fertilization(IVF) poor ovarian response(POR) human Menotrophin(hMG) Clomiphene Citrate(CC) 1 Introduction In the process of assisted reproductive technology (ART), the key step is to obtain a certain number of oocytes. Poor ovarian response (POR) refers to a disease in which the ovary reacts poorly to gonadotropins (Gn) stimulation, resulting in a decrease in the number of obtained oocytes. POR is characterized by high Gn dosage, high cycle cancellation rate and low clinical pregnancy rate[ 1 ]. The incidence of POR in all patients seeking ART for pregnancy is about 9–24%[ 2 ], in patients older than 40 years, the incidence of POR is more than 50%[ 1 ]. Clomiphene citrate (CC) is a selective estrogen receptor modulator (SERM). It can block the negative feedback effect of circulating endogenous estrogen by blocking the hypothalamic estrogen receptor, thus increasing Gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH) and luteinizing hormone (LH)[ 3 ]. Human Menotrophin (hMG) is Gn extracted from the urine of postmenopausal women, which contains 1:1 ratio of FSH and LH, so it has the dual role of FSH and LH, and can act on both FSH receptor and LH receptor [ 4 ], therefore, it is a good choice for POR patients. The combination of CC and Gn is favored by clinicians because of its simple medication, lower treatment cost, and reduced Gn injection times. It is generally believed that patients with POR have poor response to Gn, so the dosage of Gn should be increased. However, the occurrence of POR can be caused by a variety of reasons, in some patients are related to the decreased density of FSH receptor and LH receptor, gene mutations and single nucleic acid polymorphisms, while in aged patients are mostly absolute insufficient ovarian reserve[ 5 – 7 ]. For aged patients with absolute reduced ovarian reserve, simply increasing Gn dosage may not improve the number of oocytes obtained and the quality of oocytes [ 4 ]. Therefore, we designed a retrospective analysis to review the aged POR patients admitted to the Reproductive Medicine Center of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from January 1, 2018 to January 1, 2023 using CC combined with hMG for controlled ovarian superinduction (COS) to explore the effect of different initiating doses of hMG on the outcome of in vitro fertilization (IVF) in aged patients with POR. 2 Methods 2.1 Study design and participants POR patients more than 40 years old treated with CC 50mg combined with or without hMG for COS in Reproductive Medicine Center of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine From January 1, 2018 to January 1, 2023 were included. A total of 142 cycles were divided into three groups according to different hMG initiation doses: the hMG initiation dose was 75IU (40 cycles) in group A, 150IU (62 cycles) in group B, and 225IU (40 cycles) in group C. The effects of different hMG initiation doses on IVF outcomes were compared. This research was approved by the Ethics Committee of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. Inclusion criteria: POR patients ≥ 40 years old who met the POSEIDON stratification[ 8 ]. Exclusion criteria: (1) Patients with endometriosis, organic lesions of the uterus or endometrium, thyroid disease, or other endocrine disorders; (2) Patients with chromosomal abnormalities; (3) Allergic to ovulation stimulating drugs. All the patients started taking 50 mg CC from day3 ~ 5 of the menstrual cycle, taking five days in a row. At the same time, different doses of hMG were injected into the muscle, and the levels of FSH, LH, P and E2 were examined regularly by transvaginal ultrasound, and the dose of hMG was adjusted when necessary until the trigger day. When two or more follicles larger than 17–18 mm in diameter were observed on transvaginal ultrasound, 6000-10 000 U of human chorionic gonadotropin(hCG) was injected intramuscularly to trigger. Oocyte retrieval was performed by transvaginal ultrasound 36 hours after hCG injection. On the day of oocyte retrieval, semen was obtained by the male partner through masturbation. After gradient centrifugation, sperms were inseminated in a ratio of (4–10) *10 4 sperms/oocyte and placed in an incubator. 2.2 Study outcomes The trigger day E2, FSH, LH, P, total hMG doses, total stimulation days, endometrial thickness, average number of oocytes retrieved, MⅡ oocyte rate, fertilization rate, cleavage rate, embryo formation rate, high-quality embryo rate and other indicators were compared between the groups. Specifically defined as: MⅡ oocyte rate = (total number of MⅡ oocytes/number of oocytes retrieved) ×100%; Fertilization rate = (number of fertilized/number of MⅡ oocytes) ×100%; Cleavage rate = (number of cleavage / number of fertilization) ×100%; Embryo formation rate = (number of embryo formation/number of cleavage number) ×100%; High-quality embryo rate = (number of high-quality embryos/number of embryo formation) ×100%; Oocyte utilization rate=(number of D3 available embryos/number of oocytes retrieved) ×100%. 2.3 Statistical analysis SPSS 26.0 statistical analysis software was used to analyze the data. Measurement data consistent with normal distribution were statistically described by mean ± standard deviation (x ± S). Independent sample t-test was used for comparison between groups, and paired sample t-test was used for comparison within groups. The median (25th percentile, 75th percentile) [M(Q1,Q3)] was described for normality, and the Kruskal-Wallis test was used for independent comparison between groups, and the constituent ratio or rate (%) was used for enumeration data. The non-parametric test and chi-square test were used for comparison of continuous variables and categorical variables between groups. P < 0.05 was considered statistically significant. 3 Results 3.1 Comparison of baseline characteristics of patients A total of 146 POR patients were included in this study, and each patient was included in only one oocyte retrieval cycle, for a total of 142 cycles. There were no significant differences in age, body mass index (BMI), anti-Mullerian hormone (AMH), male age, antral follicle count (AFC), and infertility years among the three groups ( P > 0.05). As shown in Table 1 . Table 1 Comparison of baseline characteristics of patients [M(Q 1 , Q 3 )] Group A Group B Group C H-value P-value Oocyte retrieval cycle 40 62 40 Age(years) 43.00(41.25, 44.00) 42.00(41.00, 45.00) 43.00(41.25, 45.00) 0.618 0.734 BMI (kg/m2) 21.70(20.80, 23.60) 21.95(20.78, 23.75) 23.30(20.80, 25.15) 2.914 0.233 AMH (ng/ml) 0.76(0.23, 1.50) 0.75(0.38, 1.30) 0.73(0.40, 1.21) 0.082 0.960 AFC 3.00(2.00, 4.00) 3.00(2.00, 4.00) 3.00(2.00, 5.00) 1.185 0.553 Age (paternal) 42.00(40.00, 48.00) 41.00(36.75, 46.00) 42.00(40.00, 46.75) 0.224 0.894 Infertility duration 3.0(2.0, 5.0) 5.0(3.0, 7.0) 2.0(3.0, 5.0) 0.230 0.891 Data are expressed as [M(Q 1 , Q 3 )] or numbers (%). 3.2 Comparison of ovarian response index in each group There was no significant difference in the ovarian response indexes among the groups of baseline E2, FSH, LH and P ( P > 0.05). The differences of the trigger day FSH, LH, total hMG dose and total stimulation days were statistically significant( P < 0.05), while there was no significant difference in the trigger day E2, P and endometrial thickness, as shown in Table 2 . Table 2 Comparison of ovarian response index in each group [M(Q 1 , Q 3 )] Group A Group B Group C H-value P-value Baseline E2 (pmol/L) 168.00(74.00, 310.75) 143.50(99.75, 304.00) 159.00(64.00, 245.00) 0.333 0.847 FSH (IU/L) 8.87(5.667, 14.01) 7.96(5.70, 11.20) 8.44(6.35, 10.10) 0.987 0.611 LH(IU/L) 3.53(2.44, 5.39) 3.17(2.20, 5.16) 3.24(2.27, 4.09) 0.968 0.616 P 0.60(0.33, 1.00) 0.60(0.30, 1.06) 0.70(0.30, 0.95) 0.014 0.993 Endometrial thickness(mm) 5.60(5.00, 6.55) 5.00(4.23, 6.00) 5.00(4.40, 6.23) 2.731 0.255 Triger day E2 (pmol/L) 1578.00(939.00, 2439.25) 1728.50(961.00, 2804.00) 1935.50(1232.00, 3515.50) 1.722 0.423 FSH (IU/L) 14.00(9.24, 21.68) 10.18(8.00, 14.91) 13.66(9.79, 17.51) 7.905 0.019* LH(IU/L) 8.02(5.19, 12.07) 5.30(4.12, 10.02) 5.08(3.30, 8.60) 7.466 0.024* P 0.75(0.60, 1.18) 0.85(0.60, 1.30) 1.00(0.53, 1.68) 1.366 0.505 Endometrial thickness(mm) 8.00(6.15, 8.98) 8.00(6.00, 9.13) 8.00(6.00, 10.95) 0.429 0.807 Total hMG dose(U) 450.00(300.00, 703.13) 900.00(450.00, 1200.00) 1631.25(1350.00, 2193.75) 66.679 0.000* Total stimulation days 6.00(3.25, 8.00) 6.00(3.00, 7.25) 8.00(6.25, 9.00) 18.747 0.000* * P < 0.05 3.3 Comparison of IVF outcomes With the increase of hMG initiation dose, the average number of oocytes retrieved increased, pair-to-pair comparison showed that the the average number of oocytes retrieved in Group A was significantly lower than that in the Group B and Group C( P < 0.05), but there was no statistically significant difference between Group B and Group C. Compared with Group B, the fertilization rate and oocyte utilization rate of patients in Group C were significantly lower ( P 0.05), as shown in Table 3 . As for the pregnancy outcomes, there was no statistically significant difference in the embryo implantation rate, clinical pregnancy rate, live birth rate and miscarriage rate among the three groups ( P > 0.05), as shown in Table 3 . Table 3 Comparison of IVF Outcomes Group A Group B Group C GroupA vs GroupB GroupA vs GroupC GroupB vs GroupC ALL IVF cycle 40 62 40 No. of retrieved oocytes 1.00(1.00,2.00) 2.00(1.75,3.00) 3.00(1.00,5.00) 0.003* 0.000* 0.119 0.000* MII oocyte rate(%) 92.06%(58/63) 95.36%(144/151) 90.70%(117/129) 0.528 0.754 0.122 0.296 Fertilization rate(%) 84.48%(49/58) 89.58%(129/144) 80.34%(94/117) 0.311 0.505 0.035* 0.11 Cleavage rate(%) 95.92%(47/49) 96.90%(125/129) 97.87% (92/94) 0.746 0.501 0.657 0.804 Embryo formation rate(%) 76.60%(36/47) 80.80%(101/125) 72.83%(67/92) 0.542 0.631 0.165 0.38 High-quality embryo rate(%) 63.89% (23/36) 71.29%(72/101) 74.63%(50/67) 0.408 0.253 0.635 0.517 Oocyte utilization rate(%) 57.14%(36/63) 66.89%(101/151) 51.94%(67/129) 0.176 0.497 0.011* 0.036* Embryo implantation rate(%) 7.69%(2/24) 11.84%(9/68) 2.17%(1/45) 0.787 0.572 0.093 0.128 Clinical pregnancy rate(%) 9.09%(2/22) 17.39%(8/46) 3.33%(1/30) 0.59 0.781 0.136 0.155 Live birth rate(%) 4.17%(1/24) 11.76%(8/68) 2.22%(1/45) 0.498 1 0.139 0.131 Miscarriage rate(%) 50.00%(1/2) 12.50%(1/8) 0.00%(0/1) 0.843 1 1 0.491 Data are expressed as [M(Q1, Q3)] or numbers (%). * P < 0.05 4 Discussion The prevalence of POR ranges from 9–24% in all patients receiving ART[ 9 ], such patients have poor response to Gn, resulting in fewer oocytes retrieved in IVF cycles, high cycle cancellation rate, and low clinical pregnancy rate. Therefore, the selection of ovulation induction regimen and dose in POR patients remains a challenge for clinicians. There are two widely accepted protocols for the diagnosis of POR——the Bologna criteria[ 1 ]and the POSEIDON stratification[ 8 ]. Compared with the Bologna criterion, the POSEIDON stratification classifies patients into different prognostic categories based on low ovarian response heterogeneity. Patients in the first and second groups of POSEIDON stratification had good ovarian reserve but may have abnormal density and polymorphism of FSH receptor and LH receptor, resulting in gonadotropin resistance. For such patients, increasing Gn dosage or different combinations of gonadotrophins may ameliorate low ovarian response. For patients in the third and fourth groups, the main reason for the low ovarian response was the absolute insufficiency of ovarian reserve, and merely increasing the dosage of Gn may not increase the number of oocytes retrieved. CC is a tristyrane-derived non-steroidal compound, which has a weak agonistic effect and a strong antagonistic effect on estrogen. It interferes with the negative feedback effect of endogenous estrogen by competitively occupying the hypothalamic estrogen receptor, promoting the increase of secretion of FHS and LH, and stimulating follicle growth[ 10 ]. CC can also act directly on the ovary to enhance the sensitivity of granulosa cells to Gn and aromatase activity[ 11 ]. Therefore, using CC can reduce the consumption of Gn and reduce the cycle cost. Therefore, in this study, patients were divided into three groups according to the hMG initiation dose: hMG = 75IU, hMG = 150IU and hMG = 225IU. The average number of oocytes retrieved, MⅡ oocyte rate, fertilization rate, cleavage rate, embryo formation rate, high-quality embryo rate and oocyte utilization rate of the three groups were compared, and the optimal hMG initiation dose for POR patients was evaluated. The results showed that the average number of oocytes retrieved were increased in hMG = 225U group, pair-to-pair comparison showed that the the average number of oocytes retrieved in Group A was significantly lower than that in the Group B and Group C( P 0.05). However, compared with Group B, the fertilization rate and oocyte utilization rate of patients in Group C were significantly lower, and the differences were statistically significant( P 0.05). Fertilization rate and oocyte utilization rate are mainly related to oocyte quality [ 12 ]. However, the results of studies on the effects of Gn dosage on oocyte quality and embryo aneuploidy rate have not been unified. Some researchers believe that increased Gn dosage will not have adverse effects on oocyte quality and embryo aneuploidy rate[ 13 , 14 ], while some other researchers have found that increasing Gn dosage can affect oocyte cytoplasm quality and increase embryo aneuploidy rate [ 15 ]. Xu et al.[ 16 ] added different doses of FSH to the in vitro maturation (IVM) medium, and found that the increase of FSH dose would increase the first meiotic error, thus leading to an increase in the number of aneuploid oocytes. This suggests that the dose of FSH should be chosen carefully in the process of COS. There have been previous studies on the choice of Gn dosage in patients with POR. Liu et al.[ 17 ] conducted a prospective study, randomly divided POR patients into long regimen group and mild regimen group, the long regimen group was initiated with FSH 300IU, while the mild regimen group was initiated with FSH 150IU. The results showed that the increase of Gn initiation dose could increase the number of transferable embryos in POR patients. But there was no effect on pregnancy outcomes, especially not on the live birth rate, which is consistent with our conclusion. The results of randomized controlled experiment by R Moffat et al.[ 18 ] showed that compared with 150IU hMG combined with 100mg CC, 450IU hMG combined with 100mg CC group did not increase the number of oocytes obtained, and the blastocyst formation rate was significantly reduced. The results of this study were similar to our study. Reducing Gn use may lead to better oocyte quality and higher developmental potential, as well as lower drug costs. In addition, we also found that with the increase of hMG initiation dose, the number of days of stimulation did not decrease, but increased compared with other groups ( P < 0.05), suggesting that for POR patients, increasing the initial dose of hMG would not reduce the number of days of use, but increase the number of days of use. Therefore, we believe that for POR patients, the more hMG initiation dose may not the better. Due to the limited sample size, there was no difference in pregnancy outcomes among the three groups. There was no difference in the number of oocytes obtained between group B and group C, but group B achieved higher fertilization rates and oocyte utilization rate. Therefore, we can infer that 150IU initiation dose of hMG may be the bette r choice for aged POR patients. Declarations Acknowledgements We thank members of the laboratory for help and critical reading of the manuscript. Author Disclosure Statement No competing financial interests exist. Funding Information This work was supported by grants from the National Natural Science Foundation of China (Nos. 81571442 and 82104555). References Ferraretti AP, La Marca A, Fauser BCJM, Tarlatzis B, Nargund G, Gianaroli L, et al. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria†. Hum Reprod [Internet]. 2011 [cited 2022 Sep 8];26:1616–24. Available from: https://doi.org/10.1093/humrep/der092 Ubaldi F, Vaiarelli A, D’Anna R, Rienzi L. Management of Poor Responders in IVF: Is There Anything New? BioMed Res Int [Internet]. 2014 [cited 2022 Sep 8];2014:352098. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127291/ Kistner RW. Use of clomiphene citrate, human chorionic gonadotropin, and human menopausal gonadotropin for induction of ovulation in the human female. Fertil Steril. 1966;17:569–83. Boudry L, Racca A, Tournaye H, Blockeel C. Type and dose of gonadotropins in poor ovarian responders: does it matter? Ther Adv Reprod Health [Internet]. 2021 [cited 2022 Oct 18];15:26334941211024204. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243085/ Regan SLP, Knight PG, Yovich JL, Stanger JD, Leung Y, Arfuso F, et al. Infertility and ovarian follicle reserve depletion are associated with dysregulation of the FSH and LH receptor density in human antral follicles. Mol Cell Endocrinol [Internet]. 2017 [cited 2022 Sep 20];446:40–51. 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No effect of ovarian stimulation and oocyte yield on euploidy and live birth rates: an analysis of 12 298 trophectoderm biopsies. Hum Reprod Oxf Engl. 2020;35:1082–9. Baker VL, Brown MB, Luke B, Smith GW, Ireland JJ. Gonadotropin dose is negatively correlated with live birth rate: analysis of more than 650,000 assisted reproductive technology cycles. Fertil Steril. 2015;104:1145-1152.e1-5. Xu Y-W, Peng Y-T, Wang B, Zeng Y-H, Zhuang G-L, Zhou C-Q. High follicle-stimulating hormone increases aneuploidy in human oocytes matured in vitro. Fertil Steril [Internet]. 2011 [cited 2022 Sep 22];95:99–104. Available from: https://www.sciencedirect.com/science/article/pii/S0015028210006588 Liu X, Li T, Wang B, Xiao X, Liang X, Huang R. Mild stimulation protocol vs conventional controlled ovarian stimulation protocol in poor ovarian response patients: a prospective randomized controlled trial. Arch Gynecol Obstet. 2020;301:1331–9. Moffat R, Hansali C, Schoetzau A, Ahler A, Gobrecht U, Beutler S, et al. Randomised controlled trial on the effect of clomiphene citrate and gonadotropin dose on ovarian response markers and IVF outcomes in poor responders. Hum Reprod [Internet]. 2021 [cited 2022 Sep 22];36:987–97. Available from: https://doi.org/10.1093/humrep/deaa336 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2620256","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":181092819,"identity":"000bf7a9-4a1d-414e-921e-e530c76073a7","order_by":0,"name":"NINGYU SUN","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"NINGYU","middleName":"","lastName":"SUN","suffix":""},{"id":181092820,"identity":"ea7f42d8-4a7d-426e-83e3-d58cec12fcad","order_by":1,"name":"Ping Yin","email":"","orcid":"https://orcid.org/0000-0002-4150-7911","institution":"Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ping","middleName":"","lastName":"Yin","suffix":""},{"id":181092821,"identity":"26cf9481-afe3-40cc-82eb-b8183c2dae0c","order_by":2,"name":"Hua Yan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIie3PMWuDQBTA8RcO7CJ1fUK5foULQshQ6Fe5Q3Cy0PECDoJBhyR17rdwzGgQzuWyG+hglu7dXFKavSFntgz3m9+f9x6AZd0hxyuPPcpf6j1ku57LxJw8oiZsruvAX6uQ9VqZEwqxg4tlLaounvnHJRlxGOxrPKRfAWgVSZE64BUrfj0hH3z6uf2mkyJTndg+Aep9ZdhSs9DXJCCuijqhHWD4Zko4a045ETnGs3eRkzFJPE39vBHrcwLjElTh+fwoQFeFyLVyjb88l1k7oHyhr222+xlkQr1icz35x71t3LIsy7roD0pjUKOs3zBdAAAAAElFTkSuQmCC","orcid":"","institution":"","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Hua","middleName":"","lastName":"Yan","suffix":""}],"badges":[],"createdAt":"2023-02-23 11:24:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2620256/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2620256/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":34880912,"identity":"cdeeae4b-2b01-4a3c-99c0-1ac272b4ab87","added_by":"auto","created_at":"2023-03-27 19:29:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":257464,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2620256/v1/108d8365-4e89-4c1b-a1fa-bd2b861ad312.pdf"}],"financialInterests":"","formattedTitle":"Initiating Dose of hMG in Clomiphene plus hMG regimen in aged patients with poor ovarian response: More is better?","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eIn the process of assisted reproductive technology (ART), the key step is to obtain a certain number of oocytes. Poor ovarian response (POR) refers to a disease in which the ovary reacts poorly to gonadotropins (Gn) stimulation, resulting in a decrease in the number of obtained oocytes. POR is characterized by high Gn dosage, high cycle cancellation rate and low clinical pregnancy rate[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The incidence of POR in all patients seeking ART for pregnancy is about 9\u0026ndash;24%[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], in patients older than 40 years, the incidence of POR is more than 50%[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eClomiphene citrate (CC) is a selective estrogen receptor modulator (SERM). It can block the negative feedback effect of circulating endogenous estrogen by blocking the hypothalamic estrogen receptor, thus increasing Gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH) and luteinizing hormone (LH)[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Human Menotrophin (hMG) is Gn extracted from the urine of postmenopausal women, which contains 1:1 ratio of FSH and LH, so it has the dual role of FSH and LH, and can act on both FSH receptor and LH receptor [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], therefore, it is a good choice for POR patients. The combination of CC and Gn is favored by clinicians because of its simple medication, lower treatment cost, and reduced Gn injection times.\u003c/p\u003e \u003cp\u003eIt is generally believed that patients with POR have poor response to Gn, so the dosage of Gn should be increased. However, the occurrence of POR can be caused by a variety of reasons, in some patients are related to the decreased density of FSH receptor and LH receptor, gene mutations and single nucleic acid polymorphisms, while in aged patients are mostly absolute insufficient ovarian reserve[\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. For aged patients with absolute reduced ovarian reserve, simply increasing Gn dosage may not improve the number of oocytes obtained and the quality of oocytes [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e Therefore, we designed a retrospective analysis to review the aged POR patients admitted to the Reproductive Medicine Center of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine from January 1, 2018 to January 1, 2023 using CC combined with hMG for controlled ovarian superinduction (COS) to explore the effect of different initiating doses of hMG on the outcome of in vitro fertilization (IVF) in aged patients with POR.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design and participants\u003c/h2\u003e \u003cp\u003ePOR patients more than 40 years old treated with CC 50mg combined with or without hMG for COS in Reproductive Medicine Center of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine From January 1, 2018 to January 1, 2023 were included. A total of 142 cycles were divided into three groups according to different hMG initiation doses: the hMG initiation dose was 75IU (40 cycles) in group A, 150IU (62 cycles) in group B, and 225IU (40 cycles) in group C. The effects of different hMG initiation doses on IVF outcomes were compared. This research was approved by the Ethics Committee of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine.\u003c/p\u003e \u003cp\u003eInclusion criteria: POR patients\u0026thinsp;\u0026ge;\u0026thinsp;40 years old who met the POSEIDON stratification[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eExclusion criteria: (1) Patients with endometriosis, organic lesions of the uterus or endometrium, thyroid disease, or other endocrine disorders; (2) Patients with chromosomal abnormalities; (3) Allergic to ovulation stimulating drugs.\u003c/p\u003e \u003cp\u003eAll the patients started taking 50 mg CC from day3\u0026thinsp;~\u0026thinsp;5 of the menstrual cycle, taking five days in a row. At the same time, different doses of hMG were injected into the muscle, and the levels of FSH, LH, P and E2 were examined regularly by transvaginal ultrasound, and the dose of hMG was adjusted when necessary until the trigger day. When two or more follicles larger than 17\u0026ndash;18 mm in diameter were observed on transvaginal ultrasound, 6000-10 000 U of human chorionic gonadotropin(hCG) was injected intramuscularly to trigger. Oocyte retrieval was performed by transvaginal ultrasound 36 hours after hCG injection. On the day of oocyte retrieval, semen was obtained by the male partner through masturbation. After gradient centrifugation, sperms were inseminated in a ratio of (4\u0026ndash;10) *10\u003csup\u003e4\u003c/sup\u003e sperms/oocyte and placed in an incubator.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Study outcomes\u003c/h2\u003e \u003cp\u003eThe trigger day E2, FSH, LH, P, total hMG doses, total stimulation days, endometrial thickness, average number of oocytes retrieved, MⅡ oocyte rate, fertilization rate, cleavage rate, embryo formation rate, high-quality embryo rate and other indicators were compared between the groups. Specifically defined as: MⅡ oocyte rate = (total number of MⅡ oocytes/number of oocytes retrieved) \u0026times;100%; Fertilization rate = (number of fertilized/number of MⅡ oocytes) \u0026times;100%; Cleavage rate = (number of cleavage / number of fertilization) \u0026times;100%; Embryo formation rate = (number of embryo formation/number of cleavage number) \u0026times;100%; High-quality embryo rate = (number of high-quality embryos/number of embryo formation) \u0026times;100%; Oocyte utilization rate=(number of D3 available embryos/number of oocytes retrieved) \u0026times;100%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistical analysis\u003c/h2\u003e \u003cp\u003eSPSS 26.0 statistical analysis software was used to analyze the data. Measurement data consistent with normal distribution were statistically described by mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (x\u0026thinsp;\u0026plusmn;\u0026thinsp;S). Independent sample t-test was used for comparison between groups, and paired sample t-test was used for comparison within groups. The median (25th percentile, 75th percentile) [M(Q1,Q3)] was described for normality, and the Kruskal-Wallis test was used for independent comparison between groups, and the constituent ratio or rate (%) was used for enumeration data. The non-parametric test and chi-square test were used for comparison of continuous variables and categorical variables between groups. \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Comparison of baseline characteristics of patients\u003c/h2\u003e \u003cp\u003eA total of 146 POR patients were included in this study, and each patient was included in only one oocyte retrieval cycle, for a total of 142 cycles. There were no significant differences in age, body mass index (BMI), anti-Mullerian hormone (AMH), male age, antral follicle count (AFC), and infertility years among the three groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). As shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of baseline characteristics of patients [M(Q\u003csub\u003e1\u003c/sub\u003e, Q\u003csub\u003e3\u003c/sub\u003e)]\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup A\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup B\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup C\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eH-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOocyte retrieval cycle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge(years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43.00(41.25, 44.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42.00(41.00, 45.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43.00(41.25, 45.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.618\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.734\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.70(20.80, 23.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.95(20.78, 23.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23.30(20.80, 25.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.914\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.233\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAMH (ng/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.76(0.23, 1.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.75(0.38, 1.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.73(0.40, 1.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.082\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.960\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAFC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.00(2.00, 4.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.00(2.00, 4.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.00(2.00, 5.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.185\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.553\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (paternal)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42.00(40.00, 48.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.00(36.75, 46.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42.00(40.00, 46.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.224\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.894\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfertility duration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.0(2.0, 5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.0(3.0, 7.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.0(3.0, 5.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.230\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.891\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eData are expressed as [M(Q\u003csub\u003e1\u003c/sub\u003e, Q\u003csub\u003e3\u003c/sub\u003e)] or numbers (%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Comparison of ovarian response index in each group\u003c/h2\u003e \u003cp\u003eThere was no significant difference in the ovarian response indexes among the groups of baseline E2, FSH, LH and P (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). The differences of the trigger day FSH, LH, total hMG dose and total stimulation days were statistically significant(\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), while there was no significant difference in the trigger day E2, P and endometrial thickness, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of ovarian response index in each group [M(Q\u003csub\u003e1\u003c/sub\u003e, Q\u003csub\u003e3\u003c/sub\u003e)]\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup A\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup B\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup C\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eH-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eE2 (pmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e168.00(74.00, 310.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e143.50(99.75, 304.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e159.00(64.00, 245.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.333\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.847\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFSH (IU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.87(5.667, 14.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.96(5.70, 11.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.44(6.35, 10.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.987\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.611\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLH(IU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.53(2.44, 5.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.17(2.20, 5.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.24(2.27, 4.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.968\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.616\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.60(0.33, 1.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.60(0.30, 1.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.70(0.30, 0.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.993\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrial thickness(mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5.60(5.00, 6.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.00(4.23, 6.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.00(4.40, 6.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.731\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.255\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriger day\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eE2 (pmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1578.00(939.00, 2439.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1728.50(961.00, 2804.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1935.50(1232.00, 3515.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.722\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.423\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFSH (IU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14.00(9.24, 21.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.18(8.00, 14.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13.66(9.79, 17.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.905\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.019*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLH(IU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.02(5.19, 12.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.30(4.12, 10.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.08(3.30, 8.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.466\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.024*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.75(0.60, 1.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.85(0.60, 1.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.00(0.53, 1.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.366\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.505\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrial thickness(mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.00(6.15, 8.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.00(6.00, 9.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.00(6.00, 10.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.429\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.807\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal hMG dose(U)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e450.00(300.00, 703.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e900.00(450.00, 1200.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1631.25(1350.00, 2193.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e66.679\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal stimulation days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6.00(3.25, 8.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.00(3.00, 7.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.00(6.25, 9.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e18.747\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003e*\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Comparison of IVF outcomes\u003c/h2\u003e \u003cp\u003eWith the increase of hMG initiation dose, the average number of oocytes retrieved increased, pair-to-pair comparison showed that the the average number of oocytes retrieved in Group A was significantly lower than that in the Group B and Group C(\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), but there was no statistically significant difference between Group B and Group C. Compared with Group B, the fertilization rate and oocyte utilization rate of patients in Group C were significantly lower (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). There was no significant difference in MII oocyte rate, Cleavage rate, embryo formation rate and high-quality embryo rate among the three groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05), as shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eAs for the pregnancy outcomes, there was no statistically significant difference in the embryo implantation rate, clinical pregnancy rate, live birth rate and miscarriage rate among the three groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05), as shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of IVF Outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup A\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGroup B\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGroup C\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eGroupA vs GroupB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGroupA vs GroupC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eGroupB vs GroupC\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eALL\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIVF cycle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo. of retrieved oocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.00(1.00,2.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.00(1.75,3.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.00(1.00,5.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.003*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.000*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMII oocyte rate(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e92.06%(58/63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95.36%(144/151)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90.70%(117/129)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.528\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.754\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.296\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFertilization rate(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84.48%(49/58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e89.58%(129/144)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80.34%(94/117)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.311\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.505\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.035*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCleavage rate(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e95.92%(47/49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e96.90%(125/129)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e97.87%\u003c/p\u003e \u003cp\u003e(92/94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.746\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.501\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.657\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.804\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmbryo formation rate(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76.60%(36/47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80.80%(101/125)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e72.83%(67/92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.542\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.631\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.165\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.38\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh-quality embryo rate(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63.89%\u003c/p\u003e \u003cp\u003e(23/36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71.29%(72/101)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e74.63%(50/67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.408\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.253\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.635\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.517\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOocyte utilization rate(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57.14%(36/63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.89%(101/151)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51.94%(67/129)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.176\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.497\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.011*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.036*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmbryo implantation rate(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.69%(2/24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.84%(9/68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.17%(1/45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.787\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.572\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.093\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.128\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical pregnancy rate(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.09%(2/22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.39%(8/46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.33%(1/30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.781\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.155\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLive birth rate(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.17%(1/24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.76%(8/68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.22%(1/45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.498\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.139\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.131\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMiscarriage rate(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.00%(1/2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.50%(1/8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.00%(0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.843\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.491\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eData are expressed as [M(Q1, Q3)] or numbers (%).\u003c/p\u003e \u003cp\u003e \u003csup\u003e*\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eThe prevalence of POR ranges from 9\u0026ndash;24% in all patients receiving ART[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], such patients have poor response to Gn, resulting in fewer oocytes retrieved in IVF cycles, high cycle cancellation rate, and low clinical pregnancy rate. Therefore, the selection of ovulation induction regimen and dose in POR patients remains a challenge for clinicians.\u003c/p\u003e \u003cp\u003eThere are two widely accepted protocols for the diagnosis of POR\u0026mdash;\u0026mdash;the Bologna criteria[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]and the POSEIDON stratification[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Compared with the Bologna criterion, the POSEIDON stratification classifies patients into different prognostic categories based on low ovarian response heterogeneity. Patients in the first and second groups of POSEIDON stratification had good ovarian reserve but may have abnormal density and polymorphism of FSH receptor and LH receptor, resulting in gonadotropin resistance. For such patients, increasing Gn dosage or different combinations of gonadotrophins may ameliorate low ovarian response. For patients in the third and fourth groups, the main reason for the low ovarian response was the absolute insufficiency of ovarian reserve, and merely increasing the dosage of Gn may not increase the number of oocytes retrieved.\u003c/p\u003e \u003cp\u003eCC is a tristyrane-derived non-steroidal compound, which has a weak agonistic effect and a strong antagonistic effect on estrogen. It interferes with the negative feedback effect of endogenous estrogen by competitively occupying the hypothalamic estrogen receptor, promoting the increase of secretion of FHS and LH, and stimulating follicle growth[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. CC can also act directly on the ovary to enhance the sensitivity of granulosa cells to Gn and aromatase activity[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Therefore, using CC can reduce the consumption of Gn and reduce the cycle cost.\u003c/p\u003e \u003cp\u003eTherefore, in this study, patients were divided into three groups according to the hMG initiation dose: hMG\u0026thinsp;=\u0026thinsp;75IU, hMG\u0026thinsp;=\u0026thinsp;150IU and hMG\u0026thinsp;=\u0026thinsp;225IU. The average number of oocytes retrieved, MⅡ oocyte rate, fertilization rate, cleavage rate, embryo formation rate, high-quality embryo rate and oocyte utilization rate of the three groups were compared, and the optimal hMG initiation dose for POR patients was evaluated. The results showed that the average number of oocytes retrieved were increased in hMG\u0026thinsp;=\u0026thinsp;225U group, pair-to-pair comparison showed that the the average number of oocytes retrieved in Group A was significantly lower than that in the Group B and Group C(\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), but there was no statistically significant difference between Group B and Group C(\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). However, compared with Group B, the fertilization rate and oocyte utilization rate of patients in Group C were significantly lower, and the differences were statistically significant(\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). There was no significant difference in MII oocyte rate, cleavage rate, embryo formation rate and high-quality embryo rate (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05). Fertilization rate and oocyte utilization rate are mainly related to oocyte quality [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, the results of studies on the effects of Gn dosage on oocyte quality and embryo aneuploidy rate have not been unified. Some researchers believe that increased Gn dosage will not have adverse effects on oocyte quality and embryo aneuploidy rate[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], while some other researchers have found that increasing Gn dosage can affect oocyte cytoplasm quality and increase embryo aneuploidy rate [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Xu et al.[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] added different doses of FSH to the in vitro maturation (IVM) medium, and found that the increase of FSH dose would increase the first meiotic error, thus leading to an increase in the number of aneuploid oocytes. This suggests that the dose of FSH should be chosen carefully in the process of COS. There have been previous studies on the choice of Gn dosage in patients with POR. Liu et al.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] conducted a prospective study, randomly divided POR patients into long regimen group and mild regimen group, the long regimen group was initiated with FSH 300IU, while the mild regimen group was initiated with FSH 150IU. The results showed that the increase of Gn initiation dose could increase the number of transferable embryos in POR patients. But there was no effect on pregnancy outcomes, especially not on the live birth rate, which is consistent with our conclusion. The results of randomized controlled experiment by R Moffat et al.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] showed that compared with 150IU hMG combined with 100mg CC, 450IU hMG combined with 100mg CC group did not increase the number of oocytes obtained, and the blastocyst formation rate was significantly reduced. The results of this study were similar to our study. Reducing Gn use may lead to better oocyte quality and higher developmental potential, as well as lower drug costs. In addition, we also found that with the increase of hMG initiation dose, the number of days of stimulation did not decrease, but increased compared with other groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), suggesting that for POR patients, increasing the initial dose of hMG would not reduce the number of days of use, but increase the number of days of use.\u003c/p\u003e \u003cp\u003eTherefore, we believe that for POR patients, the more hMG initiation dose may not the better. Due to the limited sample size, there was no difference in pregnancy outcomes among the three groups. There was no difference in the number of oocytes obtained between group B and group C, but group B achieved higher fertilization rates and oocyte utilization rate. Therefore, we can infer that 150IU initiation dose of hMG may be the bette\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003er\u003c/span\u003e choice for aged POR patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank members of the laboratory for help and critical reading of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Disclosure Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo competing financial interests exist.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by grants from the National Natural Science Foundation of China (Nos. 81571442\u0026nbsp;and\u0026nbsp;82104555).\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFerraretti AP, La Marca A, Fauser BCJM, Tarlatzis B, Nargund G, Gianaroli L, et al. ESHRE consensus on the definition of \u0026lsquo;poor response\u0026rsquo; to ovarian stimulation for in vitro fertilization: the Bologna criteria\u0026dagger;. Hum Reprod [Internet]. 2011 [cited 2022 Sep 8];26:1616\u0026ndash;24. Available from: https://doi.org/10.1093/humrep/der092\u003c/li\u003e\n\u003cli\u003eUbaldi F, Vaiarelli A, D\u0026rsquo;Anna R, Rienzi L. Management of Poor Responders in IVF: Is There Anything New? BioMed Res Int [Internet]. 2014 [cited 2022 Sep 8];2014:352098. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127291/\u003c/li\u003e\n\u003cli\u003eKistner RW. Use of clomiphene citrate, human chorionic gonadotropin, and human menopausal gonadotropin for induction of ovulation in the human female. Fertil Steril. 1966;17:569\u0026ndash;83.\u003c/li\u003e\n\u003cli\u003eBoudry L, Racca A, Tournaye H, Blockeel C. Type and dose of gonadotropins in poor ovarian responders: does it matter? Ther Adv Reprod Health [Internet]. 2021 [cited 2022 Oct 18];15:26334941211024204. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243085/\u003c/li\u003e\n\u003cli\u003eRegan SLP, Knight PG, Yovich JL, Stanger JD, Leung Y, Arfuso F, et al. Infertility and ovarian follicle reserve depletion are associated with dysregulation of the FSH and LH receptor density in human antral follicles. Mol Cell Endocrinol [Internet]. 2017 [cited 2022 Sep 20];446:40\u0026ndash;51. Available from: https://www.sciencedirect.com/science/article/pii/S0303720717300874\u003c/li\u003e\n\u003cli\u003eAchrekar SK, Modi DN, Desai SK, Mangoli VS, Mangoli RV, Mahale SD. Poor ovarian response to gonadotrophin stimulation is associated with FSH receptor polymorphism. Reprod Biomed Online. 2009;18:509\u0026ndash;15.\u003c/li\u003e\n\u003cli\u003eAlviggi C, Conforti A, Caprio F, Gizzo S, Noventa M, Strina I, et al. In Estimated Good Prognosis Patients Could Unexpected \u0026ldquo;Hyporesponse\u0026rdquo; to Controlled Ovarian Stimulation be Related to Genetic Polymorphisms of FSH Receptor? Reprod Sci Thousand Oaks Calif. 2016;23:1103\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eHumaidan P, Alviggi C, Fischer R, Esteves SC. The novel POSEIDON stratification of \u0026lsquo;Low prognosis patients in Assisted Reproductive Technology\u0026rsquo; and its proposed marker of successful outcome. F1000Research [Internet]. 2016 [cited 2022 Oct 18];5:2911. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302217/\u003c/li\u003e\n\u003cli\u003eDrakopoulos P, Bardhi E, Boudry L, Vaiarelli A, Makrigiannakis A, Esteves SC, et al. Update on the management of poor ovarian response in IVF: the shift from Bologna criteria to the Poseidon concept. Ther Adv Reprod Health. 2020;14:2633494120941480.\u003c/li\u003e\n\u003cli\u003ePeeraer K, Debrock S, De Loecker P, Tomassetti C, Laenen A, Welkenhuysen M, et al. Low-dose human menopausal gonadotrophin versus clomiphene citrate in subfertile couples treated with intrauterine insemination: a randomized controlled trial. Hum Reprod Oxf Engl. 2015;30:1079\u0026ndash;88.\u003c/li\u003e\n\u003cli\u003eDickey RP, Holtkamp DE. Development, pharmacology and clinical experience with clomiphene citrate. Hum Reprod Update. 1996;2:483\u0026ndash;506.\u003c/li\u003e\n\u003cli\u003eKeefe D, Kumar M, Kalmbach K. Oocyte competency is the key to embryo potential. Fertil Steril. 2015;103:317\u0026ndash;22.\u003c/li\u003e\n\u003cli\u003eWu Q, Li H, Zhu Y, Jiang W, Lu J, Wei D, et al. Dosage of exogenous gonadotropins is not associated with blastocyst aneuploidy or live-birth rates in PGS cycles in Chinese women. Hum Reprod Oxf Engl. 2018;33:1875\u0026ndash;82.\u003c/li\u003e\n\u003cli\u003eIrani M, Canon C, Robles A, Maddy B, Gunnala V, Qin X, et al. No effect of ovarian stimulation and oocyte yield on euploidy and live birth rates: an analysis of 12\u0026thinsp;298 trophectoderm biopsies. Hum Reprod Oxf Engl. 2020;35:1082\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eBaker VL, Brown MB, Luke B, Smith GW, Ireland JJ. Gonadotropin dose is negatively correlated with live birth rate: analysis of more than 650,000 assisted reproductive technology cycles. Fertil Steril. 2015;104:1145-1152.e1-5.\u003c/li\u003e\n\u003cli\u003eXu Y-W, Peng Y-T, Wang B, Zeng Y-H, Zhuang G-L, Zhou C-Q. High follicle-stimulating hormone increases aneuploidy in human oocytes matured in vitro. Fertil Steril [Internet]. 2011 [cited 2022 Sep 22];95:99\u0026ndash;104. Available from: https://www.sciencedirect.com/science/article/pii/S0015028210006588\u003c/li\u003e\n\u003cli\u003eLiu X, Li T, Wang B, Xiao X, Liang X, Huang R. 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Available from: https://doi.org/10.1093/humrep/deaa336\u003c/li\u003e\n\u003c/ol\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":"in vitro fertilization(IVF), poor ovarian response(POR), human Menotrophin(hMG), Clomiphene Citrate(CC)","lastPublishedDoi":"10.21203/rs.3.rs-2620256/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2620256/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eObject: This study was to investigate the effect of different human Menotrophin (hMG) initiation doses on in vitro fertilization (IVF) outcomes in aged poor ovarian response(POR) patients undergoing ovulation induction with Clomiphene Citrate (CC) combined with hMG; Method: The clinical data of 142 POR patients more than 40 years old were collected and were divided into 3 groups according to the initiation dose of hMG (Group A=75IU, Group B=150IU, Group C=225IU). The baseline characteristics and IVF outcomes were compared; Results: We found that with the increase of hMG initiation dose, the average number of oocytes retrieved increased, pair-to-pair comparison showed that the the average number of oocytes retrieved in Group Awas significantly lower than that in the Group B and Group C(\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). Compared with Group B, the fertilization rate and oocyte utilization rate of patients in Group C were significantly lower (\u003cem\u003eP\u003c/em\u003e\u0026lt;0.05). There was no significant difference in MII oocyte rate, Cleavage rate, embryo formation rate, high-quality embryo rate and pregnancy outcomes among the three groups(\u003cem\u003eP\u003c/em\u003e\u0026gt;0.05). Conclusions: For aged POR patients receiving CC combined with hMG, increasing hMG cannot improve patients' IVF outcomes and Pregnancy outcomes. 150IU of hMG initiation dose may be the bette\u003cu\u003er\u003c/u\u003e choice for aged POR patients.\u003c/p\u003e","manuscriptTitle":"Initiating Dose of hMG in Clomiphene plus hMG regimen in aged patients with poor ovarian response: More is better?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-03-09 12:02:03","doi":"10.21203/rs.3.rs-2620256/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":"9ff09f9c-46da-465f-9d41-95ddb69f70f6","owner":[],"postedDate":"March 9th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-06-08T18:44:19+00:00","versionOfRecord":[],"versionCreatedAt":"2023-03-09 12:02:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-2620256","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2620256","identity":"rs-2620256","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}