Clinical Efficacy of TCM Multi-channel Intervention Plus Antagonist Regimen on Ovarian Function，TCM Syndromes and Natural Conception in Poor Ovarian Responders Undergoing IVF-ET / 中国实验方剂学杂志

ObjectiveTo objectively analyze the effects of traditional Chinese Medicine （TCM） multi-channel intervention on the ovarian function，TCM syndromes and natural conception of poor ovarian responders（kidney-Yin deficiency，liver depression and blood stasis pattern） who planned to receive another in vitro fertilization embryo transfer（IVF-ET）antagonist regimen. MethodThe 128 low-prognosis patients （kidney Yin deficiency，liver depression and blood stasis pattern） who attended the West China Second University Hospital， Sichuan University and the Hospital of Chengdu University of Traditional Chinese Medicine from August 2020 to February 2023 and met the inclusion criteria were selected，and then divided into the treatment group and the control group according to the random number table，with 64 patients in each group. The control group was treated with oral dehydroepiandrosterone（DHEA），while the treatment group was treated with multi-channel TCM（oral TCM decoction + auricular point sticking + Bushen Huoxue prescription through retention enema）. After 3 menstrual cycles，the relevant indicators for ovarian function evaluation，TCM syndrome scores and natural conception were collected from both groups. ResultCompared with the situation before treatment，the basal follicle stimulating hormone（bFSH），bFSH/basal luteinizing hormone（bLH），basal estradiol（bE2），antral follicle count（AFC），the number of oocytes obtained，the number of normal fertilization，the number of superior embryos and TCM syndrome scores in the treatment group were improved after treatment（P<0.05，P<0.01）. For the control group， the bFSH/bLH and TCM syndrome scores were increased after treatment（P<0.05）， while the bFSH，bFSH/bLH，bE2，AFC，the number of oocytes obtained，the number of normal fertilization，and the number of superior embryos showed no significant difference after treatment. Compared with the control group after treatment，bFSH，bFSH/bLH，bE2，AFC，the number of normal fertilization，the number of superior embryos and TCM syndrome scores in the treatment group were better （P<0.05，P<0.01），while there was no significant difference in the number of oocytes obtained. After treatment，there were 3 cases of natural conception in the treatment group，while there were no natural conception in the control group. ConclusionFor patients with poor ovarian response and kidney Yin deficiency，liver depression and blood stasis pattern，multi-channel intervention of TCM plus the antagonist regimen can reduce bFSH，bFSH/bLH values，improve the levels of bE2，increase AFC，the number of oocytes obtained，the number of normal fertilization and the number of superior embryos，improve ovarian function，menstruation and TCM syndromes，improve their quality of life，and even enable some patients to get pregnant naturally before re-progression and improve their pregnancy outcome.

Mechanism of protective effect of resveratrol on poor ovarian response in mice / 中国中药杂志

This study aims to investigate the therapeutic effects and potential mechanisms of resveratrol(Res) on poor ovarian response(POR) in mice. The common target genes shared by Res and POR were predicted by network pharmacology, used for Gene Ontology(GO) annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment, and then validated by animal experiments. The mice with regular estrous cycle after screening were randomized into normal, POR, and low-and high-dose(20 and 40 mg·kg~(-1), respectively) Res groups. The normal group was administrated with an equal volume of 0.9% sodium chloride solution by gavage, and the mice in other groups with tripterygium glycosides suspension(50 mg·kg~(-1)) by gavage for 2 weeks. After the modeling, the mice in low-and high-dose Res groups were treated with Res by gavage for 2 weeks, and the mice in normal and POR groups with an equal volume of 0.9% sodium chloride solution by gavage. Ovulation induction and sample collection were carried out on the day following the end of treatment. Vaginal smears were collected for observation of the changes in the estrous cycle, the counting of retrieved oocytes, and the measurement of ovarian wet weight and ovarian index. The enzyme-linked immunosorbent assay(ELISA) was employed to measure the levels of anti-mullerian hormone(AMH), follicle-stimulating hormone(FSH), estradiol(E_2), and luteinizing hormone(LH) in the serum. The ovarian tissue morphology and granulosa cell apoptosis were observed by hematoxylin-eosin(HE) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL), respectively. Western blot was employed to determine the protein levels of phosphatidylinositol 3-kinase(PI3K), protein kinase B(AKT), forkhead box O(FOXO) 3a, hypoxia-inducible factor(HIF)-1α, B-cell lymphoma-2(Bcl-2), and Bcl-2-associated X protein(Bax). A total of 222 common targets shared by Res and POR were collected. GO annotation indicated that these targets were mainly involved in oxidative stress response. KEGG enrichment analysis revealed that Res can intervene in POR via PI3K/AKT, HIF-1, and FOXO signaling pathways. Animal experiments showed that the model group had higher rate of estrous cycle disorders, lower number and poorer morphology of normally developed follicles at all levels, more atretic follicles, higher apoptosis of ovarian granulosa cells, lower number of retrieved oocytes, lower ovarian wet weight and ovarian index, higher serum levels of FSH and LH, lower levels of AMH and E_2, higher expression levels of HIF-1α, FOXO3a and Bax, and lower expression levels of PI3K, AKT, and Bcl-2 in the ovarian tissue than the normal group. Compared with the POR group, low-and high-dose Res decreased the rate of estrous cycle disorders, improved the follicle number and morphology, reduced atretic follicles, promoted the apoptosis of ovarian granulosa cells, increased retrieved oocytes, ovarian wet weight and ovarian index, and lowered serum FSH and LH levels. Moreover, Res down-regulated the expression levels of HIF-1α, FOXO3a and Bax, and up-regulated the expression levels of PI3K, AKT and Bcl-2 in the ovarian tissue. In summary, Res can inhibit apoptosis and mitigate poor ovarian response in mice by regulating the PI3K/AKT/FOXO3a and HIF-1α pathways.

Construction of a clinical prediction model for the impact of acupuncture on pregnancy outcomes in poor ovarian response (POR) patients based on a patient registry research platform / 中国针灸

OBJECTIVES@#To construct a clinical prediction model for the impact of acupuncture on pregnancy outcomes in poor ovarian response (POR) patients, providing insights and methods for predicting pregnancy outcomes in POR patients undergoing acupuncture treatment.@*METHODS@#Clinical data of 268 POR patients (2 cases were eliminated) primarily treated with "thirteen needle acupuncture for Tiaojing Cuyun (regulating menstruation and promoting pregnancy)" was collected from the international patient registry platform of acupuncture moxibustion (IPRPAM) from September 19, 2017 to April 30, 2023, involving 24 clinical centers including Acupuncture-Moxibustion Hospital of China Academy of Chinese Medical Sciences. LASSO and univariate Cox regression were used to screen factors influencing pregnancy outcomes, and a multivariate Cox regression model was established based on the screening results. The best model was selected using the Akaike information criterion (AIC), and a nomogram for clinical pregnancy prediction was constructed. The prediction model was evaluated using receiver operating characteristic (ROC) curves and calibration curves, and internal validation was performed using the Bootstrap method.@*RESULTS@#(1) Age, level of anti-Müllerian hormone (AMH), and total treatment numbers of acupuncture were independent predictors of pregnancy outcomes in POR patients receiving acupuncture (P<0.05). (2) The AIC value of the best subset-Cox multivariate model (560.6) was the smallest, indicating it as the optimal model. (3) The areas under curve (AUCs) of the clinical prediction model after 6, 12, 24, and 36 months treatment were 0.627, 0.719, 0.770, and 0.766, respectively, and in the validation group, they were 0.620, 0.704, 0.759, and 0.765, indicating good discrimination and repeatability of the prediction model. (4) The calibration curve showed that the prediction curve of the clinical prediction model was close to the ideal model's prediction curve, indicating good calibration of the prediction model.@*CONCLUSIONS@#The clinical prediction model for the impact of acupuncture on pregnancy outcomes in POR patients based on the IPRPAM platform has good clinical application value and provides insights into predicting pregnancy outcomes in POR patients undergoing acupuncture treatment.

Analysis of related factors and prediction of poor ovarian response in patients with controlled ovarian stimulation / 中华妇产科杂志

Objective:To explore the related factors of poor ovarian response (POR) in patients receiving controlled ovarian stimulation (COS) and to establish the nomogram for predicting POR in patients who received in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI).Methods:In this retrospective research, clinical data of 17 164 cycles of patients who received IVF/ICSI treatment at Henan Provincial People′s Hospital from September 1st, 2016 to September 1st, 2020 were analyzed. Independent correlative factors affecting the occurrence of POR were screened by logistic regression, which were the model enrollment variables in the prediction model. Totally 13 266 cycles with well-record of enrollment variables were screened, and these data were randomly divided into model group (9 896 patients) and validation group (3 370 patients) according to 3∶1. The nomogram was established according to the regression coefficient of the relevant variables. The prediction accuracy of the nomogram was evaluated by calculating area under the receiver operating characteristic curve (AUC).Results:Multivariate logistic regression analysis showed age, infertility type, body mass index, anti-Müllerian hormone, basal follicle stimulating hormone, basal estrogen, antral follicle number, previous times of POR, history of ovarian surgery, ovulation stimulation protocol and average amount of gonadotropin were independent correlative factors affecting the occurrence of POR (all P<0.05). In the model group, according to the above factors, the prediction model and nomogram of POR risk were constructed and the validation group verified the model. The AUC of the model group was 0.893 (95% CI: 0.885-0.900), and the AUC of the validation group was 0.890 (95% CI: 0.878-0.903). Conclusion:The influencing factors of POR after COS in patients treated by IVF/ICSI are screened, and the nomogram for predicting POR established in this study is proved to be effective, simple, intuitive and clear in predicting the occurrence of POR.

Influence of female age on the fresh cycle live birth rate of different controlled ovarian hyperstimulation protocols in poor ovarian response patients / 中华妇产科杂志

Objective:To investigate the influence of age on the fresh cycle live birth rate in patients with poor ovarian response in different controlled ovarian hyperstimulation groups.Methods:The clinical data of 3 342 patients in The First Affiliated Hospital of Zhengzhou University from February 2014 to November 2018 were retrospectively collected, including early-follicular phase long-acting gonadotropin-releasing hormone (GnRH) agonist long protocol group (1 375 cases), mid-luteal phase short-acting GnRH agonist long protocol group (1 161 cases) and GnRH antagonist protocol group (806 cases); each group was divided into 4 subgroups according to age: ≤30 years, 31－35 years, 36－40 years and >40 years, the pregnancy outcomes in each age subgroup were analyzed under different controlled ovarian hyperstimulation protocols.Results:In early-follicular phase long-acting GnRH agonist long protocol group, the final live birth rates of each age subgroup were 39.4% (228/579), 36.1% (135/374), 16.6% (48/290) and 3.0% (4/132); in mid-luteal phase short-acting GnRH agonist long protocol group, live birth rates of each age subgroup were 32.1% (99/308), 20.8% (55/264), 13.0% (45/346) and 7.0% (17/243); in GnRH antagonist protocol group, live birth rates of each age subgroup were 22.8% (26/114), 16.3% (25/153), 11.2% (31/278), and 3.8% (10/261); the live birth rate of each group decreased significantly with the increase of age (all P<0.01). When the age≤35 years old, the fresh cycle live birth rate of the early-follicular phase long-acting GnRH agonist long protocol group was significantly better than those of the other two groups (all P<0.01). The multivariate logistic regression analysis of age and live birth rate of the three controlled ovarian hyperstimulation groups showed age was the independent influence factor ( OR=0.898, 95% CI: 0.873-0.916, P<0.01; OR=0.926, 95% CI: 0.890-0.996, P<0.01; OR=0.901, 95% CI: 0.863-0.960, P<0.01). Conclusions:Age is an independent influencing factor for the prediction of fresh cycle live birth rate in low ovarian response patients. No matter which controlled ovarian hyperstimulation protocol is adopted, the final live birth rate decreases significantly with the increase of women′s age. In addition, the early-follicular phase long-acting GnRH agonist long protocol has the highest fresh cycle live birth rate among all controlled ovarian hyperstimulation groups.

Effect of Modified Wuzi Yanzongwan Periodic Staging Treatment on Outcome of Assisted Pregnancy in Patients with Poor Ovarian Response / 中国实验方剂学杂志

Objective:To observe the effect of modified Wuzi Yanzongwan periodic staging treatment on the outcome of assisted pregnancy in patients with poor ovarian response （POR） and kidney deficiency syndrome. Method:One hundred and four patients were randomly divided into observation group and control group， with 52 cases in each group. Both groups received gonadotropin releasing hormone （GnRH） antagonist regimen. The patients in control group additionally took Bushen Yutaiwan orally， 5 g/time， 3 times/day. The patients in observation group additionally took modified Wuzi Yanzongwan during pre-ovulation and post-ovulation periods， 1 dose/day. The treatment courses were 3 menstrual cycles （or termination after clinical pregnancy） in both groups. The number of eggs obtained， the number of available embryos， the number of fertilization， the number of high-quality embryos， the number of embryos implanted， the number of cycles cancelled， and the clinical pregnancy were recorded. Human chorionic gonadotropin （HCG） was injected， and then follicle-stimulating hormone （FSH）， luteinizing hormone （LH）， estrogen （E₂）， anti-Müllerian hormone （AMH）， basal antral follicle count （AFC） and endometrial thickness were measured daily. The number of days and dosage of Gn used， scores of kidney deficiency syndrome were recorded before and after treatment， and the adverse reactions during the study period were recorded. Result:The number of eggs captured， rate of harvested eggs， number of available embryos， rate of available embryos， number of high-quality embryos， rate of high-quality embryos， and fertilization rate in observation group were higher than those in control group （<italic>P</italic><0.05 or <italic>P</italic><0.01）. The cycle cancellation rate was lower than that in the control group； the embryo implantation rate and clinical pregnancy rate were superior than those in control group， but the difference was not statistically significant. The FSH level and FSH/LH ratio in observation group were lower than those in control group during HCG day （<italic>P</italic><0.01）， while E₂， AMH， AFC and endometrial thickness were higher than those in control group （<italic>P</italic><0.01）. Simultaneously， the number of days and amount of Gn used in observation group was lower than that in control group （<italic>P</italic><0.01）. Conclusion:The Modified Wuzi Yanzongwan periodic staging treatment combined with GnRH antagonist scheme for patients with POR kidney deficiency syndrome， can regulate the level of endocrine hormones， promote follicular development， improve ovarian reserve， increase the number of eggs obtained， improve egg quality， help improve pregnancy outcomes， and increase the chances of successful pregnancy with assisted reproductive technology. It is worthy of further clinical research.

Acupuncture combined with medication improves endocrine hormone levels and ovarian reserve function in poor ovarian response patients undergoing in vitro fertilization-embryo transplantation / 针刺研究

OBJECTIVE: To observe the clinical effect of acupuncture plus medication in the treatment of poor ovarian response (POR) patients and to explore its mechanisms in assisting pregnancy. METHODS: A total of 100 volunteer POR women undergoing in vitro fertilization-embryo transplantation (IVF-ET) were recruited in the present study. On the 1st cycle of IVF-ET, these POR women received microstimulation of ovulation program (oral administration of Clomiphene, muscular injection of Menotrophin, Chorionic Gonadotrophin triggering, etc.). Before receiving the 2nd period of IVF-ET, these patients were equally and randomly divided into control, medication (Climen, composed of estradiol valerate and cyproterone acetate), acupuncture and acupuncture+medication (combined treatment) groups according to the random number table. Patients of the medication group were asked to orally take Climen (1 tablet/d for 21 days) beginning from the 3rd day of the menstruation, which was repeated for 3 menstrual cycles. Patients of the acupuncture group received manual acupuncture stimulation of Guanyuan (CV4), and bilateral Taixi (KI3), Sanyinjiao (SP6) of and Tai-chong (LR3) from day 8 to 15 of menstruation (follicular phase), once daily for 3 menstrual cycles. On the 2nd day of menstruation of the 1st and 2nd IVF-ET cycle, the ovarian reserve function was detected, including measurement of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) contents by using radioimmunoassay, and serum anti-mullerian hormone (AMH) level by using ELISA, and the antral follicles count (AFC) of the ovaries by using a color Doppler ultrasonic diagnosis apparatus. At the end of ovulation induction, the assisted pregnancy indexes and outcomes were detected, including administration of dosage and days of gonadotropin (Gn), the diameter of dominant oocyte, level of E2 on the trigger day, the numbers of ultrasound-guided-retrieved oocyte and the cultivated high-quality embryo (grade 1 and 2). RESULTS: After the treatment, the contents of serum FSH, LH and E2 in the medication, acupuncture and combined treatment groups were significantly reduced (P0.05). CONCLUSION: Acupuncture combined with medication improves the level of endocrinal hormones and ovarian reservation function in POR women undergoing IVF-ET, benefiting the ovary environment of pregnancy.

Criteria, diagnosis and treatment of decreased ovarian function: Recent progress / 第二军医大学学报

Fallopian tube factors and decreased ovarian function are the main causes of female infertility. Decreased ovarian function includes premature ovarian failure, diminished ovarian reserve, premature ovarian insufficiency and poor ovarian response. The main feature of ovarian function decline is the decrease in the number and/or the low quality of ova, manifested as ovulation disorders, infertility and reproductive endocrine disorders. This article summarizes the progress in different evaluation criteria and treatment of decreased ovarian function, hoping to provide reference for future diagnosis and treatment.

Analysis of 120 Cases of Poor Ovarian Response Patients in in Vitro Fertilization Treatment for Ovulation Induction / 沈阳医学院学报

Objective: To investigate the clinical outcome of ovulation induction in patients with poor ovarian response treated with in vitro fertilization. Methods: A total of 120 patients with poor ovarian response in our hospital from Nov 2013 to Oct 2015 were en?rolled and were divided into 3 groups according to the different treatment methods. The clinical outcome were compared. Results:There was no significant difference in fertilization rate, cleavage rate, available embryo rate, good embryo rate and pregnancy rate in 3 groups ( P>0?05) . The time and doses of gonadotropin in minimal ovarian stimulation group were significantly lower than those in antagonist protocol group and luteal?phase ovulation induction group ( P<0?05) . The embryo freezing rate in minimal ovarian stimula?tion group was significantly higher than that in antagonist protocol group ( P<0?05 ) . The number of oocytes in antagonist protocol group was significantly higher than those in minimal ovarian stimulation group and luteal?phase ovulation induction group, and the em?bryo transplantation cancellation rate was lower than those in minimal ovarian stimulation group and luteal?phase ovulation induction group ( P<0?05) . Conclusion: Minimal ovarian stimulation method has good curative effect, and more suitable for the treatment of poor ovarian response.

What Number of Oocytes Is Appropriate for Defining Poor Ovarian Response?

PURPOSE: This study attempted to derive an objective and sophisticated definition of poor ovarian response (POR). MATERIALS AND METHODS: A total of 176 consecutive in vitro fertilization (IVF) cycles (137 patients) with conventional ovarian stimulation during 2009 to 2012 were studied by retrospective analysis. Optimal oocyte number (total or mature) was determined by statistics-based (distribution of oocyte number) and prognosis-based approaches (prediction for IVF outcome). Receiver operating characteristics curve analysis was used to show what number of oocytes could predict IVF pregnancy and whether clinical and laboratory variables could predict newly defined POR. RESULTS: The 25th percentile of the distribution corresponded to total oocytes 5 and mature oocyte >1. Considering the incidence of POR (34.1%), a reasonable definition of POR was decided as total oocytes < or =2 or mature oocyte < or =1. For the prediction of this new definition, the extreme cut-off value (by setting a false positive rate of 5%) of serum anti-Mullerian hormone (AMH) was < or =0.76 ng/mL, which was better than serum follicle stimulating hormone or age. A new simple definition of POR was derived as total oocytes < or =2 or mature oocyte < or =1 in a previous cycle or a serum AMH level of < or =0.76 ng/mL. When this simple criterion was re-applied to our data, the predictive performance was similar to the Bologna criteria. CONCLUSION: We here propose a new definition of POR, which is simple and supported by statistical and prognostic analyses.

What Number of Oocytes Is Appropriate for Defining Poor Ovarian Response?

PURPOSE: This study attempted to derive an objective and sophisticated definition of poor ovarian response (POR). MATERIALS AND METHODS: A total of 176 consecutive in vitro fertilization (IVF) cycles (137 patients) with conventional ovarian stimulation during 2009 to 2012 were studied by retrospective analysis. Optimal oocyte number (total or mature) was determined by statistics-based (distribution of oocyte number) and prognosis-based approaches (prediction for IVF outcome). Receiver operating characteristics curve analysis was used to show what number of oocytes could predict IVF pregnancy and whether clinical and laboratory variables could predict newly defined POR. RESULTS: The 25th percentile of the distribution corresponded to total oocytes 5 and mature oocyte >1. Considering the incidence of POR (34.1%), a reasonable definition of POR was decided as total oocytes < or =2 or mature oocyte < or =1. For the prediction of this new definition, the extreme cut-off value (by setting a false positive rate of 5%) of serum anti-Mullerian hormone (AMH) was < or =0.76 ng/mL, which was better than serum follicle stimulating hormone or age. A new simple definition of POR was derived as total oocytes < or =2 or mature oocyte < or =1 in a previous cycle or a serum AMH level of < or =0.76 ng/mL. When this simple criterion was re-applied to our data, the predictive performance was similar to the Bologna criteria. CONCLUSION: We here propose a new definition of POR, which is simple and supported by statistical and prognostic analyses.