Application of mesenchymal stem cell therapy for premature ovarian insufficiency: Recent advances from mechanisms to therapeutics

The incidence of premature ovarian insufficiency(POI)is increasing worldwide,particularly among younger women,posing a significant challenge to fertility.In addition to menopausal symptoms,POI leads to several complications that profoundly affect female reproductive function and overall health.Unfortunately,current clinical treatment strategies for this condition are limited and often yield unsatisfactory outcomes.These approaches typically involve hormone repla-cement therapy combined with psychological support.Recently,mesenchymal stem cell(MSC)therapies for POI have garnered considerable attention in global research.MSCs can restore ovarian reproductive and endocrine functions through diverse mechanisms,including controlling differentiation,promoting angiogenesis,regulating ovarian fibrosis,inhibiting apoptosis,enhancing autocrine and paracrine effects,suppressing inflammation,modulating the immune system,and genetic regulation.This editorial offers a succinct summary of the application of MSC therapy in the context of POI,providing evidence for groundbreaking medical approaches that have potential to enhance reproductive health and overall well-being for women.

Significance of oxidative stress and antioxidant capacity tests as biomarkers of premature ovarian insufficiency: A case control study

BACKGROUND Premature ovarian insufficiency(POI)is a condition that causes secondary amenorrhea owing to ovarian hypofunction at an early stage.Early follicular depletion results in intractable infertility,thereby considerably reducing the quality of life of females.Given the continuum in weakened ovarian function,progressing from incipient ovarian failure(IOF)to transitional ovarian failure and further to POI,it is necessary to develop biomarkers for predicting POI.The oxidative stress states in IOF and POI were comprehensively evaluated via oxidative stress[diacron-reactive oxygen metabolites(d-ROMs)]test and anti-oxidant capacity[biological antioxidant potential(BAP)].METHODS Females presenting with secondary amenorrhea over 4 mo and a follicle stimulating hormone level of>40 mIU/mL were categorized into the POI group.Females presenting with a normal menstrual cycle and a follicle stimulating hormone level of>10.2 mIU/mL were categorized into the IOF group.Healthy females without ovarian hypofunction were categorized into the control group.Among females aged<40 years who visited our hospital from January 2021 to June 2022,we recruited 11 patients into both POI and IOF groups.For the potential antioxidant capacity,the relative oxidative stress index(BAP/d-ROMs×100)was calculated,and the oxidative stress defense system was comprehensively evaluated.RESULTS d-ROMs were significantly higher in the POI and IOF groups than in the control group,(478.2±58.7 U.CARR,434.5±60.6 U.CARR,and 341.1±35.1 U.CARR,respectively)(U.CARR is equivalent to 0.08 mg/dL of hydrogen peroxide).However,no significant difference was found between the POI and IOF groups.Regarding BAP,no significant difference was found between the control,IOF,and POI groups(2078.5±157.4μmol/L,2116.2±240.2μmol/L,and 2029.0±186.4μmol/L,respectively).The oxidative stress index was significantly higher in the POI and IOF groups than in the control group(23.7±3.3,20.7±3.6,and 16.5±2.1,respectively).However,no significant difference was found between the POI and IOF groups.CONCLUSION High levels of oxidative stress suggest that evaluating the oxidative stress state may be a useful indicator for the early detection of POI.

Analysis of oxidative stress and antioxidative potential in premature ovarian insufficiency

BACKGROUND Premature ovarian insufficiency(POI)is characterized by an early decline in ovarian function,inducing secondary amenorrhea.While the cause of POI has not yet been identified,the function of mitochondria in the ovaries and the cytotoxicity associated with reactive oxygen species(ROS)have been implicated in follicle pool depletion and a decline in follicle quality.Recently developed tests have enabled easy measurement of diacron-reactive oxygen metabolites(d-ROMs)and biological antioxidant potential(BAP).The combination of these two tests is used to comprehensively assess oxidative stress in the blood.AIM To comprehensively assess the oxidative stress of d-ROMs and BAP in POI.METHODS Participants were classified into two groups:A POI group of 11 women aged<40 years examined between January 2021 and June 2022 with a history of secondary amenorrhea for at least 4 mo in our hospital and an FSH value of≥40 mIU/mL;and a control group of healthy women of the same age with normal ovarian function in our hospital.Plasma d-ROMs and BAP were measured in both these groups underwent.Differences between groups were assessed using the t-test.RESULTS The mean age and mean body mass index(BMI)were 35.8±3.0 years and 20.1±1.9 kg/m2 in the control group and 35.8±2.7 years and 19.4±2.5 kg/m2 in the POI group,respectively.The mean gravidity and parity in control and POI groups were 0.6±0.7 and 0.4±0.5 and 0.6±0.9 and 0.3±0.5,respectively.The two groups did not differ significantly in terms of mean age,BMI,gravidity,or parity.The d-ROMs level was significantly higher in the POI group than in the control group(478.2±58.7 vs 341.1±35.1 U.CARR;P<0.001);however,the BAP level did not significantly differ between the two groups(2078.5±157.4 vs 2029.0±186.4μmol/L).The oxidase stress index(d-ROMs/BAP×100)was significantly higher in the POI group than in the control group(23.7±3.3 vs 16.5±2.1;P<0.001).CONCLUSION Oxidative stress was significantly greater in the POI group than in the control group,suggesting oxidative stress as a factor that can serve as a POI biomarker.

Premature ovarian insufficiency identified as a kidney deficiency and liver constraint pattern treated by Professor Zhiqiang Guo:A retrospective analysis

Objective:To study the efficacy of Professor Zhiqiang Guo's unique sequential herbal therapy in the treatment of premature ovarian insufficiency(POI)of the kidney deficiency and liver constraint pattern.Methods:Ninety patients with POI who consulted with Professor Guo at Dongzimen Hospital,Beijing University of Chinese Medicine from January 2012 to December 2015 were enrolled.Treatment consisted of sequential therapy using traditional Chinese medicine formulae with the actions of nourishing the liver and kidney.Course of treatment was 3 consecutive menstrual cycles for each participant except for those who became pregnant during treatment.Baseline data including age,course of disease,past medical history,lifestyle,pregnancy outcome,menstrual status(cycle length,menstrual flow duration and volume),as well as gonadal hormone levels before and after treatment were recorded and analyzed.Results:During treatment,18(20.0%)participants became pregnant.Symptoms including scanty menstrual flow,irritability,low libido,insomnia and excessive dreaming at night,nightsweats,hot flashes,and depression were markedly alleviated.Changes in follicle-stimulating hormone(FSH)and luteinizing hormone(LH)levels at early follicular stage were observed(P=.009 and P=.002,respectively),and FSH/LH differed significantly pre-and posttreatment(P=.0.44).Conclusion:Professor Guo's sequential Chinese herbal therapy with the actions of nourishing the liver and kidney to treat POI can enhance ovarian function,promote pregnancy,and improve quality of life.

Research on the aetiology and treatment of premature ovarian insufficiency

Premature ovarian insufficiency,as a complex gynaecological disease,seriously threatens the physical and mental health of women of childbearing age.The main reasons for its pathogenesis are summarized.As a complex gynaecological disease,premature ovarian insufficiency seriously threatens the physical and mental health of women of childbearing age.The causes of the disease mainly include genetic defects,autoimmune disorders,radiotherapy and chemotherapy,infection,surgery,adverse environmental exposures and other factors.In more than half of cases,the cause remains unclear.In the clinic,hormone replacement therapy is used mainly to relieve the symptoms of oestrogen deficiency.This article reviews the research progress on the causes and treatment of premature ovarian insufficiency in recent years.

Effect on serum metabolomics of rats with premature ovarian insufficiency by Zhibian(BL54) through Shuidao(ST28) acupuncture

OBJECTIVE:To analyze the serum metabolic targets of the"Zhibian(BL54)through Shuidao(ST28)"acupuncture technique in cyclophosphamide(CTX)-induced premature ovarian insufficiency(POI)model rats and to elucidate the potential molecular mechanism of acupuncture in improving POI.METHODS:We used an intraperitoneal injection of CTX to establish the POI rat model(POI group)and compared serum hormone levels and ovarian histopathological changes to evaluate the effect of the Zhibian(BL54)through Shuidao(ST28)technique(ZS+POI group)on ovarian function.Then,nontargeted metabolomics was performed using rat serum by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry(UPLC-Q-TOF/MS).RESULTS:After acupuncture intervention,the serum hormone levels and ovarian pathological morphology of POI rats were effectively improved.Moreover,UPLC-Q-TOF/MS results showed that the ZS+POI group showed a significant reversal of the levels of 6 differential metabolites.Among them,the levels of four serum metabolic markers,divanillyltetrahydrofuran ferulate,trans-ferulic acid,tryptamine,and neuraminic acid,increased significantly.Further analysis of biological effects showed that all metabolites were involved in the regulation of reproductive hormone levels and antioxidant and antiapoptotic effects.CONCLUSIONS:The"Zhibian(BL54)through Shuidao(ST28)"acupuncture method may improve the ovarian function of POI rats by regulating serum metabolite markers to exert antioxidant and antiapoptotic effects,which provides a theoretical basis for the clinical application of acupuncture in the treatment of POI.

Pharmacological methods for ovarian function and fertility preservation in women with cancer:A literature review

Oncofertility is an extremely significant topic that is increasingly being discussed owing to increased evidence indicating that fertility preservation does not affect the treatment outcomes of patients with cancer but significantly contributes to preserving life quality.The effect of chemotherapy can range from minimal effects to complete ovarian atrophy.Limited data are available on the effects of monoclonal antibodies and targeted therapies on the ovaries and fertility.Temporary ovarian suppression by administering a gonadotropin-releasing hormone agonist(GnRHa)during chemotherapy decreases the gonadotoxic effect of chemotherapy,thereby diminishing the chance of developing premature ovarian insufficiency(POI).At present,the concomitant administration of GnRH analogs during chemotherapy is the only accepted pharmacological method for preserving ovarian function.Notably,most randomized studies on the effectiveness of luteinizing hormone-releasing hormone agonists during chemotherapy in preventing POI have been conducted in women with breast cancer,with a considerably small number of studies on patients with hematological malignancies.Furthermore,most randomized controlled trials on breast cancer have revealed a decrease in treatment-induced POI risk,regardless of the hormone receptor status.In addition,studies on hematological malignancies have yielded negative results;nevertheless,thefindings must be interpreted with caution owing to numerous limitations.Current guidelines from the American Society of Clinical Oncology and ESMO Clinical Practice Guidelines recommend sperm,oocyte,and embryo cryopreservation as a standard practice and only offering GnRHa to patients when proven fertility preservation methods are not feasible.In this manuscript,we present a comprehensive literature overview on the application of ovarian suppression with GnRHa during chemotherapy in patients with cancer by addressing preclinical and clinical data,as well as future perspectives in thisfield that upcoming research should focus on.

Effect of Ningxin-Yishen Formula on D-galactose-induced Premature Ovarian Insufficiency Mice by Inhibiting p53

Background:The prevalence of premature ovarian insufficiency(POI)is gradually increasing,safer and more effective treatments are urgently needed.Objective:The aim of this study was to evaluate the effects of Ningxin-Yishen formula(NXYSF)on D-galactose-induced POI mice as well as to shed a light on its potential mechanisms.Methods:Six to eight weeks old female C57BL/6 mice were used in this study and randomly divided into six groups:control group;model group;estradiol valerate(EV)treatment group and NXYSF treatment group with graded doses(9.5,19,and 38 g·kg^(−1)/d).Both EV and NXYSF treatments were initiated at the 15th day of modeling and lasted for 28 days.Afterwards,the ovarian function was evaluated in each group by analyzing the proportion of primordial follicles as well as the serum sex hormone levels.Furthermore,network pharmacology approach was performed to elucidate the potential targets of NXYSF,which was verified through western blotting experiments finally.Results:NXYSF could significantly reverse the inefficiency of weight gain caused by POI,and promote the devel-opment of primordial follicles.In addition,it could restore the abnormal serum anti-Müllerian hormone(AMH),estradiol(E 2),luteinizing hormone(LH)and follicle-stimulating hormone(FSH).Moreover,some crucial key gene targets including TP53 were as propose to be relate with the effect of NXYSF through network pharmacology anal-ysis.Last but importantly,western blotting experiments confirmed that NXYSF could inhibit the expression of p53 protein in mouse ovaries.

Ningxin Tongyu Zishen Tang in Treatment of Premature Ovarian Insufficiency:A Retrospective Control Study

Background:Premature ovarian insufficiency(POI)is a common refractory disease in gynecology,and its etiology and pathogenesis are complex.Psychological stress exerts an impact on women’s physical and mental health,and in turn affects the ovarian reserve function,which is one of the important etiologies and pathogenesis of POI.The compound formula Ningxin Tongyu Zishen Tang(NTZT)is composed of Chinese herbal medicines which can nourish heart and tranquilize mind,tonify kidney and supplement essence.By comparing the menstrual symptoms,traditional Chinese medicine(TCM)symptoms and the levels of serum sex hormone before and after treatment,the NTZT is clarified for its curative effect and advantages in patients with POI.Objective:The study aimed to observe the effects of NTZT on menstrual symptoms,TCM symptoms and the levels of serum sex hormone in POI patients.Methods:60 POI patients were divided into two groups,namely observation group and control group,with 30 patients in each group.The patients in both groups were treated by hormone replacement therapy(HRT).The observation and control groups received treatment with NTZT and or Liuwei Dihuang Wan(LDW),respectively.All of the patients were treated for 3 months continuously.The menstrual symptoms,TCM symptoms and the levels of serum sex hormone of the two groups were investigated before and after treatment.Results:It was found that the menstrual symptoms,TCM symptoms and the levels of serum sex hormone improved dramatically after treatment in the observation group(P<0.01).By comparison,the menstrual symptoms and the levels of serum sex hormone improved significantly(P<0.01),but no obvious improvement in TCM symptoms(P>0.05)in the control group was observed.Compared with the control group,the observation group showed significant improvement in TCM symptoms and the levels of serum sex hormone(P<0.01),but no significant difference was observed in the menstrual symptoms(P>0.05).In addition,there was no any adverse events such as gastrointestinal dysfunction and drug allergyobserved in both groups,indicating the safety of the two TCM formulas.Conclusion:The study found that NTZT could restore menstruation and improve the levels of sex hormone in patients with POI.It was also found that NTZT could eliminate the feelings of vexation,insomnia and dream-fulness,as well as tidal fever and sweating,aching pain of loins,and vaginal dryness significantly.It can be proved that NTZT is effective in treating patients with POI owing to its effects of nourishing heart and tranquil-izing mind,tonifying kidney and supplementing essence together,leading to elimination of psychological stress,which further promotes the development of the ovaries.

miRNA-146通过调控TLR4/NF-κB信号通路促进 POI模型卵巢颗粒细胞生长的机制研究

目的 探讨小鼠原发性卵巢功能不全(POI)模型的微小RNA(miRNA)-146、Toll样受体4(TLR4)和核转录因子-κB(NF-κB)的水平及对卵巢颗粒细胞生长的影响。方法 取健康雌性BALB/c小鼠40只,随机分为POI组和对照组,每组20只。采用实时荧光定量PCR(qRT-PCR)检测血清miRNA-146水平;采用酶联免疫吸附试验(ELISA)检测肿瘤坏死因子-α(TNF-α)和白细胞介素-6(IL-6)表达水平;采用蛋白质印迹法检测小鼠卵巢组织TLR4和NF-κB蛋白水平。采用miRNA-146模拟物或抑制剂转染小鼠卵巢颗粒细胞,评估卵巢颗粒细胞增殖、生长活力和细胞凋亡率及TLR4、NF-κB通路蛋白的表达。采用Spearman相关分析POI模型miRNA-146水平与TLR4和NF-κB水平的相关性。结果 POI组的miRNA-146水平显著低于对照组(P<0.05),TNF-α、IL-6、TLR4、NF-κB水平高于对照组(P<0.05)。miRNA-146模拟物在卵巢颗粒细胞中呈高表达水平,且呈浓度依赖趋势。miRNA-146转染后,miRNA-146模拟物组细胞凋亡率低于对照组,miRNA-146抑制剂组细胞凋亡率高于对照组,差异均有统计学意义(P<0.01)。Spearman相关性分析结果显示,POI小鼠的miRNA-146水平与TLR4、NF-κB水平呈负相关(r=-0.725、-0.681,P<0.05)。结论 上调miRNA-146水平具有促进卵巢颗粒细胞生长的作用,其机制可能与miRNA-146负性调控TLR4/NF-κB信号通路和下调TNF-α、IL-6的表达相关,miRNA-146有望作为评估卵泡质量的指标之一。

Systematic evaluation on the clinical efficacy of acupoint stimulation therapy for treatment of premature ovarian insufficiency on the basis of network Meta-analysis

Objective To systematically evaluate the effectiveness and safety of acupoint stimulation therapy for treatment of premature ovarian insufficiency（POI）. Methods Computer retrieval was carried out in such databases as Pub Med, Embase, Cochrane Library, web of science, Chinese biomedicine database（CBM）, China National Knowledge Infrastructure（CNKI）, Wan Fang and VIP in order to collect the randomized controlled trials（RCT） concerning acupoint stimulation therapy for treatment of POI. Software R 3.40 and stata 14.0 were used for Meta-analysis and network Meta-analysis, and Rev Man 5.3 was used for plotting the risk bias diagrams. Results Fortythree RCTs were included in total, involving 3046 POI patients and 18 acupoint stimulation therapies and comprehensive therapies. Metaanalysis showed：（1） The curative effects of acupoint stimulation therapy（RR=1.25, 95%CI [1.07,1.45]）, acupoint stimulation therapy＋Chinese herbal medicine（RR=1.25, 95%CI [1.18,1.32]） and acupoint stimulation therapy＋ hormone replacement therapy（HRT）（RR=1.20, 95%CI [1.12,1.29]） were all superior to that of HRT, indicating that the differences were statistically significant（Z=2.90, P=0.04; Z=7.56, P〈0.000 01; Z=4.06, P〈0.000 01）.（2） Compared with HRT, the occurrence rate of adverse effect of acupoint stimulation therapy was lower, and the safety was superior to that of HRT（RR=0.18, 95%CI [0.08,0.41]）, indicating that the differences were statistically significant（Z=4.08, P〈0.000 1）. Forty-two direct comparisons and 110 indirect comparisons were generated according to network Meta-analysis, among which, 38 comparisons were statistically significant. Network Metaanalysis results with HRT as control showed： the therapeutic measures ranking top 3 according to the curative effect sequence were catgut embedment in acupoint, moxibustion and warming-needle moxibustion, successively, and all the 3 measures were monotherapies without reflecting the advantages of comprehensive therapy. HRT ranked 17 th among the 18 included therapeutic measures. Conclusion On the basis of current evidences, acupoint stimulation therapy has a better clinical efficacy and safety for treatment of POI when compared with HRT. The acupoint stimulation therapies ranking the top 3 have more significant curative effects, but the long-term efficacy and the effect on the ovarian function still need to be further explored. In addition, the conclusion of this study still needs to be verified through a large number of RCTs with reasonable designs and appropriate methods.

滋肾安坤颗粒治疗免疫性POI小鼠疗效及对细胞因子IL-2、IL-6、TGF-β的影响

目的观察滋肾安坤颗粒治疗免疫性早发性卵巢功能不全(POI)小鼠疗效及对白细胞介素2(IL-2)、白细胞介素6(IL-6)、转化生长因子β(TGF-β)的影响。方法筛选动情周期规律的雌性小鼠,以小鼠透明带3(ZP3)为抗原复制免疫性POI小鼠模型。设滋肾安坤颗粒低、高剂量进行治疗,以戊酸雌二醇为阳性对照。巴氏染色法观察动情周期,HE染色法观察卵巢组织形态学变化,ELISA法检测血清雌二醇(E2)、促卵泡激素(FSH)、抗苗勒管激素(AMH)、IL-2、IL-6、TGF-β水平。结果与空白对照组比较,模型组小鼠动情周期延长紊乱,卵巢间质炎性细胞浸润,生长卵泡减少,闭锁卵泡增多(P<0.05,P<0.01);血清E2、AMH、TGF-β水平降低(P<0.01),血清FSH、IL-2、IL-6水平升高(P<0.01)。与模型组比较,各治疗组动情周期紊乱、炎性细胞浸润有改善,其中滋肾安坤高剂量组生长卵泡增加,戊酸雌二醇组闭锁卵泡减少(P<0.05);滋肾安坤高剂量组、戊酸雌二醇组血清E2、AMH、TGF-β水平升高(P<0.05,P<0.01),滋肾安坤高剂量组血清FSH、IL-6水平降低(P<0.05),各治疗组血清IL-2水平降低(P<0.05,P<0.01)。结论滋肾安坤颗粒可改善免疫性POI小鼠血清生殖激素和IL-2、IL-6、TGF-β水平,降低卵巢炎性反应,调节免疫紊乱,提高卵巢储备能力,发挥对卵巢的保护作用。

Extracellular vesicles from iPSC-MSCs alleviate chemotherapy-induced mouse ovarian damage via the ILK-PI3K/AKT pathway

Chemotherapy can significantly reduce follicle counts in ovarian tissues and damage ovarian stroma,causing endocrine disorder,reproductive dysfunction,and primary ovarian insufficiency(POI).Recent studies have suggested that extracellular vesicles(EVs)secreted from mesenchymal stem cells(MSCs)exert therapeutic effects in various degenerative diseases.In this study,transplantation of EVs from human induced pluripotent stem cell-derived MSCs(iPSC-MSC-EVs)resulted in significant restoration of ovarian follicle numbers,improved granulosa cell proliferation,and inhibition of apoptosis in chemotherapy-damaged granulosa cells,cultured ovaries,and in vivo ovaries in mice.Mechanistically,treatment with i PSC-MSC-EVs resulted in up-regulation of the integrinlinked kinase(ILK)-PI3K/AKT pathway,which is suppressed during chemotherapy,most likely through the transfer of regulatory microRNAs(miRNAs)targeting ILK pathway genes.This work provides a framework for the development of advanced therapeutics to ameliorate ovarian damage and POI in female chemotherapy patients.

六味地黄丸治疗早发性卵巢功能不全模型小鼠的分子机制

背景:在临床上,大多数治疗早发性卵巢功能不全的方剂均以六味地黄丸为基础方演变而来,并且取得了较好的疗效。目前对六味地黄丸的实验研究大多为体内动物模型的形态学观察及生理生化指标的检测,而分子机制方面的研究报道较少。目的:探讨六味地黄丸治疗早发性卵巢功能不全的分子作用机制。方法:环磷酰胺120 mg/kg联合白消安12 mg/kg腹腔注射制备早发性卵巢功能不全小鼠模型,然后用六味地黄丸混悬液对早发性卵巢功能不全小鼠进行干预,干预12周采用ELISA法检测小鼠血清中促卵泡刺激素、促黄体生成素、雌激素、抗苗勒氏管激素、8-羟脱氧鸟苷、总抗氧化能力、活性氧水平;苏木精-伊红染色观察小鼠卵巢形态学改变;透射电镜观察小鼠卵泡颗粒细胞超微结构及颗粒细胞线粒体的凋亡情况;免疫组化法检测六味地黄丸对小鼠卵巢颗粒细胞中核受体转录辅激活因子(receptor gamma coactivator-1 alpha,PGC-1α)、线粒体转录因子A(mitochondrialtranscriptionfactorA,TFAM)的表达水平。结果与结论:①与模型组比较,实验组小鼠血清促卵泡刺激素、促黄体生成素、活性氧、8-羟脱氧鸟苷水平降低(P<0.05),雌激素、抗苗勒氏管激素、总抗氧化能力水平升高(P<0.05);②苏木精-伊红染色发现模型组小鼠卵巢组织中闭锁卵泡和黄体较多,个别可见次级卵泡,间质纤维化增生;实验组小鼠卵巢组织可见大量闭锁卵泡,黄体较少,边缘可见原始卵泡,次级卵泡较少,未见明显成熟卵泡;③透射电镜发现实验组小鼠卵巢颗粒细胞内细胞器较完整;④免疫组化结果显示,实验组小鼠卵巢组织PGC-1α的表达水平在第4周稍有升高至第8,12周无明显变化,与模型组有明显差异;实验组小鼠卵巢组织TFAM的表达水平在第4周时短暂升高,然后稍有所下降,但结果均与模型组有明显差异;⑤结果表明,六味地黄丸通过PGC-1α-TFAM-ROS信号通路在一定程度上抑制早发性卵巢功能不全小鼠卵巢颗粒细胞凋亡,从而改善卵巢的内分泌功能,提高机体抗氧化能力,减轻氧化应激损伤程度。

人胎盘来源的间充质干细胞移植对递增负荷训练诱导的POI大鼠卵巢功能的影响

随着女性生育年龄的推迟,30~39岁早发性卵巢功能不全(premature ovarian insufficiency,POI)患者的治疗需求增加。先前的研究证实,不同组织来源的干细胞可以恢复POI小鼠的卵巢功能。本研究旨在探讨人胎盘间充质干细胞(human placenta-derived mesenchymal stem cell,hpMSC)移植治疗递增负荷训练诱导的POI的效果和潜在机制。首先,采用为期9周的递增负荷跑台训练建立POI大鼠模型;然后,通过尾静脉注射给予hpMSC移植治疗;最后,通过激素水平和组织学分析评估卵巢功能,利用hpMSC示踪、酶联免疫吸附试验(en-zyme linked immunosorbent assay,ELISA)、免疫印迹分析、免疫组织化学染色和实时荧光定量PCR评估损伤和修复的分子机制。结果显示,移植后的hpMSC定植在卵巢间质;hpMSC移植增加了卵母细胞的端粒长度,减少了氧化应激反应,下调了Bax(Bcl-2-associated X protein)和胱天蛋白酶-3(caspase-3)的蛋白质水平,与此同时,卵泡刺激素(follicle-stimulating hormone,FSH)的水平、FSH与黄体生成素(luteinizing hormone,LH)的比值(FSH/LH)下降,各级卵泡数量增加。实验结果表明,hpMSC移植可以修复递增负荷训练诱导的POI大鼠的卵巢损伤,改善卵巢功能。

基于6种机器学习算法的早发性卵巢功能不全影响因素分析

目的:通过机器学习算法对早发性卵巢功能不全(POI)的影响因素进行特征排序,找出对POI影响较大的因素。方法:先制定纳入和剔除标准,选取因月经不调就诊的500例患者,根据中医证型进行年龄和职业差异性分析。再通过逻辑回归、支持向量机、决策树、随机森林、极端梯度提升和K-最近邻6种机器学习算法对患者进行POI预测分类,根据算法求得的马修斯相关系数和AUC进行预测精准度比较。通过随机森林中的准确度和基尼不纯度下降对POI影响因素进行特征排序,结合逐步剔除法得到对POI影响程度排序前五的特征因素。结果:随机森林的算法在马修斯相关系数、准确率和AUC中均获得了最大值,分别为0.399、0.717和0.908。POI的影响因素有子宫或盆腔手术史、受教育程度、年龄、减肥史和吸烟史,这些因素的Borda计数得分依次为手术史(2.446)、受教育程度(2.924)、年龄(4.060)、减肥史(5.303)、吸烟史(6.429)。结论:随机森林的性能在预测POI患者中优于其他5种算法,当患者的数据信息不足时,医生可先通过这5个特征因素的指标对月经不调患者进行初步干预。

AMH联合卵巢超声影像学参数对早发性卵巢功能不全的预测价值

目的 探讨育龄期女性不同年龄的性激素、抗苗勒氏管激素(anti-Müllerian hormone, AMH)水平和卵巢超声影像学参数的变化,分析其对早发性卵巢功能不全(premature ovarian insufficiency, POI)的预测价值并建立预测模型。方法 选择2018年2月至2022年6月就诊于西安交通大学第一附属医院的1 968名育龄期女性为研究对象,检测其性激素、AMH、窦卵泡计数(antral follicle count, AFC)、卵巢总体积、卵巢皮质体积、卵巢髓质体积、卵巢总面积、卵巢皮质面积、卵巢髓质面积,分析不同年龄各项指标的变化及其对POI的预测价值,采用AMH联合卵巢超声影像学参数建立预测POI的模型。结果 1 968名研究对象中POI患病率为3.10%,30~39岁年龄组POI的患病率显著高于20~29岁年龄组(P<0.05)。30~34岁组血清AMH水平显著低于20~24岁组和25~29岁组(P<0.05),35~39岁组血清卵泡刺激素(follicle stimulating hormone, FSH)、黄体生成素(luteinizing hormone, LH)水平显著高于30~34岁组(P<0.05),而血清雌二醇(estradiol, E2)和AMH水平、AFC、卵巢体积、卵巢皮质体积、卵巢面积、卵巢皮质面积均显著低于30~34岁组(P<0.05)。POI组患者的血清FSH、LH水平显著高于同龄女性卵巢功能正常者(P<0.05),而血清E2、AMH水平显著低于同龄女性卵巢功能正常者(P<0.05)。POI组患者的AFC、卵巢体积、卵巢皮质体积、卵巢髓质体积、卵巢面积、卵巢皮质面积和卵巢髓质面积均显著低于同龄女性卵巢功能正常者(P<0.05)。对POI的预测价值分析结果显示,激素水平中AMH的预测价值最高(AUC=0.957),其次为E2(AUC=0.840)。超声影像学参数中AFC的预测价值最高(AUC=0.867),其次为卵巢皮质体积(AUC=0.835)。AMH联合卵巢超声影像学参数建立的模型对POI具有较好的预测价值,其灵敏度为94.86%,特异度为91.23%,AUC为0.960,截断值为12分。结论 育龄期女性中30~39岁年龄组POI的患病率较高,AMH联合卵巢超声影像学参数建立的模型对POI具有一定的预测价值,特别对隐匿期女性获得临床关注。

关元命门序贯针刺激活FSHR/cAMP/PKA通路促进早发性卵巢功能不全模型大鼠颗粒细胞增殖的机制研究

【目的】观察关元命门序贯针刺方案对早发性卵巢功能不全(POI)模型大鼠的治疗作用及机制。【方法】将雌性SD大鼠分为空白组、模型组、蛋白激酶A(PKA)抑制剂(H89)+针刺组、针刺组各12只。除空白组,其他3组大鼠采用雷公藤多苷片灌胃制备POI模型。模型成功建立后,空白组和模型组每日捆绑一次;针刺组大鼠在动情间期取关元穴针刺,在动情前期取命门穴针刺;H89+针刺组按照针刺组针刺方案干预,在每次针刺前30 min内腹腔注射H89。连续干预20 d。各组大鼠分别在干预后第1个动情间期和动情前期取材。酶联免疫吸附分析(ELISA)检测动情间期促卵泡激素(FSH)、雌二醇(E2)水平,Western Blot法检测动情间期促卵泡激素受体(FSHR)、芳香化酶P450(P450arom)蛋白表达,细胞计数试剂盒8(CCK-8)法检测动情间期和动情前期颗粒细胞活性,免疫组织化学法检测动情前期增殖细胞核抗原(PCNA)蛋白表达水平。【结果】(1)与空白组比较,模型组和H89+针刺组血清FSH水平显著升高(P<0.01),E2水平显著降低(P<0.001);H89+针刺组FSH水平与模型组无差异(P>0.05),E2水平低于模型组(P<0.05);针刺组FSH水平低于模型组和H89+针刺组(P<0.05),与空白组无差异(P>0.05),E2水平显著高于模型组和H89+针刺组(P<0.01),仍低于空白组(P<0.05)。(2)模型组和H89+针刺组FSHR、P450arom蛋白表达均低于空白组(P<0.01);H89+针刺组FSHR蛋白表达水平与模型组无差异(P>0.05),P450arom蛋白表达水平低于模型组(P<0.05);针刺组FSHR、P450arom蛋白表达水平均高于模型组和H89+针刺组(P<0.05),但仍低于空白组(P<0.05)。(3)模型组和H89+针刺组GCs活性和PCNA平均光密度值均低于空白组(P<0.05);H89+针刺组GCs活性和PCNA平均光密度值均低于模型组(P<0.05);针刺组的GCs活性和PCNA平均光密度值显著高于模型组和H89+针刺组(P<0.05或P<0.01)。【结论】关元命门序贯针刺方案可通过上调促卵泡激素受体(FSHR)/环磷酸腺苷(cAMP)/蛋白激酶A(PKA)通路FSHR、P450arom蛋白的表达,调控性激素水平,提高GCs活性和促进GCs细胞增殖,从而改善POI。

间充质干细胞来源的外泌体治疗早发性卵巢功能不全的研究进展

早发性卵巢功能不全(POI)是一种常见的妇科疾病,影响许多年轻女性的生活质量和生育能力。临床上常用的激素替代治疗只能暂缓POI患者的症状,无法修复受损的卵巢组织。最近的研究表明,间充质干细胞来源的外泌体在治疗POI中展现出巨大潜力。本文总结了人间充质干细胞来源的外泌体在治疗POI方面的研究进展,为未来在POI诊疗中应用外泌体提供实验基础和相关理论依据。

分期针刺任督经穴治疗早发性卵巢功能不全的临床观察

目的观察分期针刺任督经穴治疗早发性卵巢功能不全(POI)的临床疗效。方法选取2021年6月至2022年12月就诊于上海市静安区中医医院的104例POI患者作为研究对象,按照完全随访化方法分为分期组、任脉组、督脉组、西药组,各26例。比较各组患者治疗前后血清性激素水平、窦卵泡计数(AFC),以及治疗和随访过程中共5个访视点的Kupperman(K)表和月经不调症状分级量化(MDQ)表评分。结果治疗后,四组血清卵泡刺激素(FSH)水平下降,雌二醇(E_(2))水平上升(P<0.05);西药组、督脉组和分期组AFC升高(P<0.01),分期组AFC改善优于任脉组(P<0.05)。西药组K表和MDQ表评分在治疗期间下降(P<0.01);随访期间K表不再下降(P>0.05),MDQ表上升(P<0.01)。任脉组K表评分在1MC和随访期间下降(P<0.05),MDQ表评分在3MC下降(P<0.01)。督脉组K表和MDQ表评分在3MC下降(P<0.01);随访期间MDQ表评分下降(P<0.05)。分期组K表评分在每个访视点均下降(P<0.05),MDQ表评分在3MC和随访期间下降(P<0.01)。结论分期针刺任督经穴治疗POI的临床疗效显著。