Clinical observation of Kuntai capsule combined with Fenmotong in treatment of decline of ovarian reserve function

BACKGROUND Decreased ovarian reserve function is an ovarian hypofunction disease that occurs in women before 40 years of age,leading to a decline in fertility and perimeno-pausal symptoms,such as irregular menstruation,amenorrhea,infertility,de-creased libido,and autonomic nervous dysfunction.Fenmatong(FMT)is a com-pound mixture of estradiol tablets and estradiol didroxyprogesterone tablets,which can improve ovarian reserve function by supplementation of exogenous estrogen.However,this treatment has also been shown to cause breast pain,gastrointestinal discomfort,irregular vaginal bleeding,and changes in sexual desire.In severe cases,FMT can promote the development of breast cancer,endometrial cancer,and venous embolic disease.AIM To observe the effects of Kuntai capsules and FMT on endocrine indexes and uterine artery blood circulation in patients with decreased ovarian reserve func-tion.METHODS Patients(130)with decreased ovarian reserve function,who were treated in our hospital from May 2018 to May 2020,were divided into two groups:The FMT group,in which patients were treated with FMT,and the observation group,in which patients were treated with Kuntai capsules.Chinese medicine symptom scores,uterine artery blood flow parameters,ovarian ultrasound test indexes,pictorial blood loss assessment chart(PBAC)scores,and hormone levels were recorded,and total effective rates were calculated for both groups.RESULTS The total effective rate in the observation group was higher than that in the FMT group(P<0.05).After treatment,primary symptoms,including low menstrual volume,delayed menstruation,red color and thick consistency of menses,di-zziness,palpitation,weakness at the waist and knee,insomnia and excessive dreaming,irritability,and dryness and astringency of the pudendal canal in the observation group decreased,and scores for primary and secondary symptoms in the observation group were significantly lower than those in the FMT group(P<0.05).The systolic peak flow rate(PSV),end-diastolic flow rate(EDV),ovarian diameter,sinus follicle count,and resistance index(RI)of the uterine arteries in the observation group and FMT group increased after treatment.Notably,the PSV,EDV,ovarian diameter,and antral follicle count in the observation group were higher than those in the FMT group,whereas the RI in the observation group was lower than that in the FMT group(P<0.05).The PBAC scores in the observation and FMT groups increased after treatment,with that in the ob-servation group becoming significantly higher than that in the FMT group(P<0.05).After treatment,estradiol(E2)and anti-Mullerian hormone(AMH)levels increased,whereas follicle-stimulating hormone(FSH)levels decreased in the observation group and FMT group;E2 and AMH levels became significantly higher and FSH levels became significantly lower in the observation group than in the FMT group(P<0.05).CONCLUSION Compared with FMT,Kuntai capsules promoted uterine artery blood circulation,improved menstruation,relieved symptoms,regulated endocrine function,and improved curative effects.

Meta-analysis of Kuntai Capsules combined with Diane-35 in treatment of PCOS

Objective:To systematically evaluate the clinical efficacy of Kuntai Capsules combined with Diane-35 in the treatment of polycystic ovarian syndrome(PCOS).Methods:The randomized controlled trials(RCTs)of Kuntai Capsules combined with Diane-35 in the treatment of PCOS from databases establishment to April 2020 were searched in Chinese and English databases,and then meta-analysis was performed using RecMan 5.3 software.Results:A total of 132 articles were collected and 14 studies were included.The total sample size was 1254 cases,including 627 cases in the experimental group and 627 cases in the control group.Meta-analysis showed that the combined group was significantly superior to the single group in terms of overall response rate(OR=5.53,95%CI[3.25,9.41],P<0.01),ovulation rate(OR=3.54,95%CI[2.13,5.88],P<0.01),and pregnancy rate(OR=3.21,95%CI[2.00,5.14],P<0.01).In terms of serum sex hormone levels,the combined group was significantly better than the singer group for the regulation of follicle-stimulating hormone(FSH)(MD=-2.09,95%CI[-2.16,-2.01],P<0.01),luteinizing hormone(LH)(MD=-2.15,95%CI[-2.35,-1.95],P<0.01),estrogen(E2)(MD=36.47,95%CI[34.97,37.96],P<0.01),and testosterone(T)(MD=-1.95,95%CI[-2.77,-1.14],P<0.01).In addition,the combined group also showed some advantages over the single group in improving the level of insulin resistance(HOMA-IR)and pancreatic beta cells function(HOMA-β).Conclusion:Kuntai Capsules combined with Diane-35 had certain efficacy advantage in the treatment of PCOS compared with control group.However,the data indicate that the methodological quality of the studies are low,there was potential publication bias,no define conclusion could be drawn,and more high-quality RCTs studies are needed for further validation.

Protective Effect and Mechanism of Kuntai Capsule on Angiotensin II-Induced Hypertension in Ovariectomized Rats

Objective To explore the protective effect and mechanism of Kuntai(KT)Capsule on angiotensin II(Ang II)-induced hypertension in ovariectomized(OVX)rats.Methods Fifty-four rats were randomly divided into 6 groups according to a random number table,9 in each group:control,OVX sham+Ang II,OVX,OVX+Ang II,OVX+Ang II+E2,and OVX+Ang II+KT.OVX rats model was constructed by retroperitoneal bilateral ovariectomy.After 4 weeks of pretreatment with KT Capsule[0.8 g/(kg·d)and 17-β-estradiol(E2,1.2 mg/(kg·d)]respectively,Ang II was injected into a micro-osmotic pump with a syringe to establish a hypertensive rat model.Blood pressure of rat tail artery was measured in a wake state of rats using a non-invasive sphygmomanometer.Blood pressure changes were compared between the intervention groups(OVX+Ang II+KT,OVX+Ang II+E2)and the negative control group(OVX+Ang II).Serum malondialdehyde(MDA)level and superoxide dismutase(SOD)activity were detected respectively.The expressions of oxidative stress-related protein superoxide dismutase2(SOD2)and anti-thioredoxin(TRX),autophagy marker protein[beclin1,light chain(LC)3 II/I ratio and autophagy canonical pathway protein phosphatidylinositol 3-kinase(PI3K)/serine/threonine kinase(AKT)-mammalian target of rapamycin(mTOR)]were evaluated by Western blotting.Results Compared with the OVX+Ang II group,the systolic blood pressure of OVX+Ang II+KT group was significantly lowered(P<0.05)but not the diastolic blood pressure.Besides,SOD2 and TRX protein levels in mycardial tissues were significantly reduced in the OVX+Ang II+KT group compared with the OVX+Ang II group(P<0.05).Oxidative stress serum markers MDA and SOD were down-and up-regulated in the OVX+Ang II+KT group,respectively(P<0.05).Compared with OVX+Ang II group,the levels of cardiac proteins beclin-1 and LC3II/LC3 I in OVX+Ang II+KT group were also up-regulated(P<0.05),and the expression levels of p-PI3K,p-AKT and mTOR protein were down-regulated(P<0.05).Conclusion KT could protect blood pressure of Ang II-induced OVX rats by inhibiting oxidative stress and up-regulating protective autophagy.

Efficacy and Safety Investigation of Kuntai Capsule for the Add-back Therapy of Gonadotropin Releasing Hormone Agonist Administration to Endometriosis Patients： A Randomized,Double-blind, Blank-and Tibolone-controlled Study

Background：As a Chinese Traditional Medicine product,Kuntai capsule could improve the peri-menopausal symptoms in postmenopausal women.But it is still not clear whether Kuntai capsule has a good effect on alleviating peri-menopausal symptoms induced by gonadotropin releasing hormone agonist （GnRH-a） treatment.The purpose of this study was to investigate the clinical effectiveness and safety of Kuntai capsule,on peri-menopausal symptoms in endometriosis （EMS） patients,with postoperative GnRH-a treatment.Methods：Ninety EMS ovarian cyst women with postoperative GnRH-a administration were enrolled in the study,and were randomly divided into Kuntai group,Tibolone group,or blank Control group.The therapeutic strategy in Kuntai group was 4 Kuntai capsules tid,po for 12 weeks after the first GnRH-a injection,while Tibolone 2.5 mg qd,po for 12 weeks in Tibolone group.There was no drug addition in Control group.Climacteric complaints were evaluated by Kupperman menopausal index （KMI） and hot flash/sweating score.Liver and renal functions,lipid profile,serum sex hormone levels and endometrial thickness were measured,and the frequency of adverse events in Kuntai and Tibolone groups was recorded.Results：（l） Before GnRH-a therapy,the baseline parameter results were comparable in the three groups （P ＞ 0.05）.（2） After GnRH-a therapy,KMI and hot flash/sweating scores in all the three groups increased significantly （P ＜ 0.05）.At the 4th week after GnRH-a therapy,KMI and hot flash/sweating score results were as follows：Control group ＞ Kuntai group ＞ Tibolone group （P ＜ 0.05）; at the 8th and 12th week after GnRH-a therapy,KMI and hot flash/sweating score in Control group were significantly higher than the other two groups （P ＜ 0.05）,and no significant difference was identified between Kuntai and Tibolone group （P ＞ 0.05）.（3） No statistical change took place in the liver and renal functions and lipid profile in all the three groups after the treatment （P ＞ 0.05）.（4） The posttherapeutic serum follicle-stimulating hormone （FSH）,luteinizing hormone （LH） and estradiol （E2） level and endometrial thickness decreased significantly in all the three groups （P ＜ 0.05）.After therapy,serum E2 level in Tibolone group was obviously higher than the other two groups （P ＜ 0.05）,while FSH and LH levels were obviously lower （P ＜ 0.05）.（5） The incidence of vaginal bleeding,breast distending pain in Tibolne group was obviously higher than Kuntai group （P ＜ 0.05）.Conclusions：Kuntai capsule is effective on the peri-menopausal symptoms induced by postoperative GnRH-a administration to EMS patients,although its clinical effect might be a few weeks later than Tibolone.Kuntai capsule might be a little safer than Tibolone tablet.

Heyan Kuntai capsule versus dehydroepiandrosterone in treating Chinese patients with infertility caused by diminished ovarian reserve： a multicenter, randomized controlled trial

OBJECTIVE: To evaluate the clinical efficacy and safety of Heyan Kuntai capsule(HYKT) in treating women with infertility caused by diminished ovarian reserve(DOR).METHODS: One hundred eight eligible patientsfrom three Chinese hospitals were randomly divided into an HYKT treatment group(n = 55) or a dehydroepiandrosterone(DHEA) treatment group(n =53). Patients in the HYKT group were treated orally with four 0.5 g HYKT three times a day; patients in the DHEA group were treated with one 25.0 mg DHEA capsule three times a day. All patients were treated for 3 months and followed up over a3-month period.RESULTS: Of 108 patients, 12 dropped out: six from the HYKT group, and six from the DHEA group. Eleven patients got pregnant during the treatment. Serum anti-Müllerian hormone levels and antral follicle counts increased significantly in both groups after treatment(P < 0.05) especially in the HYKT group(P < 0.05). Serum follicle stimulating hormone(FSH) levels and FSH/luteinizing hormone ratios decreased(P < 0.05) with no significant difference between the two groups. Estradiol levels in the HYKT group and DHEA-sulfate levels in the DHEA group both increased(P < 0.05). The spontaneous pregnancy rates were 12% and 11% in the HYKT and DHEA groups, respectively(not significant). During the follow-up period, 16 patients in the HYKT group underwent in vitro fertilization-embryo transfer(IVF-ET) and the number of retrieved oocytes was(5.1 ± 1.8). In DHEA group, 20 patients underwent IVF-ET and the number of retrieved oocyte was(4.2 ± 1.9)(not significant); clinical pregnancy rates were 38% in the HYKT group and 20%in DHEA group(not significant). No significant adverse reactions were observed.CONCLUSION: HYKT can improve the ovarian re-serve and hormone levels in patients with infertility caused by DOR. Pregnancy rates after HYKT treatment were similar to those of DHEA treatment.HYKT might be an alternative to the treatment of infertility caused by DOR.

A Multi-center,Randomized,Controlled and Open Clinical Trial of Heyan Kuntai Capsule (和颜坤泰胶囊) and Hormone Therapy in Perimenopausal Women

Objective： To evaluate the efficacy and safety of Heyan Kuntai Capsule（和颜坤泰胶囊, HYKT） and hormone therapy（HT） on perimenopausal syndromes（PMSs）. Methods： From 2005 to 2008, 390 women with PMSs were recruited from 4 clinic centers. The inclusion criteria included ages 40 to 60 years, estradiol（E2） below 30 ng/L, and follicle stimulating hormone（FSH） above 40 IU/L, etc. The patients were randomly assigned to HYKT group or HT group by random number table method, administrated HYKT or conjugated estrogen with/without medroxyprogesterone acetate tablets for 12 months. During treatment, the patients were interviewed quarterly, Kupperman Menopausal Index（KMI） scores, hot flush scores, insomnia scores, Menopause-Specific Quality of Life（MENQOL） scores and adverse effects were used for evaluating drug efficacy and safety respectively. The last interview was made at the end of 12-month treatment. Results： After treatment, KMI scores of HYKT group and HT group were both significantly decreased compared with baseline（P〈0.01） and there was no significant difference between groups（P〉0.05）, except that KMI of HYKT group was higher after 3-month treatment（P〈0.05）. After treatment, hot flush and insomnia scores were both improved significantly in two groups（P〈0.01）; and HT had a better performance than HYKT in improving hot flush（P〈0.05）. MENQOL were significantly improved in both groups after treatment（P〈0.01）; but there was no significant difference between two groups（P〉0.05）. The incidence of adverse event in the HYKT group was much lower than that in the HT group（P〈0.01）. Conclusions： HYKT could effectively relieve PMSs and improve patient quality of life without severe adverse reactions. Although HYKT exerted curative effects more slowly than hormone, it possessed better safety profile than hormone.

Effects of Heyan Kuntai Capsule(和颜坤泰胶囊)on Follicular Development and Oocyte Cohesin Levels in Aged Mice

Objective： To evaluate the effect of Heyan Kuntai Capsule （和颜坤泰胶囊, HYKT） on the ovarian function of aged mice and expressions of cohesion complexes in oocytes. Methods： Twenty-five 9-month-old female C57BL/6J mice were randomly divided into 5 groups by block randomization method （n=5 per group）, including the control group （saline）, 17β-estradiol group [E2, 100 μg/（kg·d）], and low-, medium-, and high- dose of HYKT groups [0.3, 0.9, 2.7 g/（kg·d）, respectively]. All mice were treated by intragastric administration for 4 weeks. Hematoxylin and eosin staining and anti-VASA staining were used to detect the amounts of follicles. The apoptosis of follicles was measured by anti-gamma H2A histone family member X （γ, H2AX） staining and TdT-mediated dUTP Nick-End Labeling （TUNEL） assay. The density of cohesin subunits, REC8 meiotic recombination protein （REC8）, structural maintenance of chromosome （SMC） 1 β and SMC3 in oocytes were evaluated by immunofluorescent staining. Results： After administration of E2 and high-dose of HYKT, the total number of follicles as well as the number of primordial and primary follicles were significantly increased （P〈0.05）. Anti-γ/H2AX staining and TUNEL assay demonstrated that high-dose of HYKT and E2 partly suppressed the apoptosis of follicles （P〈0.05）. Furthermore, it showed an increased trend in the levels of REC8 and SMC1 β, after administration with E2 and HYKT, and no obvious change in the level of SMC3. Conclusion： HYKT could enhance the number of follicles, suppress apoptosis of oocytes and have a trend to elevate the meiotic-specific cohesin subunits （REC8 and SMC1 β） in oocytes of aged mice, indicating a beneficial effect on the ovarian function in terms of the quantity and quality of follicles.