Kuntai capsule for the treatment of diminished ovarian reserve: A systematic review and meta-analysis of randomized controlled trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Diminished ovarian reserve (DOR) results in reduced fertility. Kuntai capsule, a Chinese patent medicine, which can nourish the heart and kidneys, has shown promising efficacy in its treatment. However, there is no enough clinical evidence to confirm the efficacy and safety of Kuntai capsule. AIM OF THE STUDY: This review aims to evaluate Kuntai capsule's potential benefits and detriments for diminished ovarian reserve. MATERIALS AND METHODS: Databases namely China National Knowledge Infrastructure, WANFANG Database, Chinese Science and Technology Journal Database, Chinese Biomedical Literature Database, PubMed, Cochrane Library, and Embase were searched from their inception to July 2023. We included randomized controlled trials (RCTs) comparing Kuntai capsule to hormone therapy (HT) and Kuntai capsule in combination with HT to HT alone for DOR treatment. The risk of bias was evaluated using RoB 1.0. A Meta-analysis was performed using RevMan 5.4 software. The primary outcomes were antral follicle count (AFC) and serum anti-Müllerian hormone (AMH), secondary outcomes were follicle-stimulating hormone (FSH) and adverse reactions. RESULTS: A Meta-analysis of 12 randomized controlled trials (RCTs), encompassing a total of 905 DOR patients was conducted. The results indicated that the combination of Kuntai capsule with HT exhibited superior efficacy in enhancing AFC (MD = 1.34, 95% CI [0.96,1.72]) and AMH levels (MD = 1.09 (ng/mL) 95% CI[0.80,1.38]), Kuntai capsule demonstrated improvements in AFC (MD = 0.65, 95% CI [0.48,0.83]) in DOR patients compared to HT alone. CONCLUSIONS: Based on the available results, the combination of Kuntai capsule with HT appears to improve the AFC, AMH and FSH levels of DOR patients. Kuntai capsule alone appears to improve the AFC and FSH levels of DOR patients. However, included trials had methodological quality issues, further standardized research is required.

Kuntai capsule attenuates premature ovarian insufficiency by activating the FOXO3/SIRT5 signaling pathway in mice: A comprehensive study using UHPLC-LTQ-Orbitrap and integrated pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Classical prescriptions are not only a primary method of clinical treatment in traditional Chinese medicine (TCM) but also represent breakthroughs in the inheritance and development of this field. Kuntai capsule (KTC), a formulation based on a classical prescription, comprises six TCMs: Rehmanniae Radix Praeparata, Coptidis Rhizoma, Paeoniae Radix Alba, Scutellariae Radix, Asini Corii Colla, and Poria. This formulation possesses various beneficial effects, such as nourishing yin and blood, clearing heat and purging fire, and calming the nerves and relieving annoyance. The investigation of the efficacy and mechanism of KTC in regulating anti-aging factors in the treatment of premature ovarian insufficiency (POI) is not only a prominent topic in classical prescription research but also a crucial issue in the treatment of female reproductive aging using TCM. AIM OF THE STUDY: To evaluate the therapeutic effect of KTC on POI and its underlying mechanism. MATERIALS AND METHODS: Healthy and specific pathogen-free (SPF) female Kunming mice aged 6-8 weeks were selected. After acclimatization, the mice were randomly divided into a control, model, and high, middle, and low dose groups of KTC (1.6, 0.8, and 0.4 mg/kg, respectively). Except for the control group, the animals in the other groups were administered a single intraperitoneal injection of 120 mg/kg cyclophosphamide and 30 mg/kg Busulfan to induce the model of POI. After modeling, the mice were treated with the corresponding drugs for 7 days. Serum and ovarian tissues were collected, and the levels of serum follicle-stimulating hormone (FSH), estradiol (E2), and superoxide dismutase 2 (SOD2) were determined using enzyme-linked immunosorbent assay (ELISA). The chemical composition of KTC was characterized and analyzed using ultra-high-pressure liquid chromatography-linear ion trap-Orbitrap tandem mass spectrometry. A "drug-component-target-pathway-disease" network was constructed using network pharmacology research methods to identify the key active components of KTC in treating POI and to elucidate its potential mechanism. The protein expression of the FOXO3/SIRT5 pathway was detected by western blotting. RESULTS: Compared to the model group, the high-dose group of KTC showed a significant increase in ovarian index, significant increase in levels of E2 and SOD2, and a significant decrease in FSH levels. Through systematic analysis of the chemical constituents of KTC, 69 compounds were identified, including 7 organic acids, 14 alkaloids, 28 flavonoids, 15 terpenoids, 2 lignans, 2 phenylpropanoids, and 1 sugar. Based on network pharmacology research methods, it was determined that KTC exerts its therapeutic effect on POI through multiple components (paeoniflorin and malic acid), multiple targets (FOXO3 and SIRT5), and multiple pathways (prolactin signaling pathway, longevity regulating pathway, and metabolic pathways). The accuracy of the network pharmacology prediction was further validated by detecting the protein expression of SIRT5 and FOXO3a, which showed a significant increase in the middle and high-dose groups of KTC compared to the model group. CONCLUSIONS: KTC may effectively treat POI through a multi-component, multi-target, multi-pathway approach, providing an experimental basis for using KTC based on classical prescriptions in the treatment of POI.

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- ß -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.

Protective Effect and Mechanism of Kuntai Capsule on Angiotensin II -Induced Hypertension in Ovariectomized Rats / 中国结合医学杂志

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.

The effect of Kuntai capsule on ovarian function in cisplatin-induced premature ovarian insufficiency rats.

Objective: This study aims to evaluate the effect of Kuntai capsule on ovarian function in cisplatin-induced premature ovarian insufficiency rats and to explore the mechanism of Kuntai capsule on the ovarian function of rats. Methods: Seventy-four female Sprague-Dawley rats were used for this study. Eight of the rats were randomly assigned to the Control group. The remaining sixty-six rats were utilized to establish the POI model via Cisplatin and then randomly divided into four groups: the model Control group, the Estradiol group, and groups treated with low and high doses of Kuntai capsule. For the 28-day administration, the Control and model Control groups were intragastrically administered with 2.0 mL of 0.9% sodium chloride daily, the Estradiol group with 2.0 mL of Estradiol suspension (0.2mg/kg/d), and the low dose Kuntai capsule group and the high dose Kuntai capsule group with 2.0 mL of Kuntai capsule suspension (0.6g/kg/d, 1.8g/kg/d, respectively). Sex hormone levels, estrous cycle, and ovarian coefficient of the five groups were compared, histological sections analyzed follicle counts, and the protein expressions of growth differentiation factor 9, light chain 3 A-II, and Beclin 1 in the ovarian tissue were detected by Western blotting. Results: After the 28-day administration, the serum Estradiol and Follicle-Stimulating Hormone levels of the group treated with low dose of Kuntai capsule were not significantly different from the Control group, the serum anti-Müllerian Hormone level of the group treated with high dose of Kuntai capsule was significantly higher than the Estradiol group. The estrous cycle of the group treated with low dose of Kuntai capsule was significantly lower than the model Control group. Regarding ovarian coefficient, resting and growing follicles, growth differentiation factor 9, light chain 3 A-II, and Beclin 1 expression, both Kuntai capsule groups outperformed the model Control group with the statistical difference (P<0.05). Conclusion: Kuntai capsule can improve the estrous cycle and ovarian coefficient of rats with premature ovarian insufficiency, maintain the number of resting and growing follicles, and up-regulate the protein expression of growth differentiation factor 9, light chain 3 A-II, and Beclin 1 of rats' ovaries.

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 perimenopausal symptoms, such as irregular menstruation, amenorrhea, infertility, decreased libido, and autonomic nervous dysfunction. Fenmatong (FMT) is a compound 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 function. 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, dizziness, 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 observation 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.

Kuntai Capsule Combined With Letrozole on Gonadal Hormone Levels and Ovarian Function in Patients With PCOS: A Systematic Review and Meta-Analysis.

Background: The efficacy of Kuntai capsule combined with letrozole (LE) in improving ovarian function of polycystic ovary syndrome (PCOS) has been evaluated before, but there is still a lack of evidence-based support for the regulation of sex hormone levels. In recent years, new randomized clinical trials (RCTs) have been reported on the effect of combined therapy on regulating sex hormone levels. Objective: We aimed to systematically evaluate the efficacy of Kuntai capsule combined with LE in the treatment of PCOS. Methods: A search across the China Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), Wanfang database, PubMed, Web of Science, The Cochrane Library, and Embase was conducted on Kuntai capsule combined with LE in the treatment of PCOS. The time of the self-built database was up to April 30, 2021. RCTs of LE in the control group and LE combined with Kuntai capsule in the experimental group were selected. RevMan5.3 software was used for data analysis. Results: A total of 17 studies were gathered, which included 1,684 patients. The meta-analysis results showed that the total effective rate of the combined group was 93.36% and that of the LE group was 78.15%. The improvement in the ovulation rate, pregnancy rate, number of mature follicles, endometrial thickness, cervical mucus score, and serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL) in the combined group was consistent with the results of a previous meta-analysis and was better than that in the LE group (p < 0.05). In addition, the combination group was better than the LE group in regulating the levels of estradiol (E2) and testosterone (T) (p < 0.05). There were no adverse drug reactions in the two groups during treatment. Conclusion: As a type of pure traditional Chinese medicine preparation, Kuntai capsule combined with LE had a better effect than LE alone in the treatment of PCOS, with advantages mainly reflected in enhancing ovarian function and regulating the levels of sex hormones in vivo, among others, but the value of combined therapy still needs to be verified by more high-quality RCTs.

Mechanism and experimental verification of antioxidant action of Heyan Kuntai Capsule based on systematic pharmacology / 中草药

Objective: To explore and verify the potential antioxidation mechanism of traditional Chinese medicine Heyan Kuntai Capsule (HKC). Methods: Gene targets of 21 ingredients of HKC were searched for through Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and analysis platform, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis with Database for Annotation, Visualization and Integrated Discovery (DAVID) tools. Further, the anti-oxidative function of HKC was validated in an in vitro H2O2-induced oxidative stress model in MII oocytes. Results: A total of 151 genes were obtained as targets to 21 components of HKC, whose GO were further significantly enriched in mitochondrion, superoxide dismutase activity and energy pathways, while KEGG showed the enrichment in PI3K/AKT, mTOR and ErbB1 signaling pathways. Afterwards, it was confirmed that HKC increased ATP production in H2O2-treated MII oocytes by improving mitochondrial function and reduced the dissipation of mitochondrial membrane potential (ΔΨm) to exert the antioxidation effect. Conclusion:s HKC exerts anti-oxidative effect by improving mitochondrial function.

Kuntai capsule attenuates premature ovarian failure through the PI3K/AKT/mTOR pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Kuntai capsule (KTC), a type of herb formulas, was first described in the book of Shang Han Za Bing Lun in the third century. KTC has been widely used for the clinical treatment of menopausal syndrome. Considering that premature ovarian failure is also known as premature menopause, this study was designed to investigate the effects and mechanisms of KTC on a mouse model of premature ovarian failure. MATERIALS AND METHODS: Forty-five female C57BL/6 mice were chosen for this study. Fifteen of the mice were separated into the Control group. The remaining thirty were used to establish the premature ovarian failure model by injecting intraperitoneally with 75 mg/kg cyclophosphamide and then by randomly dividing the mice into two groups. One group was considered the Model group, the other group treated with the Kuntai capsule intragastrically every day for one week called the KTC group. After treatment, mice were sacrificed for sampling. The ovaries morphology of mice was observed by hematoxylin and eosin (HE) staining, and all follicles were counted under microscope. Western blotting was used to detect the PI3K/AKT/mTOR pathway activation. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2) and anti-mullerian hormone (AMH)levels were measured by enzyme-linked immunosorbent assay (ELISA). The fertility was observed by giving treated mice 8 weeks for breeding. RESULTS: We found that primordial follicle counts were increased in the KTC group compared to the Model group. The phosphorylation of PI3K, AKT, mTOR, 4E-BP1 and S6K in the KTC group significantly reduced compared to Model group. Serum FSH and LH levels in the KTC group were decreased compared to the Model group, while, serum E2 and AMH levels in the KTC group were increased compared with the Model group. The litter size in the KTC group was improved compared to Model group. CONCLUSIONS: The KTC showed protective potentials of ovarian reserve and fertility to attenuate premature ovarian failure, which was relatively associated with activation of the PI3K/AKT/mTOR signaling pathway.

Effects of Kuntai capsule on GnRH-a-induced perimenopause symptoms:a prospective randomized controlled study / 中国实用妇科与产科杂志

OBJECTIVE: To evaluate the effect of Kuntai capsule on the gonadotrophin releasing hormone agonist(GnRH-a)-induced perimenopaus symptoms and the sex hormone levels.METHODS: A total of 99 patients with uterine fibroids,adenomyosis or moderate to severe endometriosis who needed the treatment of GnRH-a at Sun Yat-sen Memorial Hospital of Sun Yat-sen University from June 2015 to March 2016 were collected and randomly divided into research group(Kuntai capsule)and control group(Tibolone). GnRH-a was injected once every 28 days and first injection of GnRH-a was administered on the 2 nd to 4 th day of menstrual period or retraction bleeding after surgery.Kuntai capsule or Tibolone was orally taken beginning from the first GnRH-a injection,and the co-administration of Caltrate D-600 and alfacalcidol was given in both groups.The Kupperman scores,sex hormone levels including folliclestimulating hormone(FSH)and estrogen(E_2),and adverse events were recorded.RESULTS: Kuntai capsule kept the perimenopause symptoms at mild level with the slow increase of Kupperman scores,whose effect was significantly superior to Tibolone(P<0.05)after 8 weeks of treatment,especially in paresthesia,nervousness,and formication.The FSH and E_2 levels in both Kuntai and Tibolone groups were obviously decreased when compared with the pre-treatment(P<0.05),and these hormone levels in Kuntai group were comparable to those in Tibolone group.No adverse events occurred in either group. CONCLUSION: In the short-term treatment of GnRH-a,Kuntai capsule exhibits significant alleviating effects on perimenopause symptoms caused by GnRH-a with high safety and few adverse reactions.

Effects of Heyan Kuntai Capsule () on Follicular Development and Oocyte Cohesin Levels in Aged Mice.

OBJECTIVE: To evaluate the effect of Heyan Kuntai Capsule (, 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), 17ß-estradiol group [E2, 100 µg/(kg•d)], and low-, medium-, and highdose 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 (γH2AX) 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) 1ß 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-γH2AX 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 SMC1ß, 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 SMC1ß) in oocytes of aged mice, indicating a beneficial effect on the ovarian function in terms of the quantity and quality of follicles.

Hormone-like activities of Kuntai capsule in the uteri of ovariectomized rats and immature rabbits.

OBJECTIVE: To investigate the hormone-like activities of Kuntai capsule (KTC) in the uteri of ovariectomized rats and immature rabbits. METHODS: Following bilateral ovariectomy, rats were randomly divided into six groups including sham group, control group, estradiol valerate group, KTC 0.24, 0.6, and 1.5 g/kg groups. The rats were treated with 0.5% CMC-Na, estradiol valerate and KTC (0.24, 0.6, and 1.5 g/kg), respectively for 28 consecutive days. Then the estrous cycle, uterine changes and pathological changes were examined. Serum levels of estradiol (E2), and progesterone (P4) were measured by enzyme-linked immunosorbent assay (ELISA). Protein levels of estradiol receptor (ER), progesterone receptor (PR), vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA) and nuclear-associated antigen-67 (Ki-67) in uterine tissues were detected by western blot. Immature rabbits were estrogen-primed prior to intragastric administration with KTC for 6 d consecutively. Then, the uteri underwent hematoxylin-eosin staining to observe endometrial transformation. RESULTS: Compared with the control group, 0.6 and 1.5 g/kg KTC markedly decreased the uterine organ coefficient and endometrial thickness (P < 0.05). The serum level of P4 was increased in the KTC 0.6 g/kg group (P < 0.05). There were no significant variations in the serum level of E2 in the KTC groups compared with the control group. ER¦Â, but not ER¦Á, was markedly upregulated after KTC administration (P < 0.05). Furthermore, 1.5 g/kg KTC significantly decreased the protein level of PRA (P < 0.05) and 0.6 g/kg KTC increased the protein level of PRB in the uteri (P < 0.05). VEGF was highly expressed after treatment with 0.24 and 0.6 g/kg KTC, and Ki-67 was markedly reduced in ovariectomized rats treated with 1.5 g/kg KTC. No difference was found in the expression of PCNA. KTC 0.24 and 0.6 g/kg promoted endometrial transformation in immature rabbit uteri. CONCLUSION: KTC does not demonstrate obvious estrogen-like effect on uteri after ovariectomy, but it does exhibit weak progestogen-like effect, by which mechanism of action is yet to be further investigated.

A Multi-center, Randomized, Controlled and Open Clinical Trial of Heyan Kuntai Capsule () and Hormone Therapy in Perimenopausal Women.

OBJECTIVE: To evaluate the efficacy and safety of Heyan Kuntai Capsule (, 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 patients 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 () on Follicular Development and Oocyte Cohesin Levels in Aged Mice / 中国结合医学杂志

<p><b>OBJECTIVE</b>To evaluate the effect of Heyan Kuntai Capsule (, HYKT) on the ovarian function of aged mice and expressions of cohesion complexes in oocytes.</p><p><b>METHODS</b>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 [E, 100 μg/(kg•d)], and low-, medium-, and highdose 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 HA histone family member X (γHAX) 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) 1β and SMC3 in oocytes were evaluated by immunofluorescent staining.</p><p><b>RESULTS</b>After administration of E 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-γHAX staining and TUNEL assay demonstrated that high-dose of HYKT and E partly suppressed the apoptosis of follicles (P<0.05). Furthermore, it showed an increased trend in the levels of REC8 and SMC1β, after administration with E and HYKT, and no obvious change in the level of SMC3.</p><p><b>CONCLUSION</b>HYKT could enhance the number of follicles, suppress apoptosis of oocytes and have a trend to elevate the meiotic-specific cohesin subunits (REC8 and SMC1β) in oocytes of aged mice, indicating a beneficial effect on the ovarian function in terms of the quantity and quality of follicles.</p>

Effect of calcitriol combined with Kuntai capsule on serum monocyte chemotactic factor -1 and leptin and pregnancy rate of prognosis in patients with polycystic ovary syndrome / 中国综合临床

Objective To investigate the application effect of calcitriol combined with Kuntai capsule in patients with polycystic ovary syndrome. Methods Ninety-seven cases with polycystic ovary syndrome were enrolled in the study and were randomly divided into two groups, 48 cases in the control group were given clomifene citrate capsules, and 49 cases in the observation group were treated with calcitriol combined with Kuntai capsule on the basis of the control group. The treatment effect,endometrial thickness,number of mature follicles,cervical mucus score and sex hormones (luteinizing hormone (LH),androgen,testosterone (T),follicle stimulating hormone (FSH),estradiol (E2)) before and after the treatment,the serum monocyte chemotactic factor -1 (MCP-1) and Leptin level of the two groups were observed and compared. And the rate of pregnancy and the incidence of adverse reactions were recorded. Results The total efficiency of the observation group was 95.92%(47/49),higher than that of the control group (79.17%(38/48))(χ2 ＝6.277,P＝0.012).The endometrial thickness,the number of mature follicles and the cervical mucus score of the observation group were significantly higher than those of the control group(t＝4. 978,7. 175,7. 387,P＜0. 05). After 3 months,the serum levels of T,FSH,LH,MCP-1 and Leptin in the observation group were lower than those in the control group,and the serum E2 level was higher than in the control group(P＜0. 05). The pregnancy rate of the observation group the was 69. 39%( 34/49 ), higher than that of the control group ( 47. 92%( 23/48 )), the difference was statistically significant (χ2＝4. 613,P＝0. 032). The incidence of adverse reactions was 12. 24%(6/49) in the observation group and 8. 33%(4/48) in the control group. There was no significant difference between the two groups(P＞0. 05). Conclusion Calcitriol combined with Kuntai capsule can improve the serum MCP-1,Leptin levels and sex hormone levels in patients with polycystic ovary syndrome,and improve the prognosis of pregnancy rate. Besides,the effect is remarkable with high medication safety.

A Multi-center, Randomized, Controlled and Open Clinical Trial of Heyan Kuntai Capsule () and Hormone Therapy in Perimenopausal Women / 中国结合医学杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of Heyan Kuntai Capsule (, HYKT) and hormone therapy (HT) on perimenopausal syndromes (PMSs).</p><p><b>METHODS</b>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).</p><p><b>CONCLUSIONS</b>HYKT could effectively relieve PMSs and improve patients quality of life without severe adverse reactions. Although HYKT exerted curative effects more slowly than hormone, it possessed better safety profile than hormone.</p>

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 patients from 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 a 3-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 c1.8). 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 reserve 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.

Protective effects and mechanisms investigation of Kuntai capsule on the ovarian function of a novel model with accelerated aging ovaries.

ETHNOPHARMACOLOGICAL RELEVANCE: Kuntai capsule, a traditional Chinese medicine, has been widely used for the clinical treatment of menopausal syndrome. However, its mechanisms remain poorly understood. Considering that aging ovaries are the primary cause of menopause, this study was designed to investigate the effects and mechanisms of Kuntai capsule on ovarian function in a novel mice model with accelerated aging ovaries. MATERIALS AND METHODS: Seventy-five female C57BL/6 mice were chosen for this study. Fifteen of the mice were separated into the normal control group (NC). The remaining sixty were used to establish the novel accelerated aging ovary model by superovulation and oxidative stress and then by randomly dividing the mice into four equal groups. One group was considered the model group (Mod). The other three groups were treated with low (0.4g/kg), middle (0.8g/kg) and high (1.6g/kg) doses of Kuntai capsule intragastrically every day for 4 weeks. During the treatment, the body weight and fur condition of all mice were recorded. All the mice were forced to swim to record their exhaustive swimming time (EST), which measures their strength. Mice were then sacrificed for sampling. Ovarian reserve was evaluated using follicle counts and AMH expression. Ovarian function was evaluated using estrous cycle, sex hormone level and litter experiments. Ovarian follicles were categorized and counted to estimate ovarian reserve, and ovarian histologic sections were stained for terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) to detect apoptotic cells. The ultrastructure of ovarian cells was observed using transmission electron microscopy. Western blotting was used to measure expression of Bax, Bcl2, AMH and SOD2 protein. RESULTS: Compared with the NC GROUP, the Mod group clearly displayed worse fur condition and ovarian function. These situations showed some improvement after Kuntai capsule treatment. Specifically, the fur condition and the EST of the Kuntai capsule groups were superior to the fur condition and EST of the Mod group. In cases of damaged ovarian function, Kuntai capsule can regulate the estrous cycles, increase hormone secretion and fertility and significantly decrease atretic follicles. The transmission electron microscopy results revealed that Kuntai capsule rescued the ovarian ultrastructure of mice. TUNEL staining confirmed that the apoptotic cells were reduced after Kuntai capsule treatment. Western blotting revealed that Kuntai capsule can increase AMH, SOD2, and Bcl2 protein expression and decrease Bax expression. CONCLUSIONS: Kuntai capsule may improve damaged ovarian function, which may be related to its antioxidant and anti-apoptosis effects.

Effect and mechanism of Kuntai Capsule on premature ovarian failure in rats / 药物评价研究

Objective To explore the effect and mechanism of Kuntai Capsule (KC) on premature ovarian failure in rats.Methods Totally 40 SD female rats were randomly divided into four groups:control group,model group,Kuntai Capsule (KC) group and conjugated estrogens tablets (CET) group.The premature ovarian failure model in rats was made by ig administration of 75 mg/kg tripterygium.After the model was established,rats were continually treated with 0.6 and 0.625 g/kg of KC and CET respectively by ig administration for 36 d.HE staining was used to observe the morphology of ovary and count the number of follicle.The enzyme-linked immunosorbent assay (Elisa) method was used for the detection of follicle stimulating hormone (FSH),luteinizing hormone (LH),serum estradiol (E2),and anti-Mueller tube hormone (AMH) level.The real-time fluorescence quantitative PCR (qRT-PCR) method was used to detect the mRNA expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).Results Compared with control group,the number of primordial follicles,preantral follicles and antral follicles were significantly reduced,the number of atretic follicles was increased (P ＜ 0.05),E2 and AMH significantly decreased (P ＜ 0.05),FSH and LH levels increased significantly (P ＜ 0.05),and the levels of VEGF and bFGF mRNA in model group were significantly decreased (P ＜ 0.05).Compared with model group,the number of primordial follicles,preantral follicles,and antral follicles were significantly increased,the number of atretic follicles was significantly reduced (P ＜ 0.05),E2 and AMH significantly increased (P ＜ 0.05),FSH and LH levels significantly decreased (P ＜ 0.05),and the levels of VEGF and bFGF mRNA in KC group were significantly increased (P ＜ 0.05).Conclusion By regulating the level of hormone and up-regulating the expression of VEGF and bFGF,KC can repair the damaged ovarian tissue and promote the growth and development of the follicle,so as to inhibit the premature exhaustion of mRNA.

Chinese herbal medicine Kuntai capsule for treatment of menopausal syndrome: a systematic review of randomized clinical trials.

OBJECTIVES: Kuntai capsule has been widely used for the treatment of menopausal syndrome in China for long time. We conducted this review to assess efficacy and safety of Kuntai capsule for the treatment of menopausal syndrome. METHODS: We searched studies in PubMed, ClinicalTrials, the Cochrane Library, China National Knowledge Infrastructure Database(CNKI), China Science and Technology Journal Database (VIP), Wan fang Database and Chinese Biomedical Literature Database(CBM) until November 20, 2014. Randomized trials on Kuntai capsule for menopausal syndrome, compared with placebo or hormone replacement therapy (HRT) were included. Two reviewers independently retrieved the randomized controlled trials (RCTs) and extracted the information. The Cochrane risk of bias method was used to assess the quality of the included studies, and a Meta-analysis was conducted with Review Manager 5.2 software. RESULTS: A total of 17 RCTs (1455 participants) were included. The studies were of low methodological quality. Meta-analysis indicated that there was no statistical difference in the Kupperman index (KI) [WMD=0.51, 95% CI (-0.04, 1.06)], the effective rate of KI [OR=1.21, 95% CI (0.72, 2.04)], E2 level [WMD=-15.18, 95% CI (-33.93, 3.56)], and FSH level [WMD=-3.46, 95% CI (-7.2, 0.28)] after treatment between Kuntai versus HRT group (P>0.05). However, Compared with HRT, Kuntai capsule could significantly reduce the total incidence of adverse events [OR=0.28, 95% CI (0.17, 0.45)]. CONCLUSIONS: Kuntai capsule may be effective for treating menopausal syndrome and lower risk of side effects. The studies we analyzed were of low methodological quality. Therefore, more strictly designed large-scale randomized clinical trials are needed to evaluate the efficacy of Kuntai capsule in menopausal syndrome.