Prevention and Treatment of Age-related Ovarian Hypofunction with Traditional Chinese Medicine： A Review / 中国实验方剂学杂志

Age-related ovarian hypofunction includes a decrease in follicle quantity and quality as well as alterations in the ovarian microenvironment，the mechanisms of which are mainly related to mitochondrial dysfunction，free radical and antioxidant systems，telomere and telomerase alterations，and apoptosis，and is one of the major factors contributing to infertility in advanced maternal age （AMA）. Despite the tremendous progress in assisted reproductive technology in recent decades，few breakthroughs have been made in alleviating age-related ovarian hypofunction and improving reproductive outcomes for AMA. In recent years，there has been an increasing number of studies on the multi-level and multi-targeted mechanisms of traditional Chinese medicine （TCM） to improve age-related ovarian hypofunction by modulating mitochondrial homeostasis，alleviating oxidative stress，and inhibiting apoptosis，while more high-quality randomized controlled trials have demonstrated the clinical efficacy of TCM in assisted reproductive technology. Given this，this article presented a systematic review of recent research and randomized controlled trials on the mechanism of Chinese medicine active ingredients，single Chinese medicine， and Chinese medicine compounds in delaying age-related ovarian hypofunction，to clarify the current status and shortcomings of the research. This paper provides medication management of TCM for effectively alleviating age-related ovarian hypofunction and improving reproductive outcomes for AMA.

Factors affecting decreased ovarian reserve among women of childbearing age / 预防医学

Objective@#To investigate the factors affecting decreased ovarian reserve (DOR) among women of childbearing age, so as to provide insights into prevention of DOR.@*Methods@#Women with DOR at ages of 18 to 40 years that were admitted to Department of Gynecology, Ningbo Women and Children's Hospital during the period from January 2021 to June 2022 were recruited (DOR group), while healthy women at ages of 18 to 40 years during the same period served as normal controls. Participants' demographics, exercise, diet, previous medical history, childbearing history and menstruation were collected using questionnaire surveys. The follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH) and estradiol (E2) levels were tested. Factors affecting DOR were identified among women of childbearing age using a multivariable logistic regression model.@*Results@#There were 200 participants in the DOR group, with a median (interquartile range) age of 32 (9) years, and 200 participants in the normal group, with a median (interquartile range) age of 29 (12) years. Multivariable logistic regression analysis showed that underweight (OR=2.935, 95%CI: 1.374-6.269), overweight/obesity (OR=2.612, 95%CI: 1.335-5.065), high-oil-high-glucose-high-salt diet (OR=2.653, 95%CI: 1.616-4.357), menstrual disorder (OR=1.977, 95%CI: 1.284-3.041) and lack of exercise (OR=3.392, 95%CI: 2.052-5.606) were statistically correlated with the development of DOR among women of childbearing age.@*Conclusions@#Underweight, overweight/obesity, high-oil-high-glucose-high-salt diet, menstrual disorder and lack of exercise are factors affecting the development of DOR among women of childbearing age.

Moxibustion alleviates decreased ovarian reserve in rats by restoring the PI3K/AKT signaling pathway / 中西医结合学报

OBJECTIVE@#Moxibustion, a common therapy in traditional Chinese medicine, has potential benefits for treating decreased ovarian reserve (DOR). The present study investigates the protective effect of moxibustion in a rat model of DOR and explores the possible mechanisms.@*METHODS@#Sixty-four female Sprague-Dawley rats were randomly divided into four groups: control, DOR, moxibustion (MOX), and hormone replacement therapy (HRT). The DOR rat model was established by intragastric administration of 50 mg/kg Tripterygium glycoside suspension (TGS), once daily for 14 days. MOX and HRT treatments were given from the day TGS administration was initiated. The ovarian reserve function was evaluated by monitoring the estrus cycle, morphological changes in ovaries, levels of serum estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and anti-Mullerian hormone (AMH), pregnancy rate and embryo numbers. Terminal-deoxynucleotidyl transferase-mediated nick-end-labeling staining was used to identify ovarian granulosa cell apoptosis, while the protein and mRNA expressions of Bax, B-cell lymphoma-2 (Bcl-2), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in ovarian tissues were examined by immunohistochemistry, Western blot and quantitative reverse transcription-polymerase chain reaction.@*RESULTS@#Compared with the DOR group, MOX improved the disordered estrous cycle, promoted follicular growth, reduced the number of atresia follicles, increased the concentrations of serum E2 and AMH, and decreased serum FSH and LH concentrations. More importantly, the pregnancy rate and embryo numbers in DOR rats were both upregulated in the MOX treatment group, compared to the untreated DOR model. Further, we found that the MOX group had reduced apoptosis of ovarian granulosa cells, increased Bcl-2 expression and reduced expression of Bax. Furthermore, the PI3K/AKT signaling pathway was triggered by the moxibustion treatment.@*CONCLUSION@#Moxibustion improved ovarian function and suppressed apoptosis of ovarian granulosa cells in a rat model of DOR induced by TGS, and the mechanism may involve the PI3K/AKT signaling pathway.

Study on Improvement Effects and Its Mechanism of Guiyuan Decoction Formula Granules on Model Mice with Decreased Ovarian Reserve / 中国药房

OBJECTIVE：To study the improvement eff ects and its mech anism of Guiyuan decoction formula granules （GDFG） on model mice with decreased ovarian reserve （DOR）. METHODS ：Totally 42 female ICR mice whith with normal estrous cycle were randomly divided into control group ，model group ，estradiol valerate group （positive control ，0.15 mg/kg）and GDFG low-dose，medium-dose and high-dose groups （0.75，1.49，2.98 g/kg），with 7 mice in each group. Except for control group ，other groups were given cisplatin （3 mg/kg）intraperitoneally to establish DOR model. After modeling ，administration groups were given relevant medicine intragastrically；model group and control group were given normal saline intragastrically ，once a day ，for consecutive 4 weeks. After last administration ，ELISA assay was used to measure the serum levels of anti-Müllerian hormone （AMH）and follicle-stimulating hormone （FSH）in mice. Histopathological morphology of ovarian was observed by HE staining. Protein distribution of AMH receptor Ⅱ（AMHRⅡ）and Smad 4 in ovarian tissue were observed by immunohistochemistry. Protein expression of AMHR Ⅱ and Smad 4 were detected by Western blot assay. RESULTS ：Compared with control group ，theserum level of AMH ，the expression of AMHR Ⅱ and Smad 4 protein in ovarian tissue in model group were significantly decreased （P＜0.01），while the FSH level in serum was significantly increased （P＜0.01）；follicles were crumpled and lost nucleus ，ovarian interstitial were fibrosis ，luteum were loose ； AMHRⅡ and Smad 4 protein in ovarian tissue were mainly distributed in the follicle membrane and ovarian interstitial. Compared with model group ，the serum level of AMH ，the expression of AMHR Ⅱ and Smad 4 protein in ovarian tissue was increased significantly in GDFG groups （P＜0.01），while the serum level of FSH was decreased significantly （P＜0.05 or P＜0.01）；in ovarian tissue ，follicles at all levels could be found and follicle morphology was improved ，and no obvious nuclear loss and cumulus formation were found ；AMHRⅡ and Smad 4 protein were mainly distributed in the follicular nucleus （except for GDFG high-dose group) and the granular cell membrane （mainly distributed in the sinus follicles of GDFG medium-dose group ）；they were slightly distributed around the mature follicular nucleus or in corpus luteum. CONCLUSIONS ：GDFG can improve ovarian function of DOR model mice. The mechanism may be related with promoting serum level of AMH ，protein expression of AMHR Ⅱ and Smad 4，improving the distribution of AMHR Ⅱ and Smad 4 protein in ovarian granulosa cell membrane and follicular nucleus ， reducing FSH levels.

Progress in molecular mechanism and clinical application of primordial follicle activation / 中国医师杂志

With the continuous elucidation of the molecular mechanism of primordial follicle activation, clinical in vitro activation (IVA) has gradually become a clinical treatment for premature ovarian insufficiency (POI) and reduced ovarian reserve (DOR). This article will review the mechanism of phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-kinase (PI3K), hippo signal and mammalian target of rapamycin complex 1 (mTORC1) signal involved in the activation of primordial follicles, and the application of IVA in patients with POI and DOR.

Intervention Effect of New Chinese Herbal Prescription Selected by Data Mining Against Decreased Ovarian Reserve in Rats / 中国实验方剂学杂志

Objective:To select and evaluate new Chinese herbal prescription for the treatment of decreased ovarian reserve （DOR） and its appropriate dosage. Method:The literature concerning the treatment of DOR with traditional Chinese medicine （TCM） was retrieved from such databases as Chinese Journal Full-text Database， Wanfang Data Knowledge Service Platform， and Chongqing Weipu Database for Chinese Technical Periodicals （VIP）， based on which a database was established using the Traditional Chinese Medicine Inheritance Support System （TCMISS） V2.5. The data mining was then carried out to obtain the core combinations of Chinese herbs and new Chinese herbal prescription combinations， followed by the determination of the new Chinese herbal prescription by expert group discussion for experiment evaluation. The female SD rats were divided into the normal group， DOR model group， Kuntai capsule group， and low-， medium-， and high-dose new Chinese herbal prescription groups， with 12 rats in each group. Rats in the Kuntai capsule group and low-， medium-， and high-dose new Chinese herbal prescription groups were treated with Kuntai capsule solution （0.5 g·kg^-1 determined according to the dosage in the instruction） and 3.037 5， 6.075， and 9.12 g·kg^-1 new Chinese herbal prescription， respectively. After 21 days， the estrous cycle was observed by vaginal exfoliated cell smear， and the ovarian structure was observed by hematoxylin-eosin （HE） staining. The serum anti-mullerian hormone （AMH）， follicle stimulating hormone （FSH）， luteinizing hormone （LH）， and estrogen （E₂） contents as well as the reactive oxygen species （ROS）， malondialdehyde （MDA）， and glutathione （GSH） levels and superoxide dismutase （SOD）， catalase （CAT）， and glutathione peroxidase （GSH-Px） activities in ovary were detected using biochemical methods. Result:The new Chinese herbal prescription subjected to experimental evaluation was composed of 11 Chinese herbs， namely Rehmanniae Radix Praeparata 20 g， Cervi Cornus Colla 12 g， Lycii Fructus 20 g， Corni Fructus 12 g， Albiziae Cortex 9 g， Nelumbinis Plumula 3 g， Salviae Miltiorrhizae Radix et Rhizoma 20 g， Astragali Radix 30 g， Atractylodis Macrocephalae Rhizoma 12 g， Dioscoreae Rhizoma 30 g， and Glycyrrhizae Radix et Rhizoma Praeparata Cum Melle 6 g. Compared with the model group， the Kuntai capsule group and medium- and high-dose new Chinese herbal prescription groups exhibited significantly improved estrous cycle and follicular development， elevated serum AMH and E₂ and ovarian GSH （<italic>P</italic><0.05）， decreased serum FSH and LH （<italic>P</italic><0.05） and ovarian ROS and MDA （<italic>P</italic><0.05）， and enhanced SOD， CAT， and GSH-Px activities （<italic>P</italic><0.05）. There were no significant differences in the above-mentioned indexes between the Kuntai capsule group and the middle- and high-dose new Chinese herbal prescription groups， but the estrous cycle and follicular development were better in the latter two groups. Conclusion:The new Chinese herbal prescription screened by data mining is able to enhance ovarian antioxidation， promote follicular development， ameliorate serum hormone and estrous cycle， and effectively improve ovarian reserve function in DOR rats. The medium dose （6.075 g·kg^-1） has been proved optimal.

Effect of electroacupuncture combined with pill on sex hormone and Th2 cytokines in patients of decreased ovarian reserve function with liver-kidney deficiency / 中国针灸

OBJECTIVE@#To observe the effect of electroacupuncture (EA) combined with pill on clinical symptoms, levels of serum sex hormone and Th2 cytokines in patients of decreased ovarian reserve function (DOR) with liver-kidney deficiency, and to compare the efficacy between EA combined with pill and pill alone.@*METHODS@#Sixty patients with DOR were randomly divided into an observation group (30 cases, 2 cases dropped off) and a control group (30 cases, 1 case dropped off). The patients in the control group were treated with pill, 1 pill each time, 3 times a day. Based on the treatment of the control group, the patients in the observation group were additionally treated with acupuncture at Guanyuan (CV 4), Zhongji (CV 3), Guilai (ST 29), Zigong (EX-CA 1), Zusanli (ST 36), Sanyinjiao (SP 6), Taixi (KI 3) and Taichong (LR 3); EA was applied at bilateral Zusanli (ST 36) and Sanyinjiao (SP 6), with continuous wave, in frequency of 20 Hz and current intensity of 1 to 4 mA, for 20 min. The treatment was given 3 times a week. All the patients terminated treatment during menstrual period, and the treatment was given for 3 continuous menstrual cycles. The menstrual condition score and systemic symptom score were compared between the two groups before and after treatment. The levels of serum sex hormones on 2nd to 3rd day of menstruation, including follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2), and the serums levels of interleukin (IL) -4 and IL-10 secreted by Th2 cytokines were compared between the two groups before and after treatment.@*RESULTS@#After the treatment, the menstruation condition scores and systemic symptom scores in the two groups were reduced (<0.05), and the scores in the observation group were lower than those in the control group (<0.05). After the treatment, the levels of serum FSH, LH and FSH/LH were reduced (<0.05), and the E2 levels were increased in the two groups (<0.05), and the levels of FSH, LH in the observation group were lower than those in the control group (<0.05), and the E2 level was higher than that in the control group (<0.05). After the treatment, the levels of serum IL-4 and IL-10 in the two groups were increased (<0.05), and the levels of IL-4 and IL-10 in the observation group were higher than those in the control group (<0.05).@*CONCLUSION@#EA combined with pill could significantly improve menstruation, systemic symptoms and serum sex hormone levels in patients of decreased ovarian reserve function with liver-kidney deficiency, which may restore ovarian function by up-regulating the expression of Th2 cytokines.

Effects of ginger-separated moxibustion atpoints combined withformula on patients with decreased ovarian reserve function / 中国针灸

<p><b>OBJECTIVE</b>To compare the efficacy differences between ginger-separated moxibustion atpoints combined withformula andformula alone on patients with decreased ovarian reserve function.</p><p><b>METHODS</b>Fifty patients of decreased ovarian reserve function were randomly divided into an observation group and a control group, 25 cases in each one. The patients in the observation group were treated with ginger-separated moxibustion atpoints combined withformula; the moxibustion was given for 1.5 h, once every seven days, and no treatment was given during menstrual period. The patients in the control group were treated withformula. One-month treatment was taken as one treatment course, and totally three courses were given. The change of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E), anti-mullerian hormone (AMH), antral follicle count (AFC), peak systolic velocity (PSV), resistance index (RI) were observed before and after treatment in the two groups.</p><p><b>RESULTS</b>After treatment, the FSH, FSH/LH and RI were significantly lowered, but the E, AFC, PSV were significantly increased in the two groups (all<0.05); the FSH, FSH/LH and Ein the observation group were lower and AFC was higher than those in the control group (all<0.05).</p><p><b>CONCLUSION</b>The ginger-separated moxibustion atpoints combined withformula are superior toformula alone in improving ovarian reserve function.</p>

Clinical Study on Treatment of Decreased Ovarian Reserve by Yishen Huayu Decoction / 中国中医药信息杂志

Objective To observe the clinical efficacy of Yishen Huayu Decoction for decreased ovarian reserve (DOR). Methods Eighty cases of DOR were randomly divided into 2 groups, with 40 cases in each group. The treatment group was treated with oral administration of Yishen Huayu Decotion, one dose a day. The control group was given DHEA, a time of 1 tablet, 3 times a day. 2 groups were observed for 3 menstrual cycles. The levels of basic follicle stimulating hormone (bFSH), basal estradiol (bE2), luteinizing hormone (LH) and serum anti-Müllerian hormone (AMH) were measured. The number of basal follicles and the peak systolic velocity (PSV) were monitored by transvaginal sonography. Quality of life assessment and basal body temperature were measured. Results The total effective rate was 85.00% (34/40) in the treatment group and 62.50% (25/40) in the control group, with statistical significance (P<0.05). After treatment, the levels of bE2 and bFSH decreased, and the levels of AMH, ovarian antral follicles and PSV increased, which were significantly different from those before treatment (P<0.05). After treatment, the levels of bE2 and bFSH in the treatment group were lower than those in the control group, and the levels of AMH, ovarian antral follicle and PSV were higher than those in the control group, with statistical significance (P<0.05). The recovery rate of basal body temperature was 77.50%(31/40) in the treatment group and 52.50%(21/40) in the control group, with statistical significance (P<0.01). After treatment, the scores of four dimensions of life quality, daily activities, health status and self-perception were significantly improved (P<0.01), and the treatment group was higher than the control group (P<0.01). Conclution Yishen Huayu Decotion can improve the ovarian reserve function and the life quality of patients with DOR.

The applications of double stimulations and mild ovarian stimulation with GnRH-antagonist in patients with decreased ovarian reserve / 安徽医科大学学报

Objective To discuss the value of double stimulations and mild ovarian stimulation combined with Gn-RH-antagonist in patients with decreased ovarian reserve receiving in vitro fertilization and embryo transfer ( IVF-ET) . Methods 283 patients with decreased ovarian reserve who accepted in vitro fertilization were analyzed retro-spectively. 204 cases accepted double stimulations and 79 cases accepted mild ovarian stimulation combined with GnRH-antagonist, compared the outcomes of the two protocols. Results The average number of oocytes retrieved, viable embryos,high-quality embryos,consumption and duration of Gn,the serum progesterone( P) level on trigger day in the luteal phase were significantly higher than those in follicular phase. The serum luteinizing hormone( LH) level on trigger day was lower than that in follicular phase. The average number of oocytes retrieved,high-quality embryos,consumption and duration of gonadotropins( Gn) in mild stimulation combined with GnRH-antagonist were higher than those in follicular phase. LH level on trigger day was lower than those in follicular phase, while the numbers of viable embryos were similar. The consumption and duration of Gn in the luteal phase were higher than in stimulation combined with GnRH-antagonist, and there were no differences in the average number of oocytes re-trieved,viable embryos,high-quality embryos between the two groups. The cycle cancellation rate, available rate of oocytes and embryos were similar between the controlled ovarian hyperstimulation. The available rate of embryos in double stimulations was higher than mild ovarian stimulation combined with GnRH-antagonist,and the abortion rate was lower. Conclusion Controlled ovarian hyperstimulation during luteal phase can get better outcomes in patients with decreased ovarian reserve,double stimulations in the same menstrual cycle shortens the treatment time of IVF-ET,and it is a feasible method for patients with decreased ovarian reserve.