Clinical Application of Double Ovulation Stimulation in Patients with Diminished Ovarian Reserve and Asynchronous Follicular Development Undergoing Assisted Reproduction Technology

Objective This study aimed to compare the clinical effects of double ovulation stimulation(DouStim)applied during the follicular and luteal phases with the antagonist protocol in patients with diminished ovarian reserve(DOR)and asynchronous follicular development undergoing assisted reproductive technology(ART).Methods The clinical data of patients with DOR and asynchronous follicular development receiving ART from January 2020 to December 2021 were retrospectively analyzed.The patients were divided into two groups according to their ovulation stimulation protocol:DouStim group(n=30)and antagonist group(n=62).Assisted reproduction and clinical pregnancy outcomes were compared between the two groups.Results In the DouStim group,the number of oocytes retrieved,metaphase II(MII)oocytes,two-pronuclei(2PN),day 3(D3)embryos,D3 high-quality embryos as well as blastocyst formation,implantation,and human chorionic gonadotropin-positive rates were significantly greater than those in the antagonist group(all P<0.05).No significant differences were found in MII,fertilization,or continued pregnancy rates at the first frozen embryo transfer(FET),in-vitro fertilization(IVF)cancellation,or early medical abortion rates between the groups(all P>0.05).Except for the early medical abortion rate,the DouStim group generally had favorable outcomes.In the DouStim group,the dosage and duration of gonadotropin and the fertilization rate were significantly greater in the first ovulation stimulation induction than in the second ovulation stimulation induction(P<0.05).Conclusion The DouStim protocol efficiently and economically obtained more mature oocytes and high-quality embryos for patients with DOR and asynchronous follicular development.

Efficacy and Safety of the Chinese Herbal Compound TJAOA101 in Treating Diminished Ovarian Reserve: A Protocol for Multicenter, Prospective, and Pre-Post Study

Objective Diminished ovarian reserve(DOR)can lead to early menopause,poor fecundity,and an increased risk of disorders such as osteoporosis,cardiovascular disease,and cognitive impairment,seriously affecting the physical and mental health of women.There is still no safe and effective strategy or method to combat DOR.We have developed a novel Chinese herbal formula,Tongji anti-ovarian aging 101(TJAOA101),to treat DOR.However,its safety and efficacy need to be further validated.Methods In this prospective and pre-post clinical trial,100 eligible patients aged 18–45 diagnosed with DOR will be recruited.All participants receive TJAOA101 twice a day for 3 months.Then,comparisons before and after treatment will be analyzed,and the outcomes,including anti-mullerian hormone(AMH)and follicle-stimulating hormone(FSH)levels and the antral follicle count(AFC),the recovery rate of menopause,and the Kupperman index(KMI),will be assessed at baseline,every month during medication(the intervention period),and 1,3 months after medication(the follow-up period).Assessments for adverse events will be performed during the intervention and follow-up periods.Conclusion A multicenter,prospective study will be conducted to further confirm the safety and efficacy of TJAOA101 in treating DOR and to provide new therapeutic strategies for improving the quality of life in DOR patients.

Effects of Dehydroepiandrosterone on Embryo Quality and Follicular Fluid Markers in Patients with Diminished Ovarian Reserves

Background:To examine the effects of dehydroepiandrosterone(DHEA)on in vitro fertilization(IVF)intracytoplasmic sperm injection(ICSI)and the levels of follicular fluid(FF)markers,namely,anti-Müllerian hormone(AMH),insulin-like growth factor(IGF)-1,bone morphogenetic protein(BMP)-15,and growth differentiation factor(GDF)-9,in patients with diminished ovarian reserves(DORs).Methods:116 patients with DOR were randomized into two groups,DHEA group and control group.Each group contained 58 patients.The DHEA group received 75 mg/d of DHEA for 12 weeks prior to the start of IVF treatment,while the control group entered IVF treatment directly.All patients were treated with the same ovarian stimulation protocol.The primary outcome was high-quality embryo yield.Other IVF parameters,such as the clinical pregnancy rate,embryo survival rate,and intact blastomere rate,were compared between the two groups.FF samples from patients of both groups were collected to measure the levels of AMH,IGF-1,DHEA-sulfate,BMP-15,and GDF-9.Blood was also collected on day 3 of the menstrual cycle to define the baseline hormonal profile and to examine ovarian reserve markers.Results:The high-quality embryo yield was higher in DHEA group than that in control group(P=0.033).AMH and IGF-1 concentrations in FF were significantly higher in DHEA group than that in the control group(2.83±1.14 ng/L vs.1.37±0.55 ng/L,P=0.000;94.02±38.28 ng/L vs.74.03±25.46 ng/L,P=0.004,respectively).The BMP-15 level was also higher in DHEA group(relative expression were 1.80±0.41)than that in control group(relative expression were 0.79±0.16,P<0.0001);however,there was no difference in GDF-9 expression between the two groups(relative expression were 1.29±0.54 and 1.16±0.50 respectively,P>0.05)and in the clinical pregnancy rate between the two groups(13.79%vs.7.27%,respectively,P>0.05).Conclusions:In women with DOR undergoing IVF treatment,pretreatment with DHEA may increase the number of high-quality embryos,which may be due to increased levels of AMH,IGF-1,and BMP-15 in the FF.

Effect of Dual Trigger In Vitro Fertilization and Intracytoplasmic Sperm Injection During the Gonadotropin-releasing Hormone-Antagonist Cycle on Final Oocyte Maturation and Cumulative Live Birth Rate in Women with Diminished Ovarian Reserve

Objective It is well known that a dual trigger treatment can improve clinical outcomes of in vitro fertilization(IVF)in high or normal ovarian responders.However,it is not clear whether dual triggering also benefits patients with diminished ovarian reserve(DOR).The aim of this study was to investigate whether a dual trigger treatment of gonadotropin-releasing hormone(GnRH)agonist combined with human chorionic gonadotropin(hCG)for final follicular maturation improves the cumulative live birth rate(CLBR)during the GnRH-antagonist cycle in patients with DOR.Methods This retrospective study included patients with DOR who received a GnRH-antagonist protocol during IVF and intracytoplasmic sperm injection(IVF-ICSI)cycles at Peking University People’s Hospital from January 1,2017 through December 31,2017.Oocyte maturation was triggered by GnRH combined with hCG(n=110)or hCG alone(n=71).Embryos were transferred on the third day after oocyte retrieval or during a subsequent freeze-thaw cycle.Patients were followed up for 3 years.Results The dual trigger treatment did not affect CLBR,which is an overall determinant of the success rate of assisted reproductive technology(ART).Women in the dual trigger group had significantly higher rates of fertilization than those in the hCG group(90.1%vs.83.9%,P=0.040).Conclusion Dual trigger with GnRH agonist and hCG did not improve CLBR in patients with DOR,but did slightly improve fertilization rate,oocyte count,and embryo quality.

Analysis of uterine artery and sex hormones in treating diminished ovarian reserve with tiaojing decoction

Objective: To observe the effect of tiaojing decoction and climen on diminished ovarian reserve patients with de ficiency of Kidney-Yin by sex hormone and uterine artery blood flow parameters. To verify the e ffectiveness of tiaojing decoction on diminished ovarian reserve and uterine artery blood flow parameters, explore the correlation between uterine artery blood flow parameters and sex hormones. Methods: Total 60 diminished ovarian reserve patients with deficiency of Kidney-Yin were randomly divided into the experimental group (n=30, taking tiaojing decoction and climen) and the control group (n=30, taking climen) and they were treated in 3 months. Observe bFSH, bE2, uterine artery PSV, EDV, S/D, RI before and after the treatment in the 2-4 day of menstruation. Results: After treatment, serum sex hormone levels and uterine artery blood flow parameters of the two groups were significantly different (P < 0.05), and the experimental group was significantly better than the control group. There was a linear correlation between PSV and FSH, PSV and E2, FSH and E2. Conclusion: Tiaojing decoction combined with climen has significant effect on diminished ovarian reserve patients with deficiency of Kidney-Yin. Uterine artery blood flow parameters can reflect the sex hormone levels.

Treatment Progress in Diminished Ovarian Reserve:Western and Chinese Medicine

Diminished ovarian reserve(DOR),generally defined as a decreased number or quality of oocytes,has a significant impact on quality of life and fertility in women.In recent years,the incidence of DOR has been increasing and the ages of patients are younger.The search for an effective DOR treatment has emerged as one of the preeminent research topics in reproductive health.An effective DOR therapy would improve ovarian function,fertility,and quality of life in patients.In this review we evaluated DOR treatment progress both in Western medicine and Chinese medicine,and elucidated the characteristics of each treatment.

Effects of Zishen Yutai Pills on in vitro Fertilization-Embryo Transfer Outcomes in Patients with Diminished Ovarian Reserve:A Prospective,Open-Labeled,Randomized and Controlled Study

Objective:To explore the effects of Zishen Yutai Pills(ZYPs)on the quality of oocytes and embryos,as well as pregnancy outcomes in patients with diminished ovarian reserve(DOR)receiving in vitro fertilizationembryo transfer(IVF-ET).The possible mechanisms,involving the regulation of bone morphogenetic protein 15(BMP15)and growth differentiation factor 9(GDF9),were also investigated.Methods:A total of 120 patients with DOR who underwent their IVF-ET cycle were randomly allocated to 2 groups in a 1:1 ratio.The patients in the treatment group(60 cases)received ZYPs from the mid-luteal phase of the former menstrual cycle by using gonadotropin-releasing hormone(Gn RH)antagonist protocol.The patients in the control group(60 cases)received the same protocol but without ZYPs.The primary outcomes were the number of oocytes retrieved and high-quality embryos.Secondary outcomes included other oocyte or embryo indices as well as pregnancy outcomes.Adverse events were assessed by comparison of the incidence of ectopic pregnancy,pregnancy complications,pregnancy loss,and preterm birth.Contents of BMP15 and GDF9 in the follicle fluids(FF)were also quantified with enzymelinked immunosorbent assay.Results:Compared with the control group,the numbers of oocytes retrieved and high-quality embryos were significantly increased in the ZYPs group(both P<0.05).After treatment with ZYPs,a significant regulation of serum sex hormones was observed,including progesterone and estradiol.Both hormones were up-regulated compared with the control group(P=0.014 and 0.008),respectively.No significant differences were observed with regard to pregnancy outcomes including implantation rates,biochemical pregnancy rates,clinical pregnancy rates,live birth rates,and pregnancy loss rates(all P>0.05).The administration of ZYPs did not increase the incidence of adverse events.The expressions of BMP15 and GDF9 in the ZYPs group were significantly up-regulated compared with the control group(both P<0.05).Conclusions:ZYPs exhibited beneficial effects in DOR patients undergoing IVF-ET,resulting in increments of oocytes and embryos,and up-regulation of BMP15 and GDF9 expressions in the FF.However,the effects of ZYPs on pregnancy outcomes should be assessed in clinical trials with larger sample sizes(Trial reqistration No.Chi CTR2100048441).

Acupuncture versus oral medicine for women with diminished ovarian reserve:A cohort study

Objective:To observe whether electro-acupuncture(EA) is better in improving hormone levels among women with diminished ovarian reserve(DOR) compared with oral medicine [Chinese herbs with or without hormone replacement therapy(HRT)] that is often used in gynecology clinics in China.Methods:Eligible participants entered the EA group or medication group according to their preferences.Participants in the EA group received EA treatment,and participants the medication group received herbal decoction alone or combined with HRT.Reproductive hormone levels of the participants were tested before and during treatment in both groups.Results:A total of 80 women with DOR were screened and 57 cases were included(29 in the EA group and 28 in the medication group) in the final analysis.The differences in the change from baseline between the EA and medication group in mean follicle-stimulating hormone(FSH) levels were-6.6(95% Cl,-17.03 to 3.72),(P=0.848) and-7.09(95% CI,-15.86 to 1.66),(P=0.539) at weeks 12 and 24,respectively.The proportion of women with regular FSH levels in the EA and medication group was 51.3% vs 32.1% at week 12(P=0.134) and 51.3% vs 25.0% at week 24(P=0.038).Conclusion:EA might influence regulating the levels of FSH,luteinizing hormone(LH),estrogen and the FSH/LH ratio,and no difference was found between the effects of EA and oral medicine in changes of reproductive hormone levels.

Effects of Bushen Yiqi Huoxue Decoction in Treatment of Patients with Diminished Ovarian Reserve:A Randomized Controlled Trial

Objective:To explore the therapeutic effect of Bushen Yiqi Huoxue Decoction BYHD)in patients with diminished ovarian reserve(DOR).Methods:A total of 180 patients with DOR diagnosed from December2013 to December 2014 were equally assigned into progynova and duphaston(E+D)group,Zuogui Pill group and BYHD group with 60 cases in each by computerized randomization.Patients received E+D,Zuogui Pill or BYHD for 12 months,respectively.Follicle stimulating hormone(FSH),luteinizing hormone(LH),estradiol(E_(2)),anti-Mullerian hormone(AMH),antral follicle count(AFC),ovarian volume,endometrial thickness,and the resistance indices(Rls)of ovarian arteries and uterine arteries were observed before and after treatment.Results:Nine women(4 from the E+D group,3 from the Zuogui Pill group,and 2 from the BYHD group)withdrew from the study.After 6 months,Zuogui Pill and BYHD significantly decreased FSH and LH and increased endometrial thickness and AMH(all P<0.01),BYHD also resulted in E2 elevation(P<0.05),ovary enlargement(P<0.05),AFC increase(P<0.01),and RI of ovarian arteries decrease(P<0.05).After 12 months,further improvements were observed in the Zuogui Pill and BYHD groups(all P<0.01),but BYHD showed better outcomes,with lower FSH,larger ovaries and a thicker endometrium compared with the Zuogui Pill group(all P<0.01).However,E+D only significantly increased endometrial thickness(P<0.01)and no significant improvements were observed in the RI of uterine arteries in the three groups.Conclusions:BYHD had a favorable therapeutic effect in patients with DOR by rebalancing hormone levels,promoting ovulation,and repairing the thin endometrium.The combination of tonifying Shen(Kidney),benefiting qi and activating blood circulation may be a promising therapeutic strategy for DOR.

Clinical observation on herb-partitioned spreading moxibustion at Baliao points plus climen for diminished ovarian reserve

Objective:To observe the clinical efficacy of herb-partitioned spreading moxibustion at Baliao points plus climen for diminished ovarian reserve(DOR).Methods:A total of 60 patients with DOR were randomized into a spreading moxibustion group and a Western medicine group by the random number table method,with 30 cases in each group.The Western medicine group was treated with climen,starting from the 5th day of the menstrual cycle for 21 d.The spreading moxibustion group was treated with herb-partitioned spreading moxibustion at Baliao points on the basis of the medication in the Western medicine group,1 h per time,once a week.The treatment was performed for 1 month as one treatment course in both groups,for 3 courses in total.The serum follicle-stimulating hormone(FSH),luteinizing hormone(LH)and estradiol(E2)in the patients were measured before and after treatment.The peak systolic velocity(PSV)and resistance index(RI)were also detected.The traditional Chinese medicine(TCM)symptom score was evaluated.The clinical efficacy was evaluated after treatment.Results:The total effective rate in the spreading moxibustion group was 93.3%,which was significantly higher than 80.0%in the Western medicine group,and the difference between the groups was statistically significant(P<0.05).After treatment,the TCM symptom scores,the serum FSH levels,FSH/LH ratios and RI in both groups decreased,and the intra-group differences were all statistically significant(all P<0.05).The serum E2 level and PSV increased compared with those in the same group before treatment,and the intra-group differences were statistically significant(all P<0.05).After treatment,the TCM symptom score,the serum FSH level,FSH/LH ratio and RI in the spreading moxibustion group were lower than those in the Western medicine group,while the serum E2 level and PSV were higher than those in the Western medicine group,and the differences between the groups were statistically significant(all P<0.05).Conclusion:Herb-partitioned spreading moxibustion at Baliao points plus climen can produce valid therapeutic efficacy for DOR.It can improve the clinical symptoms,regulate serum hormone levels and increase ovarian blood perfusion,thus improving ovarian reserve function,producing more significant efficacy than climen alone.

Recent progress in the treatment of women with diminished ovarian reserve

Diminished ovarian reserve(DOR)refers to a decrease in the number and/or quality of oocytes in the ovary,accompanied by a decline in reproductive potential,which is generally related to advanced age or ovarian disease.In in vitro fertilization(IVF)clinical practice,managing patients with DOR remains one of the most challenging tasks.In recent years,increased research on improving ovarian function has provided us with new insights into treating patients with DOR.Many therapeutic options have been proposed to improve the ovarian function of patients with DOR,yet they are not widely utilized in clinical practice because of limited evidence of safety and effectiveness.In this review,we focus on the mechanisms from animal models and clinical trials that have been applied to the treatment of DOR in recent years,intending to improve IVF outcomes in patients with DOR.Furthermore,new insights and perspectives on the molecular and cellular regulation of follicular development and ovarian reserve are emphasized to provide more clues for research on the treatment of DOR.

Effect of Progestin-Primed Ovarian Stimulation Protocol in Infertile Women with Basal Follicle-Stimulating Hormone Levels ≥15 IU/L: A Retrospective Analysis

Objective:To evaluate the efficacy of progestin-primed ovarian stimulation(PPOS)protocol in infertile women with high basal follicle-stimulating hormone(FSH)levels≥15 IU/L.Methods:Patients with high basal FSH levels≥15 IU/L with autologous oocytes from September 2016 to March 2019 were reviewed.Either medroxyprogesterone acetate 4 mg/d or clomiphene citrate(CC)50 mg/d was administered daily from day 3 to the trigger day.When serum FSH levels decreased to≤15.0 IU/L,a low dose of human menopausal gonadotropin(hMG)75/150 IU/d was administered to promote late follicular development.Results:Two hundred and twenty women were retrospectively analyzed in this study.Among them,139 patients were administered with PPOS protocol as the study group,and 81 patients were administered with CC protocol as the control group.The numbers of received oocytes and viable embryos were higher in the study group than those in the control group(1.5±1.2 vs.1.2±0.8 and 0.8±0.8 vs.0.5±0.6,respectively,P<0.05).However,hMG duration and dosage were significantly higher in the study group than those in the control group(4.2±2.7 d vs.1.1±2.3 d and 609.1±424.5 IU vs.140.7±231.3 IU,respectively,P<0.01).Incidence of luteinizing hormone surge and cycle cancellation rate were lower in the study group than those in the control group with statistical difference(2.88%vs.16.05%and 36.50%vs.50.63%,respectively,P<0.05).Conclusions:PPOS protocol can effectively downregulate the endogenous FSH levels.Compared with CC protocol,treatment with PPOS protocol in patients with high basal FSH levels≥15 IU/L could receive more oocytes and more viable embryos.