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.

Exposure to heavy metallic and trace essential elements and risk of diminished ovarian reserve in reproductive age women: A case-control study.

The associations between metallic elements and ovarian reserve function have remained uncertain yet. In this case-control study, we involved 149 women with diminished ovarian reserve (DOR) and 151 women with normal ovarian reserve, and assessed the levels of six heavy metallic (Cr, Cd, As, Hg, Pb, and Mn) and seven trace essential (Se, Fe, Zn, Co, Mo, Cu, I) elements in their follicular fluid with inductively coupled plasma mass spectrometry. Associations were examined with logistic regressions and Bayesian kernel machine regression (BKMR). As a result, we found that the medium and the highest tertiles of Pb were significantly associated with an increased likelihood of DOR compared to the lowest tertile, while the medium or/an the highest tertiles of Cu, I, and Fe showed significantly lower likelihoods of DOR compared to the lowest tertiles. Cu and Pb showed significantly non-linear associations with ovarian reserve markers such as follicle-stimulating, anti-mullerian hormone levels, and antral follicle count. With the rising overall concentrations of heavy metals, the likelihood of DOR increased although not significant. There was a trend of a "U-shaped" association across the whole concentration range of trace essential elements and the likelihood of DOR. Our study revealed that avoiding heavy metallic elements and properly supplementing trace essential elements are conducive to ovarian function.

Efficacy and safety of Zi Gui Nv Zhen® capsules used in TCM for fertility preservation in patients with diminished ovarian reserve.

OBJECTIVE: To evaluate for the first time whether Zi Gui Nv Zhen® capsules (ZGNZC), until now used in traditional Chinese medicine (TCM) for menopausal complaints, can increase the fertility of Chinese women with diminished ovarian reserve (DOR). METHODS: Prospective, randomized, open-labeled 3-monthly study; 109 DOR patients (aged 20-40 years) receiving either ZGNZC (experimental group, n = 75) or not (control group, n = 34). Main outcomes: markers for ovarian function, thickness/type of the endometrium during ovulation, and pregnancy rate. Between-group analysis (A) comparing experimental vs. control group and within-group analysis (B) comparing data at baseline and after study in each of both groups. RESULTS: (A) Between-group-analysis: patients with ZGNZC had a higher endometrium thickness (0.75 vs. 0.62; p<.05) and higher anti-Müllerian hormone (AMH, 0.50 vs. 0.40; p<.05) than control group. Pregnancy rates were higher in the experimental than the control group (26.7% vs. 14.7%; n.s.). (B) Within-group-analysis: ZGNZC decreased levels of follicle-stimulating hormone (FSH, 11.42 vs. 8.69), increased estradiol-levels (E2, 56.09 vs. 73.36), and type A endometrium rates (5.3% vs. 39.7%) (all p< .05) and increased antral follicle count (AFC, 2 vs. 3). All hepato-renal biomarkers remained within the norm. The tolerability was good. There were no adverse events. CONCLUSIONS: In women with DOR who wish to conceive, three months' application of ZGNZC can improve ovarian function and oocyte quality by adjusting the neuroendocrine system, can improve endometrial properties and proliferation, necessary for a healthy pregnancy, and increased the clinical pregnancy rate in our prospective randomized observational study.

Mogroside-rich extract from Siraitia grosvenorii fruits protects against the depletion of ovarian reserves in aging mice by ameliorating inflammatory stress.

Mogroside-rich extract (MGE), the main bioactive component of dried Siraitia grosvenorii fruit, has long been used as a natural sweetener and traditional Chinese medicine. This extract possesses various types of pharmacological activities, such as anti-inflammatory, antioxidative, hypoglycemic and hypolipemic activities. Moreover, we recently revealed that MGE has beneficial effects on female reproduction. Increasing maternal age leads to a rapid reduction in female fertility; in particular, it dramatically decreases ovarian function. Nevertheless, whether MGE can alleviate ovarian aging and the underlying mechanisms have not yet been explored. In this study, mice were treated with MGE by supplementation in drinking water from 10 to 44 weeks of age. Then, ovarian function and molecular changes were determined. Our findings showed that MGE treatment protected aged mice from estrous cycle disorder. Moreover, MGE treatment significantly increased the ovarian reserves of aged mice. RNA-seq data showed that MGE upregulated the expression of genes related to gonad development, follicular development, and hormone secretion in ovarian tissue. Additionally, inflammatory stress was induced, as indicated by upregulation of inflammation-related gene expression and elevated TNF-α levels in the ovarian tissues of aged mice; however, MGE treatment attenuated inflammatory stress. In summary, our findings demonstrate that MGE can ameliorate age-related estrous cycle disorder and ovarian reserve decline in mice, possibly by alleviating ovarian inflammatory stress.

Folate intake and ovarian reserve among women attending a fertility center.

OBJECTIVE: To examine the association between dietary folate intake and antral follicle count (AFC) among women seeing treatment for infertility. DESIGN: Cohort study. SETTING: Academic fertility center. PATIENTS: A total of 552 women attending the Massachusetts General Hospital Fertility Center (2007-2019) who participated in the Environment and Reproductive Health Study. INTERVENTIONS: None. Folate intake was measured with a validated food frequency questionnaire at study entry. Multivariable Poisson regression models with robust standard errors were used to estimate the association of folate intake with AFC adjusting for calorie intake, age, body mass index, physical activity, education, smoking status, year of AFC, and intakes of vitamin B12, iron, and vitamin D. Nonlinearity was assessed with restricted cubic splines. MAIN OUTCOME MEASURE: AFC as measured by transvaginal ultrasonography as part of routine care. RESULTS: Among the 552 women (median age, 35.0 years; median folate intake, 1,005 µg/d), total and supplemental folate intake had a significant nonlinear relationship with AFC. There was a positive linear association with AFC up to approximately 1,200 µg/d for total folate intake and up to 800 µg/d for supplemental folate intake; however, there was no additional benefit of higher folate intakes. The magnitude of the association was modest; for example, the predicted adjusted difference in AFC between a woman consuming 400 vs. 800 µg/d of supplemental folate was approximately 1.5 follicles. CONCLUSION: Higher intake of folate, particularly from supplements, was associated with modestly higher ovarian reserve as measured by AFC among women attending a fertility center. CLINICAL TRIAL REGISTRATION NUMBER: This trial was registered at clinicaltrials.gov as NCT00011713.

Melatonin delays ovarian aging in mice by slowing down the exhaustion of ovarian reserve.

Studies have shown that melatonin (MLT) can delay ovarian aging, but the mechanism has not been fully elucidated. Here we show that granulosa cells isolated from mice follicles can synthesize MLT; the addition of MLT in ovary culture system inhibited follicle activation and growth; In vivo experiments indicated that injections of MLT to mice during the follicle activation phase can reduce the number of activated follicles by inhibiting the PI3K-AKT-FOXO3 pathway; during the early follicle growth phase, MLT administration suppressed follicle growth and atresia, and multiple pathways involved in folliculogenesis, including PI3K-AKT, were suppressed; MLT deficiency in mice increased follicle activation and atresia, and eventually accelerated age-related fertility decline; finally, we demonstrated that prolonged high-dose MLT intake had no obvious adverse effect. This study presents more insight into the roles of MLT in reproductive regulation that endogenous MLT delays ovarian aging by inhibiting follicle activation, growth and atresia.

A comparison of the efficacy and safety of traditional Chinese medicine in preconditioning patients with diminished ovarian reserve that would undergo In Vitro fertilization: A network meta-analysis protocol.

BACKGROUND: Diminished Ovarian Reserve (DOR) is a common disease in reproductive-age women in the diagnosis and treatment of infertility. The incidence of DOR increased quickly in recent years and had became one of the most important factors that made the quality of women life decline. Gynecology and reproductive medicine professors have made great efforts to explore good treatment methods all over the world. Traditional Chinese Medicine has made some achievement in treating DOR as a kind of complementary and alternative therapy In Vitro Fertilization (IVF) in recent years, it is indispensable to propose a network meta-analysis (NMA) protocol to discuss the efficacy and safety of TCM in IVF. METHODS: A literature search will be conducted in 8 electronic databases. RESULTS: The efficacy and safety of traditional Chinese medicine in preconditioning patients with diminished ovarian reserve that would undergo In Vitro Fertilization will be evaluated. RESULTS: The systematic review will evaluate the efficacy and safety of TCM in IVF. CONCLUSION: The result of this study will provide reliable evidence of the use of TCM in IVF. INPLASY REGISTRATION NUMBER: INPLASY2020110062. ETHICS AND DISSEMINATION: This review does not require ethical approval.

Zihuai recipe alleviates cyclophosphamide-induced diminished ovarian reserve via suppressing PI3K/AKT-mediated apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Zihuai recipe (ZHR), a Chinese herbal prescription, is widely used for the clinical treatment of Diminished ovarian reserve (DOR) infertility. However, little is known regarding its underlying mechanisms of DOR treatment. AIM OF THE STUDY: This study aimed to investigate the beneficial effects of ZHR on the treatment of DOR and to reveal the underlying mechanisms. MATERIALS AND METHODS: Sixty female 8-week-old Sprague-Dawley rats were randomly divided into the following six groups (n=10 per group): control, DOR, low-dose(2.7 g/kg/day) ZHR (L-ZHR), medium-dose(5.4 g/kg/day), ZHR (M-ZHR), high-dose(10.8 g/kg/day) ZHR (H-ZHR), and hormone replacement therapy (HRT) treatment groups. The DOR model was established in all the groups, except the control group, by a single intraperitoneal injection of 90 mg/kg cyclophosphamide. After the induction of the DOR model, rats were weighed and administered either the relevant dose of ZHR or an equal volume of saline solution (in the control and DOR groups). Rats in the HRT group received estradiol valerate tablets (0.16 mg/kg/day), and with medroxyprogesterone acetate tablets (0.86 mg/kg/day) added on day 4. After 32 days of treatment, the rats were euthanized and the ovaries were collected for sampling. Ovarian morphology was observed by hematoxylin and eosin staining and the number of follicles was counted under a microscope. The serum levels of anti-Müllerian hormone (AMH), gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) were quantified by ELISA. A TUNEL assay was used to analyze the level of apoptosis of the ovarian cells. The protein expressions of p-PI3K, p-AKT, PI3K, AKT, cleaved caspase-3, BAX, and Bcl-2 were measured by western blotting and immunohistochemistry. Data analysis was performed with SPSS 20.0 software. RESULTS: ZHR administration increased the ovarian index and the serum levels of AMH, GnRH, and E2, while lowering those of FSH and LH. ZHR treatment also increased the number of primordial, primary, secondary, and antral follicles, as well as the number of corpora lutea, but decreased the number of atretic follicles. Furthermore, ZHR administration decreased the percentage of TUNEL-positive ovarian cells. After treatment with ZHR, the protein expression levels of p-PI3K/PI3K, p-AKT/AKT, cleaved caspase-3 and BAX were decreased, whereas the level of Bcl-2 was increased. CONCLUSIONS: ZHR improved the ovarian reserve in CTX-induced DOR rats. The mechanisms of ZHR on DOR may be mediated through the regulation of gonadal hormones of the hypothalamic-pituitary-ovarian axis (HPOA), and the inhibition of PI3K/AKT-mediated apoptosis in granulosa cells.

Therapeutic Effects of Modified Gengnianchun Formula on Stress-Induced Diminished Ovarian Reserve Based on Experimental Approaches and Network Pharmacology.

AIM: To verify the effects of modified Gengnianchun formula (MGNC), a traditional Chinese medicine, on a stressed diminished ovarian reserve (DOR) animal model and predict the underlying mechanisms through network pharmacology strategies. METHODS: Sexually mature female C57BL/6 mice were allocated to five groups, abbreviated as the control (C) group, stress manipulated model (M) group, stress with normal saline gavage (N) group, stress with low-dose MGNC gavage (L) group, and stress with high-dose MGNC gavage (H) group. Body weight and the estrous cycle were monitored during the stress and gavage process. Serum stress hormones and reproductive hormones were evaluated by ELISA. Ovarian follicle counts were calculated, and ovarian follicle-stimulating hormone receptor (FSHR) and anti-Müllerian hormone (AMH) expression were assessed by Western blotting and immunohistochemistry. Network pharmacology strategies included active compound screening, drug and disease target analysis, gene ontology analysis, pathway analysis, and visualization of results. RESULTS: MGNC treatment significantly decreased serum corticosterone (CORT) and follicle-stimulating hormone (FSH) levels and increased testosterone (T) levels in the H group compared with the M and N groups. Primordial and preantral follicle counts and ovarian AMH and FSHR expression were significantly increased in the H group compared to those in the M and N groups. Through pharmacokinetic screening, we found 244 active compounds in MGNC. A total of 186 candidate intersection target genes of disease and MGNC were further screened to construct the interaction network. Gene ontology and KEGG pathway enrichment analysis ultimately unveiled a series of key targets that mainly mediated the effects of MGNC on DOR induced by chronic stress. The PI3K-Akt pathway may serve as the critical pathway underlying this therapeutic mechanism. CONCLUSION: MGNC is a promising formula to treat DOR induced by chronic stress, and the PI3K-Akt pathway may play an essential role in this effect.

Effects of Bushen Huoxue method for female with decreased ovarian reserve: A protocol for systematic review and meta-analysis.

BACKGROUND: Decreased ovarian reserve (DOR) is a common reproductive barrier in female. Bushen Huoxue (BSHX) method of TCM is widely applied to treat DOR clinically. The purpose of this study is to provide a systemic and comprehensive evaluation of BSHX in the treatment of DOR. METHODS: We have registered this protocol with OSF registry and the DOI is 10.17605/OSF.IO/QNUE2. We will search 4 English databases (PubMed, EMBASE, MEDLINE, Cochrane Library) and four Chinese databases (China national knowledge infrastructure database, Wanfang database, VIP and Superstar database) from their inception to August 10, 2020. Two authors will search and extract independently all related studies. RevMan 5.3 software will be applied to synthesize data. RESULTS: The results of this study will be published in a scientific journal after peer-review. CONCLUSION: This systematic review will provide reliable evidences for clinicians, and help them make decisions in DOR management.

Dehydroepiandrosterone supplementation improves ovarian reserve and pregnancy rates in poor responders.

OBJECTIVE: We investigated whether DHEA supplementation had an impact on ovarian reserve parameters and pregnancy rates in patients with poor ovarian response (POR) and primary ovarian insufficiency (POI). PATIENTS AND METHODS: A total of 34 people, 6 patients with POI and 28 patients with POR, were included in the study. The patients in the POR group consisted of two different groups: diminished ovarian reserve (DOR) and premature ovarian failure (PMOF). Patients in the POI and POR group were given 50 mg DHEA supplementation daily for 5 months. The primary outcome was to determine spontaneous clinical pregnancy rates. The monthly changes in the serum hormone levels and AFC were recorded for five months. AMH levels were also measured before and after treatment. RESULTS: The total follow-up time was 152 cycles. The number of pregnancies during the follow-up period was 9. The ratio of pregnancies to the number of patients was 26.5% and the rate per cycle was 5.9%. While 8 of 9 pregnancies resulted in a live birth, one resulted in a miscarriage. The rate of abortion was 11.1%. The mean AFC was 0 to 5 before treatment. Following DHEA administration, a significant increase was detected in 30.8% of the patients. There was an increase in AMH levels after DHEA, but this was not significant. The live birth rate and pregnancy rate per cycle were significantly higher in POR patients than those in POF. Patients with POF had no pregnancy. Although the PMOF patients were younger than the DOR patients, the rate of pregnancy (36% vs. 29%), and pregnancy rates per cycle (8.5% vs. 6.35%) were higher in the DOR group. The rates of live birth were the same in the PMOF and DOR groups (29% vs. 29%). CONCLUSIONS: Oral DHEA supplementation improves both ovarian reserve and pregnancy rates in women with POR.

Effectiveness of tonifying-kidney and regulating-liver therapy on diminished ovarian reserve: a systematic review and Meta-analysis of randomized controlled trials.

OBJECTIVE: To evaluate the effectiveness of the Traditional Chinese Medicine tonifying-kidney and regulating-liver therapy on diminished ovarian reserve (DOR). METHODS: The literature was comprehensively searched up to August 2019 using four Chinese and three English electronic databases to extract randomized clinical trials (RCTs) comparing Traditional Chinese Medicine tonifying-kidney and regulating-liver prescriptions (combined with hormone therapy or not) with Western Medicine. Data quality evaluation was conducted using the Cochrane risk of bias tool. Meta-analysis was conducted using Revman 5.3 software with effect estimates presented as mean difference (MD), risk ratio (RR), and 95% confidence interval (CI). RESULTS: A total of nine RCTs with 512 participants were extracted and eligible for Meta-analysis. There were no significant differences between Chinese medicine and Western Medicine on basal serum follicle-stimulating hormone (FSH) level (MD 0.11, 95% CI －0.52 to 0.74, 392 participants, seven trials), anti-Müllerian hormone level (MD 0.48, 95% CI －0.62 to 1.58, 95 participants, two trials), and the FSH and luteinizing hormone ratio (MD 0.01, 95% CI －0.95 to 0.96, 115 participants, two trials). Chinese medicine was more effective at improving Traditional Chinese Medicine symptom scores (TCMSS) (MD －2.39, 95% CI －3.83 to －0.94, 160 participants, three trials), effective rate of TCMSS (RR 1.18, 95% CI 1.02 to 1.36, 160 participants, three trials), antral follicle count (AFC) (MD 0.55, 95% CI 0.05 to 1.04, 155 participants, three trials), and FSH levels at 3 months post-treatment (MD -4.77, 95% CI －6.09 to －3.45, 137 participants, two trials). CONCLUSION: Compared with Western Medicine, tonifying-kidney and regulating-liver therapy is more effective at relieving symptoms and improving AFC and FSH at 3 months post-treatment.

The Association between Vitamin D and Anti-Müllerian Hormone: A Systematic Review and Meta-Analysis.

Accumulating evidence from animal and human studies indicates a role for vitamin D in female reproductive physiology, and numerous clinical studies have suggested its potential benefit for various aspects of human reproduction. Anti-Müllerian hormone (AMH) is an ovarian biomarker that plays an important role in folliculogenesis. It is the most sensitive ovarian reserve marker and is widely used clinically in reproductive medicine. While initial studies have suggested that vitamin D may be associated with ovarian reserve markers, including AMH, evidence has been conflicting. Currently, there is considerable debate in the field whether vitamin D has the capacity to influence ovarian reserve, as indicated by the AMH level. The current systematic review aims to evaluate and summarize the available evidence regarding the relationship between vitamin D and AMH. In total, 18 observational studies and 6 interventional studies were included in this systematic review. Cross-sectional studies have reported largely discrepant findings regarding an association between serum vitamin D and AMH levels, which are likely due to the heterogeneity in study populations, as well as the apparently complex relationship that may exist between vitamin D and AMH. However, meta-analysis of interventional studies performed herein that examined the effects of vitamin D supplementation on serum AMH levels indicates a cause-effect relationship between vitamin D and AMH, the direction of which appears to depend on a woman's ovulatory status. Serum AMH was significantly decreased following vitamin D supplementation in polycystic ovarian syndrome (PCOS) women (standardized mean difference (SMD) -0.53, 95% CI -0.91 to -0.15, p < 0.007), while it was significantly increased following vitamin D supplementation in ovulatory women without PCOS (SMD 0.49, 95% CI 0.17 to 0.80, p = 0.003). In conclusion, the results of this systematic review demonstrate that the relationship between vitamin D and AMH is a complex one, and large, randomized trials of vitamin D supplementation focusing on different vitamin D status ranges are necessary to gain more insight into the nature of this relationship and the potential benefit of vitamin D to female reproduction in general.

Dingkun Pill replenishes diminished ovarian reserve through the PI3K/AKT/mTOR signaling pathway in TWP-induced mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Diminished ovarian reserve (DOR) can lead to poor fertility and shorten the reproductive lifespan of females. The Dingkun Pill (DKP), a traditional Chinese-patented medication, has been an integral part of traditional Chinese medicinal treatment for the management of gynecological diseases for centuries. Relevant clinical studies have shown that DKP is able to protect against DOR, however, its mechanism of action is not yet fully elucidated. STUDY GOALS: This study was conducted with the aim of exploring the impact of tripterygium wilfordii polyglycosidium (TWP) on the PI3K/AKT/mTOR pathway in the context of the pathophysiology of DOR and the mechanism of action of DKP. MATERIALS AND METHODS: Eighty female balb/c mice with regular estrous cycles were assigned to Blank, Model, DKP and hormone replacement therapy (HRT) groups in a random manner. With the exception of the Blank group, mice in the other groups were exposed to 40 mg/kg/d TWP suspension for 30 days to DOR induction. Following this, either DKP or hormones were orally administrated to determine their effect on disease progression. During the experiment, changes in body weight and the estrous cycles of the mice were observed. Post treatment, serum sample anti-mullerian hormone (AMH), estradiol (E2), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were quantified using enzyme-linked immunosorbent assay (ELISA). The mice were then sacrificed in order to harvest their ovaries for hematoxylin and eosin (HE) staining. This process allowed for the assessment of ovarian morphology and follicular quantification. Apoptotic ovarian cells of the ovary were assessed using TUNEL technique, while Caspase-3 and Cytochrome C (Cyt C) expressions of the ovary were examined through immunohistochemistry (IHC). Western blotting analysis was used to quantify levels of Bax, Bcl-2, Caspase-3, Cyt C, mTOR, P-mTOR, AKT, P-AKT, P-PI3K and PI3K proteins, while mRNA levels of Bax, Bcl-2, PI3K, AKT and mTOR were measured in ovarian tissue using RT-PCR. RESULTS: The findings revealed that DKP was able to improve levels of serum hormones and promote the recovery of the estrous cycle. DKP augmented the total amount of primordial follicles while reducing the number of follicles that were atretic follicles. The apoptosis index of growing follicles and Bax, Cyt C and Caspase-3 expressions decreased, while the Bcl-2: Bax ratio increased. DKP suppressed levels of phosphorylation and the mRNA expressions of mTOR, AKT and PI3K. CONCLUSIONS: It was demonstrated that DKP was able to increase ovarian reserves through inhibition of the PI3K/AKT/mTOR signaling pathway, which lead to the suppression of primordial follicle activity and a reduction in levels of apoptosis of early growing follicles. This highlights its potentially beneficial role for the treatment of DOR.

Ovarian stimulation after dehydroepiandrosterone supplementation in poor ovarian reserve: a randomized clinical trial.

OBJECTIVE: This study aimed at improving fertility rates among infertile women with poor ovarian reserve. METHODS: This was a randomized clinical trial conducted in the outpatient clinic of a tertiary hospital. We recruited infertile women with poor ovarian reserve. The study population was divided into 2 groups, each of 25 participants. Both had induction of ovulation for three consecutive cycles. Study group took DHEA supplementation 25 mg/8 h for two consecutive cycles before induction of ovulation. Both groups were compared for outcomes of induction. Baseline ovarian reserve tests and antral follicle count (AFC) were done for both groups before induction of ovulation. The study group repeated these baseline tests after DHEA treatment to compare ovarian reserve before and after DHEA supplementation. Outcome measures were the number of mature follicles at the time of ovulation, the number of gonadotrophin ampoules needed for induction of ovulation, the duration of ovarian stimulation, E2 level at the day of HCG injection. RESULTS: The study group baseline investigations after DHEA treatment showed a statistically significant improvement compared to the control group. The outcomes of induction of ovulation in the study group showed a statistically better response than the control group. CONCLUSION: DHEA may help many poor responders so better considered for poor responder patients. TRIAL REGISTRATION NUMBER: PACTR201911829230395.

The use of autologous platelet-rich plasma (PRP) versus no intervention in women with low ovarian reserve undergoing fertility treatment: a non-randomized interventional study.

PURPOSE: To investigate the impact of a 3-month course of intracortical injections of autologous platelet-rich plasma (PRP) upon ovarian reserve markers versus no intervention in women with low ovarian reserve prior to undergoing assisted reproductive technology (ART). METHODS: Prospective controlled, non-randomized comparative study conducted in a private fertility clinic, in Venezuela. Women with abnormal ovarian reserve markers (FSH, AMH and AFC) who declined oocyte donation were allocated to one of the following groups according to patient choice: monthly intracortical ovarian PRP injections for three cycles, or no intervention. Primary outcomes were the change in FSH, AMH and AFC pre- and post-treatment. Secondary outcomes included the number of oocytes collected and fertilized, biochemical/clinical pregnancy rates and miscarriage and live birth rates. RESULTS: Eighty-three women were included, of which 46 received PRP treatment and 37 underwent no intervention. Overall median age was 41 years (IQR 39-44). There were no demographic differences between the study groups. At the 3-month follow-up, women treated with PRP experienced a significant improvement in FSH, AMH and AFC, whereas there was no change in the control group. Furthermore, overall rates of biochemical (26.1% versus 5.4%, P = 0.02) and clinical pregnancy (23.9% versus 5.4%, P = 0.03) were higher in the PRP group, while there was no difference in the rates of first trimester miscarriage and live birth between groups. CONCLUSION: PRP injections are effective and safe to improve markers of low ovarian reserve prior to ART, although further evidence is required to evaluate the impact of PRP on pregnancy outcomes.

Influence of Βeta-Cryptoxanthin Supplementation on Ovarian Reserve and Fertility Status in Aged Wistar Rats.

Previous observational studies have suggested that ß-cryptoxanthin, a micronutrient present in yellow and orange fruit and vegetables, may help delay the onset of menopause. Given the widespread social trend of delaying pregnancy, the possibility that ß-cryptoxanthin supplementation may delay age-related loss of fertility and onset of menopause is of significant interest. In a parallel study, either saline or ß-cryptoxanthin (5 µg/kg rat/day) was delivered to Wistar albino rats via an osmotic pump from 4 to 7 months of age. All control and ß-cryptoxanthin-treated dams were fertile at 7 months of age, with no differences in litter size, sex ratio, or pup viability at the time of mating at 7, 9, 11, and 15 months of age (p ≥ .05 for all). As expected, over time there was a pronounced decrease in litter size and serum anti-Müllerian hormone (AMH), but with no significant differences between the two groups at any time point. Overall, there was a positive correlation between litter size and AMH (r = 0.324, p = .012), confirming a link between this serum marker of ovarian reserve status and fertility potential. At 16 months, bilateral oophorectomies were performed at necropsy, before conducting follicle density assessments of ovarian reserve. The total number and stage of follicle development were similar between the ß-cryptoxanthin and control groups (13.8 ± 3.2 cf 10.2 ± 4.8, respectively, p > .05). ß-cryptoxanthin supplementation for 3 months early in reproductive life was not effective in delaying ovarian senescence or enhancing fertility in rats later in life, contrary to the association suggested by observational studies in humans.

[Influence of nourishing yin and tonifying yang sequential therapy combined with Western medicine on TGF-ß1/Smads signaling pathway in anovulatory infertility rats with diminished ovarian reserve].

OBJECTIVE: To explore the influence for combination of nourishing yin and tonifying yang sequential therapy (NYTYST) with Western medicine in treating anovulatory infertility rats with diminished ovarian reserve (DOR) based on TGF-ß1/Smads signaling pathway. 
 Methods: A total of 40 female rats were randomly divided into 5 groups, a normal control group, a model group, a Western medicine group, a NYTYST group and a combination group (n=8 in each group). The DOR model was established through orally taking tripterygium pill for continuous 2 weeks. The normal control group and the model group were treated with saline for 10 days. The Western medicine group was treated with hormone replacement therapy (HRT) and ovarian stimulation. The NYTYST group was treated with nourishing yin herbs in proestrus and tonifying yang herbs in late estrus and the combination group was treated with Chinese herb and Western drugs for 10 days. HE staining was used to observe histopathologic changes in ovary. Expression levels of transforming growth factor ß1 receptor (TGF-ß1R) in rats ovarian were detected by immunohistochemistry. Expression levels of Smad2, Smad3 and Smad7 protein in rat ovarian were detected by Western blot.
 Results: Compared with the control group, the numbers of developing follicles, mature follicles and corpus luteum were decreased , while atrefic follicles were increased significantly in the model group (P<0.01); the levels of TGF-ß1R, Smad2 and Smad3 were decreased significantly, while Smad7 was increased significantly (P<0.01). Compared with the model group, the numbers of developing follicles, mature follicles and corpus luteum, Smad2 and Smad3 expression were increased, while atrefic follicles and Smad7 were decreased significantly in the treatment group (P<0.05 or P<0.01). The numbers of developing follicles and corpus luteum in the combination group was superior to the Western medicine group (P<0.05). Compared with the Western medicine group, the levels of TGF-ß1R, Smad2 and Smad3 were increased significantly, while Smad7 was decreased significantly in the combination group (P<0.05 or P<0.01). 
 Conclusion: NYTYST combined with Western medicine can improve the function of ovaries reserve by up-regulation of TGF-ß1R, Smad2 and Smad3 while down-regulation of Smad7 in DOR rats.

Investigation of Allium sativum's protective effect on ovarian reserve in an experimental ovarian injury model / Investigación del efecto protector de Allium sativum de la reserva ovárica en un modelo experimental de lesión ovárica

We aimed to evaluate the effects of detorsion and Allium sativum (garlic oil) treatment on the ovarian reserve in an ovarian torsion model. Ovarian torsion may lead to loss of ovarian tissue and infertility. It is an experimental rat study that was carried out on 16 sets of ovaries each, one for treatment group and a control group. In the control group, the procedure involved only the surgically opening and closing the abdomen. Bilateral adnexal torsion/detorsion was performed after a 3-hour ischemia period for the detorsion-only group. The detorsion + Allium sativum group received a 5 ml/kg dose of Allium sativum intraperitoneally, 2 hours before surgery. After the second surgery, removed ovarian samples were evaluated for follicle counts, damage scores and other parameters. Primordial, preantral, small antral and large antral follicle counts were significantly higher in the detorsion + Allium sativum group. Degeneration, congestion, hemorrhage ,inflammation and total damage scores were significantly elevated in the detorsion only group compared to those for the detorsion + Allium sativum group. Finally, there was a significant correlation between AMH alterations and postoperative, preantral follicle count (p<0.05). As a conclusion detorsion + Allium sativum treatment may be effective in protecting the ovarian reserve after torsion.

Intentamos evaluar los efectos de la detorsión y el tratamiento con Allium sativum (aceite de ajo) en la reserva ovárica en un modelo de torsión ovárica. La torsión ovárica puede ocasionar pérdida de tejido ovárico e infertilidad. Este es un estudio experimental en ratas que se llevó a cabo en 16 sets de ovarios para cada grupo: tratamiento y control. En el grupo control, el procedimiento involucró solamente la apertura y el cierre quirúrgicos del abdomen. La torsión / detorsión anexial bilateral se realizó después de un período de isquemia de 3 horas para el grupo de solo detorsión. El grupo de detorsión + Allium sativum recibió una dosis de 5 ml / kg de Allium sativum por vía intraperitoneal, 2 horas antes de la cirugía. Después de la segunda cirugía, las muestras ováricas eliminadas se evaluaron para recuentos de folículos, puntajes de daño y otros parámetros. Los recuentos de folículos antrales primordiales, preantrales, antrales pequeños y grandes fueron significativamente mayores en el grupo con detorsión + Allium sativum. Los puntajes de degeneración, congestión, hemorragia, inflamación y daño total fueron significativamente elevados en el grupo de solo detorsión, en comparación con los del grupo de detorsión + Allium sativum. Finalmente, hubo una correlación significativa entre las alteraciones de AMH y el recuento de folículos preantrales postoperatorios (p <0,05). Como conclusión, el tratamiento con detorsión + Allium sativum puede ser eficaz para proteger la reserva ovárica después de la torsión.

Effects of dehydroepiandrosterone on the ovarian reserve and pregnancy outcomes in perimenopausal rats (DHEA and fertility in perimenopausal rats).

BACKGROUND: Dehydroepiandrosterone (DHEA) is a weak androgen and a crucial precursor of sex steroids. Exogenous supplementation of DHEA is now being commonly used to augment ovarian stimulation in women with diminished ovarian reserve. However, the effects of DHEA are controversial. AIMS: This study verifies the effects of pharmacologic doses of DHEA on the ovarian reserve variables, follicular development, reproductive function, and pregnancy outcomes of perimenopausal rats. MAIN METHODS: The reproductive function was studied by monitoring the estrous cycle and hormones. The ovarian reserve was studied by testing the anti-mullerian hormone and ovarian histology. The follicular development was studied histologically and immunohistochemically. KEY FINDINGS: DHEA supplementation at a dose of at 50 mg/kg improved the ovarian reserve and pregnancy outcomes. Higher doses of DHEA caused PCOs-like symptoms manifested by the development of cystic follicles and low ovarian reserve and pregnancy outcomes. SIGNIFICANCE: DHEA is a promising treatment that improves the ovarian reserve parameters and pregnancy outcomes. Further studies are needed to determine the optimal dose and duration.