Effects of hydroxyurea on fertility in male and female sickle cell disease patients. A systemic review and meta-analysis.

BACKGROUND: Evidence supports the benefits of hydroxyurea (HU) in adults with sickle cell disease (SCD), but reservations remain due to long-term concerns of fertility. Retrospective analysis of clinical records of SCD patients (haemoglobin SS genotype) have identified gender-related differences in disease progression. This could inform risk stratification during SCD at diagnosis with the possibility to guide therapeutic decisions. METHODS: This systemic review and meta-analysis evaluated fertility parameters in both children (aged ≥ 6 years) and adults with SCD receiving HU therapy. Studies were sourced from PubMed and EMBASE from inception to July 2023. A total of 160 potentially relevant articles were identified. RESULTS: Four studies were included that evaluated the effects of HU on sperm parameters in males. A further 4 studies assessed anti-mullerian hormone (AMH) levels and ovarian reserves in females. Differences from baseline values were used to identify compromised fertility. Amongst males, HU treatment negatively impacted the concentration of spermatozoa (MD = -15.48 million/mL; 95% CI: [-20.69, -10.26]; p< 0.001), which continued following treatment cessation (MD = -20.09 million/mL; 95% CI: [-38.78, -1.40]; P = 0.04). HU treatment also led to lower total sperm counts (MD = -105.87 million; 95% CI: [-140.61, -71.13]; P< 0.001) which persisted after treatment (MD = -53.05 million; 95% CI: [-104.96, -1.14]; P = 0.05). Sperm volume, initial forward motility and morphology were unaffected by HU treatment. In females, HU treatment decreased the mean AMH levels 1.83 (95% CI [1.42, 2.56]. A total of 18.2.% patients treated with HU showed reduced ovarian reserves. INTERPRETATION & CONCLUSIONS: This systemic review and meta-analysis suggest that the use of HU for SCD impacts seminal fluid parameters in males and can diminish AMH levels and ovarian reserves in females.

Potential clinical application of anti-Müllerian hormone testing in radioiodine treatment of thyroid carcinoma.

Differentiated thyroid cancer is the most common endocrinological malignancy. Radioiodine treatment has a clear benefit in locally aggressive and metastatic cancers. There are discussions about long-term and acute adverse events.Anti-Müllerian hormone is regarded as the best endocrine marker for evaluating the physiological loss of oocytes in healthy women with regard to age. The impact of radioiodine treatment on anti-Müllerian hormone levels has been more significantly reported in patients over 35 years of age. About reproductive dysfunction, calculations of individual absorbed doses of radioiodine in ovaries after thyroid cancer therapy have not been performed yet. The aim of our ongoing prospective study is to determine serum anti-Müllerian hormone to estimate ovarian reserve for premenopausal women treated with radioiodine and to compare anti-Müllerian hormone levels before and after radioiodine treatment. Predicting radioiodine side effects by evaluating a simple serum biomarker may help to select an appropriate treatment strategy for young women planning pregnancy, specifically in the assessment of ovarian reserve and premature ovarian failure with early onset of menopause.

Value of estrogen pretreatment in patients with diminished ovarian reserve and elevated FSH on a line antagonist regimen: a retrospective controlled study.

BACKGROUND: The key to enhancing the efficacy of antagonistic regimens in pregnancy is to better synchronize follicular growth during cycles of controlled ovarian stimulation (COS), especially in patients with diminished ovarian reserve (DOR). During in vitro fertilization-embryo transfer (IVF-ET) treatment, luteal phase estrogen pretreatment may enhance follicular development synchronization and yield of mature oocytes. However, the effect of estrogen pretreatment in DOR patients with elevated basal follicle-stimulating hormone (FSH) levels has not been well studied. METHODS: We retrospectively analyzed the clinical data of patients with elevated basal FSH levels and DOR (401 cycles) who underwent IVF/intracytoplasmic monosperm injection (ICSI)-assisted conception. Both groups were treated with a flexible gonadotropin-releasing hormone (GnRH) antagonist regimen and were further divided into two groups according to whether they received luteal estrogen pretreatment. There were 79 patients in the estrogen pretreatment group and 322 patients in the control group. On the second day of the menstrual cycle, gonadotropin (Gn) stimulation of the ovaries was initiated. The general characteristics, clinical, biological parameters and outcomes of the two groups were compared. RESULTS: The basic profiles of the two groups were similar (P > 0.05). More patients in the pretreatment group showed FSH rebound after gonadotropin (Gn) initiation, resulting in a significantly higher number of Gn days and total Gn than those in the control group (P < 0.05). There was no statistically significant difference in the number of days of antagonist use, follicle output rate (FORT), number of metaphase II(MII)eggs obtained, number of Two pronuclei (2PN) fertilized, number of D3 quality embryos, blastocyst formation rate, fresh embryo clinical pregnancy rate, cumulative pregnancy rate, and non-transferable embryo rate between the two groups (P > 0.05). CONCLUSIONS: The use of luteal phase estrogen pretreatment in patients with elevated basal FSH combined with DOR resulted in high FSH levels after the release of negative feedback, which was detrimental to early follicular growth, did not increase the follicular output rate, may have increased the use and duration of controlled ovarian stimulation drugs, and did not increase the number of eggs gained or improve clinical outcomes.

Curcumin and gallic acid have a synergistic protective effect against ovarian surface epithelium and follicle reserve damage caused by autologous intraperitoneal ovary transplantation in rats.

The objective of this study to examine the effects of curcumin and gallic acid use against oxidative stress damage in the autologous intraperitoneal ovarian transplantation model created in rats on ovarian follicle reserve, ovarian surface epithelium, and oxidant-antioxidant systems. 42 adult female Sprague Dawley rats (n=7) were allocated into 6 groups. Group 1 served as the control. In Group 2, rats underwent ovarian transplantation (TR) to their peritoneal walls. Group 3 received corn oil (CO) (0.5 ml/day) one day before and 14 days after transplantation. Group 4 was administered curcumin (CUR) (100 mg/kg/day), Group 5 received gallic acid (GA) (20 mg/kg/day), and Group 6 was treated with a combination of curcumin and gallic acid via oral gavage after transplantation. Rats were sacrificed on the 14th postoperative day, and blood along with ovaries were collected for analysis. The removed ovaries were analyzed at light microscopic, fluorescence microscopic, and biochemical levels. In Group 2 and Group 3, while serum and tissue Total Oxidant Levels (TOS) and Oxidative Stress Index (OSI) increased, serum Total Antioxidant Levels (TAS) decreased statistically significantly (p˂0.05) compared to the other groups (Groups 1, 4, 5, and 6). The ovarian follicle reserve was preserved and the changes in the ovarian surface epithelium and histopathological findings were reduced in the antioxidant-treated groups (Groups 4, 5, and 6). In addition, immunofluorescence examination revealed that the expression of Cytochrome C and Caspase 3 was stronger and Ki-67 was weaker in Groups 2 and 3, in comparison to the groups that were given antioxidants. It can be said that curcumin and gallic acid have a histological and biochemical protective effect against ischemia-reperfusion injury due to ovarian transplantation, and this effect is stronger when these two antioxidants are applied together compared to individual use.

Phthalate and DINCH exposure and ovarian reserve markers among women seeking infertility care.

Phthalate exposure can adversely impact ovarian reserve, yet investigation on the influence of its alternative substance, the non-phthalate plasticizer diisononyl-cyclohexane-1,2-dicarboxylate (DINCH), on ovarian reserve is very sparce. We aimed to investigate the associations of phthalate and DINCH exposure as well as their combined mixture with ovarian reserve. This present study included 657 women seeking infertility care in Jiangsu, China (2015-2018). Urine samples during enrollment prior to infertility treatment were analyzed using high-performance liquid chromatography-isotope dilution tandem mass spectrometry (UPLC-MS/MS) to quantify 17 phthalate metabolites and 3 DINCH metabolites. Multivariate linear regression models, Poisson regression models and weighted quantile sum (WQS) regression were performed to access the associations of 17 urinary phthalate metabolites and 3 DINCH metabolites with ovarian reserve markers, including antral follicle count (AFC), anti-Mullerian hormone (AMH), and follicle-stimulating hormone (FSH). We found that the most conventional phthalates metabolites (DMP, DnBP, DiBP, DBP and DEHP) were inversely associated with AFC, and the DINCH metabolites were positively associated with serum FSH levels. The WQS index of phthalate and DINCH mixtures was inversely associated with AFC (% change = -8.56, 95 % CI: -12.63, -4.31) and positively associated with FSH levels (% change =7.71, 95 % CI: 0.21, 15.78). Our findings suggest that exposure to environmental levels of phthalate and DINCH mixtures is inversely associated with ovarian reserve.

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.

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.

Risk factors for poor oocyte yield and oocyte immaturity after GnRH agonist triggering.

STUDY QUESTION: What are the potential risk factors for poor oocyte recuperation rate (ORR) and oocyte immaturity after GnRH agonist (GnRHa) ovulation triggering? SUMMARY ANSWER: Lower ovarian reserve and LH levels after GnRHa triggering are risk factors of poor ORR. Higher BMI and anti-Müllerian hormone (AMH) levels are risk factors of poor oocyte maturation rate (OMR). WHAT IS KNOWN ALREADY: The use of GnRHa to trigger ovulation is increasing. However, some patients may have a suboptimal response after GnRHa triggering. This suboptimal response can refer to any negative endpoint, such as suboptimal oocyte recovery, oocyte immaturity, or empty follicle syndrome. For some authors, a suboptimal response to GnRHa triggering refers to a suboptimal LH and/or progesterone level following triggering. Several studies have investigated a combination of demographic, clinical, and endocrine characteristics at different stages of the treatment process that may affect the efficacy of the GnRHa trigger and thus be involved in a poor endocrine response or efficiency but no consensus exists. STUDY DESIGN, SIZE, DURATION: Bicentric retrospective cohort study between 2015 and 2021 (N = 1747). PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients aged 18-43 years who underwent controlled ovarian hyperstimulation and ovulation triggering by GnRHa alone (triptorelin 0.2 mg) for ICSI or oocyte cryopreservation were included. The ORR was defined as the ratio of the total number of retrieved oocytes to the number of follicles >12 mm on the day of triggering. The OMR was defined as the ratio of the number of mature oocytes to the number of retrieved oocytes. A logistic regression model with a backward selection method was used for the analysis of risk factors. Odds ratios (OR) are displayed with their two-sided 95% confidence interval. MAIN RESULTS AND THE ROLE OF CHANCE: In the multivariate analysis, initial antral follicular count and LH level 12-h post-triggering were negatively associated with poor ORR (i.e. below the 10th percentile) (OR: 0.61 [95% CI: 0.42-0.88]; P = 0.008 and OR: 0.86 [95% CI: 0.76-0.97]; P = 0.02, respectively). A nonlinear relationship was found between LH level 12-h post-triggering and poor ORR, but no LH threshold was found. A total of 25.3% of patients suffered from oocyte immaturity (i.e. OMR < 75%). In the multivariate analysis, BMI and AMH levels were negatively associated with an OMR < 75% (OR: 4.34 [95% CI: 1.96-9.6]; P < 0.001 and OR: 1.22 [95% CI: 1.03-1.12]; P = 0.015, respectively). Antigonadotrophic pretreatment decreased the risk of OMR < 75% compared to no pretreatment (OR: 0.72 [95% CI: 0.57-0.91]; P = 0.02). LIMITATIONS, REASONS FOR CAUTION: Our study is limited by its retrospective design and by the exclusion of patients who had hCG retriggers. However, this occurred in only six cycles. We were also not able to collect information on the duration of pretreatment and the duration of wash out period. WIDER IMPLICATIONS OF THE FINDINGS: In clinical practice, to avoid poor ORR, GnRHa trigger alone should not be considered in patients with higher BMI and/or low ovarian reserve, balanced by the risk of ovarian hyperstimulation syndrome. In the case of a low 12-h post-triggering LH level, practicians must be aware of the risk of poor ORR, and hCG retriggering could be considered. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

The impact of follicular fluid phthalate metabolites on the ovarian reserve and ovarian function in Indian women undergoing intracytoplasmic sperm injection.

OBJECTIVE: To investigate the adverse effects of phthalate-induced ovarian toxicity on the ovarian reserve and ovarian function. To assess whether the accumulation of higher levels of selected phthalate metabolites in the follicular fluid (FF) of Indian women undergoing intracytoplasmic sperm injection (ICSI) was associated with a decline in their antral follicle count (AFC) and/or serum antimüllerian hormone (AMH) levels, suggesting a negative impact on the ovarian reserve. To evaluate the effects of follicular phthalate metabolites on peak serum estradiol (E2) levels and the total number of oocytes and mature metaphase II (MII) stage oocytes retrieved to assess the impact of phthalate toxicity on ovarian function. DESIGN: A subanalysis of an ongoing prospective cohort study was conducted to examine the association between the levels of six phthalate metabolites, namely, mono-n-butyl phthalate (MBP), mono-ethyl phthalate (MEP), mono-isononyl phthalate (MiNP), mono-isodecyl phthalate (MiDP), mono(2-ethyl-5-oxohexyl) phthalate, and mono(2-ethyl-5-hydroxyhexyl) phthalate, in the FF of Indian women undergoing ICSI and their ovarian reserve markers (AFC and serum AMH levels). To investigate the association of these follicular phthalate metabolite levels with the peak E2 levels and the total number of oocytes and number of MII stage oocytes retrieved. SETTING: In vitro fertilization center in a referral hospital in India. PATIENT(S): A total of 245 consenting Indian women who had undergone oocyte retrieval between April 2017 and mid-March 2020 were included. Each woman contributed one FF sample to the study. This was screened for six phthalate metabolites. The samples were collected before the coronavirus disease 2019 pandemic. INTERVENTION(S): Using liquid chromatography-tandem mass spectrometry, the total levels of six phthalate metabolites were quantified in the FF of 245 women. Using linear regression models that were unadjusted and adjusted for maternal age and body mass index (BMI), we evaluated the association between the follicular metabolites in these women and their AFC, serum AMH levels, peak E2 levels, total number of oocytes, and MII stage oocytes. MAIN OUTCOME MEASURE(S): To evaluate the impact of phthalate-induced ovarian toxicity on the ovarian reserve and ovarian function in Indian women undergoing ICSI by studying their accumulated levels in their FF. RESULT(S): For MiNP (a metabolite of di-isononyl phthalate), in linear regression models adjusted for age and BMI, we found that with increasing quartiles of follicular MiNP, there was a significant trend in the decrease in mean AFC (P-trend = 0.023) and a suggestive trend in the decrease in mean serum AMH levels (P-trend = 0.077). For MiDP (a metabolite of di-isodecyl phthalate), in the unadjusted regression model, we found that with increasing quartiles of follicular MiDP, there was a significant trend in the decrease in mean serum AMH levels (P-trend = 0.045). For MBP (a metabolite of dibutyl phthalate), in linear regression models adjusted for age and BMI, we found that with increasing quartiles of follicular MBP, there were significant trends in the decrease in the mean number of total oocytes retrieved (P-trend = 0.003), a decrease in the mean number of MII stage oocytes retrieved, (P-trend = 0.003) and a decrease in the mean peak E2 levels (P-trend = 0.016). Although we found that with increasing quartiles of follicular mono(2-ethyl-5-oxohexyl) phthalate there was a decrease in the mean number of total and MII stage oocytes retrieved and higher follicular MEP levels were negatively associated with the mean AFC and serum AMH levels, neither trend was statistically significant. We also found that although follicular MEP levels did not show an adverse impact on ovarian function, follicular mono(2-ethyl-5-hydroxyhexyl) phthalate levels did not show an adverse impact on both the ovarian reserve and function. CONCLUSION: In this study of 245 Indian women, higher accumulated FF levels of MiNP and MiDP were negatively associated with AFC and serum AMH levels, suggesting an adverse effect on the ovarian reserve. Higher accumulated FF levels of MBP were negatively associated with the total number of oocytes, MII stage oocytes, and peak E2 values, suggesting a negative impact on ovarian function. Although we found that phthalate-induced ovarian toxicity was statistically significant for selected phthalate metabolites, the role of the cumulative effect of multiple phthalates in the ovarian microenvironment cannot be ruled out and needs to be investigated further.

Continued exposure to D-galactose in postnatal period may inhibit excessive primordial follicle reduction in rats exposed prenatally to D-galactose.

We aimed to compare the ovarian reserve of rats exposed to oral D-galactose during prenatal and early life with rats exposed to D-galactose only during the prenatal period. Fifteen female pregnant Wistar rats were randomly divided into three groups. The first and second groups were fed a D-galactose enriched diet (35%) from the third day of pregnancy to parturition (PP) and the third day to the end of lactation (PL), respectively. The control group (C group) was fed a standard diet. The study population was the female offspring of three groups (PP', PL', and C'), in which some reproductive factors were examined between 45 and 50 days of age. When compared with the PP' group, the number of primordial follicles was significantly higher in the PL' group at PND 45-50 (40 vs. 30; p = .01); however, the antimullerian hormone level was significantly reduced in the PL' group versus control group (-2.2, 95% confidence interval [CI]: -2.83, -1.53 ng/ml p = .000), and follicle-stimulating hormone level significantly increased in PP' group versus control (4.5 mIU/ml, 95% CI: 1.40-7.62, p = .005). There was no significant difference in leukocyte infiltration or antiovarian antibody among the groups. Continued exposure to D-galactose during the lactation period inhibits the primordial follicle loss in rats in terms of producing fewer atretic follicles.

Ovarian toxicity of carboplatin and paclitaxel in mouse carriers of mutation in BRIP1 tumor suppressor gene.

More than 10% of women diagnosed with breast cancer during reproductive age carry hereditary germline pathogenic variants in high-penetrance BRCA genes or in others genes involved in DNA repair mechanisms such as PALB2, BRIP or ATM. Anticancer treatments may have an additional negative impact on the ovarian reserve and subsequently on the fertility of young patients carrying such mutations. Recently, the combination of carboplatin and paclitaxel is being recommended to these BRCA-mutated patients as neoadjuvant therapy. However, the impact on the ovary is unknown. Here, we investigated their effect of on the ovarian reserve using mice carriers of BRCA1-interacting protein C-terminal helicase-1 (BRIP1) mutation that plays an important role in BRCA1-dependent DNA repair. Results revealed that the administration of carboplatin or paclitaxel did not affect the ovarian reserve although increased DNA double-strand breaks were observed with carboplatin alone. Co-administration of carboplatin and paclitaxel resulted in a significant reduction of the ovarian reserve leading to a lower IVF performance, and an activation of the PI3K-Pten pathway, irrespective of the genetic background. This study suggests that co-administration of carboplatin and paclitaxel induces cumulative ovarian damage and infertility but a heterozygote genetic predisposition for DNA damage related to BRCA1 gene function does not increase this risk.

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.

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.

Long-term treatment of Nicotinamide mononucleotide improved age-related diminished ovary reserve through enhancing the mitophagy level of granulosa cells in mice.

Ovarian aging affects the reproductive health of elderly women due to decline in oocyte quality, which is closely related to mitochondrial dysfunction. Nicotinamide mononucleotide (NMN), as a precursor of NAD+, effectively regulate mitochondria metabolism in mice. However, roles of NMN in improving age-related diminished ovary reserve remain to be determined. In present study, 4, 8, 12, 24, 40-week old female ICR mice were collected and a 20-week-long administration of NMN was conducted to 40-week-old mice (60WN), meanwhile the control group is given water (60WC). First, we found that 20-week-long administration of NMN to 40-week-old mice exhibited anti-aging and anti-inflammatory effects on organ structures, along with the improvement of estrus cycle condition and endocrine function. The number of primordial, primary, secondary, antral follicles and corpora luteum of ovaries in 60WN group was significantly increased compared with those in 60WC group. Additionally, the protein and gene expressions of P16 of ovaries were significantly reduced in 60WN group than in 60WC group. the mitochondria biogenesis, autophagy level, and proteases activity enhanced in granulosa cells after 20-week-administration of NMN. Present results indicate that NMN has the potential to save diminished ovary reserve by long-term treatment, providing a basis for exploring the role of NMN in anti-ovarian aging by enhancing the mitophagy level of granulosa cells.

Added value of anti-Müllerian hormone serum concentration in assisted reproduction clinical practice using highly purified human menopausal gonadotropin (HP-hMG).

INTRODUCTION: The individual response to controlled ovarian stimulation (COS) depends on several factors, including the initial dose of gonadotropin. In repeated in vitro fertilization (IVF) cycles, the initial dose of gonadotropin is mainly established on the basis of the previous attempts' outcomes. Conversely, in naive patients, the ovarian response should be estimated using other criteria, such as the serum concentration of anti-Müllerian hormone (AMH). However, in clinical practice, the initial gonadotropin dose is not systematically adapted to the AMH level, despite the known relationship between AMH and ovarian reserve. MATERIAL AND METHODS: French non-interventional, longitudinal, prospective, multicentre, cohort study that included infertile women who underwent COS with highly purified human menopausal gonadotropin (HP-hMG 600 IU/mL) during their first IVF/intracytoplasmic sperm injection (ICSI) cycle. Data were collected prospectively during routine follow-up visits from COS initiation to 10-11 weeks after embryo transfer. RESULTS: Data from 235 of the 297 enrolled women were used for the study. Serum AMH level was negatively correlated with the initial and total HP-hMG doses (p<0.001), and positively correlated with the number of retrieved oocytes (p<0.007). Embryos were obtained for 94.0% of women, and fresh embryo transfer was performed in 72.8% of them. The clinical pregnancy rate was 28.5% after the first embryo transfer. CONCLUSION: Selecting the appropriate starting dose of gonadotropin is crucial to optimize the IVF/ICSI procedure. For the first attempt, the serum AMH level is a good biomarker to individualize treatment.

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.

Growth Hormone Cotreatment for Low-Prognosis Patients According to the POSEIDON Criteria.

Background: Poor ovarian response (POR) remains one of the most challenging conditions in assisted reproduction technology. Previous studies seemed to indicate that growth hormone (GH) was a potential solution for the dilemma of POR; however, the role GH played on the low-prognosis patients diagnosed and stratified by the POSEIDON criteria remains indistinct. Methods: This retrospective study was performed among women with POR according to the POSEIDON criteria who failed a previous in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle, and the subsequent cycle was under GH cotreatment and conducted within 12 months. These participants were stratified into four groups according to the POSEIDON criteria. The comparison was implemented between the failed cycle and the cycle treated with GH. Generalized estimating equation (GEE) multivariate regression was applied for data analysis. Results: A total of 428 low-prognosis women were included in this study. GH supplementation improved the live birth rates (47.66%, 28.33%, 45.45%, and 24.07%; in groups 1, 2, 3, and 4, respectively) and the clinical pregnancy rates (OR 19.16, 95% CI 7.87-46.63, p < 0.001; OR 7.44, 95% CI 1.65-33.55, p = 0.009; OR 10.19, 95% CI 2.39-43.52, p = 0.002; OR 27.63, 95% CI 4.46-171.11, p < 0.001; in groups 1, 2, 3, and 4, respectively) in all four POSEIDON groups. The number of oocytes retrieved was significantly elevated in the subgroups with normal ovarian reserve (IRR 1.47, 95% CI 1.36-1.59, p < 0.001; IRR 1.31, 95% CI 1.15-1.49, p < 0.001; in groups 1 and 2, respectively). The number of day-3 good-quality embryos was significantly elevated in the subgroups with either normal ovarian reserve or aged young (IRR 2.13, 95% CI 1.78-2.56, p < 0.001; IRR 1.54, 95% CI 1.26-1.89, p < 0.001; IRR 1.47, 95% CI 1.10-1.98, p = 0.010; in groups 1, 2, and 3, respectively). Conclusion: Growth hormone cotreatment could ameliorate the pregnancy outcome for women with POR under the POSEIDON criteria who failed a previous IVF/ICSI cycle. The application of growth hormone for low-prognosis women who experienced a failed cycle might be considered and further studied.

Impact of perioperative use of GnRH agonist or dienogest on ovarian reserve after cystectomy for endometriomas: a randomized controlled trial.

BACKGROUND: Ovarian endometrioma is a common gynecological disease that is often treated with surgery or hormonal treatment. Ovarian cystectomy, a surgical procedure for ovarian endometrioma, can result in impaired ovarian reserve. METHODS: We conducted a randomized controlled trial to evaluate the efficacy of hormonal treatment [gonadotropin-releasing hormone agonist (GnRHa) or dienogest (DNG)] for preserving ovarian reserve after cystectomy for ovarian endometrioma. The primary endpoint was the level of serum Anti-Müllerian hormone (AMH) as a marker of ovarian reserve. RESULTS: Before and after laparoscopic surgery, 22 patients in the GnRHa group and 27 patients in the DNG group were administered hormonal treatment for a total of 4 months. After 1-year follow-up, >60% of the patients in the DNG group retained over 70% of their pretreatment AMH levels, whereas no patient in the GnRHa group retained their AMH levels after cystectomy (P < 0.01). Interleukin-6 (IL-6) is a key cytokine involved in inflammation. Compared with the GnRHa group, patients in the DNG group had lower IL-6 levels at the end of treatment. CONCLUSIONS: Our data revealed that DNG is more effective than GnRHa in preserving ovarian reserve after cystectomy of ovarian endometrioma. This is achieved through the reduction of the inflammatory response during the perioperative period and other endometriosis-related inflammatory reactions. TRIAL REGISTRATION: The registration number of this trial is UMIN-CTR, UMIN000018569, registered 6 August 2015, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021492 , and Japan Registry of Clinical Trials, jRCTs041180140, registered 29 March 2019, https://jrct.niph.go.jp/en-latest-detail/jRCTs041180140 . This randomized controlled trial was conducted in accordance with the CONSORT guidelines.

Effects of PD-1 blockade on ovarian follicles in a prepubertal female mouse.

Immunotherapy has emerged at the forefront of cancer treatment. Checkpoint inhibitor pembrolizumab (KEYTRUDA), a chimeric antibody which targets programmed cell death protein 1 (PD-1), has been approved by the Food and Drug Administration (FDA) for use in pediatric patients with relapsed or refractory classical Hodgkin's lymphoma. However, there is currently no published data regarding the effects of pembrolizumab on the ovary of female pediatric patients. In this study, prepubertal immunocompetent and immunodeficient female mice were injected with pembrolizumab or anti-mouse PD-1 antibody. The number of primordial follicles significantly decreased post-injection of both pembrolizumab and anti-mouse PD-1 antibody in immunocompetent mice. However, no changes in follicle numbers were observed in immunodeficient nude mice. Superovulation test and vaginal opening experiments suggest that there is no difference in the number of cumulus-oocyte complexes (COCs) and the timing of puberty onset between the control and anti-mouse PD-1 antibody treatment groups, indicating that there is no effect on short-term fertility. Elevation of pro-inflammatory cytokine TNF-α following COX-2 upregulation was observed in the ovary. CD3+ T-cell infiltration was detected within some ovarian follicles and between stromal cells of the ovaries in mice following treatment with anti-mouse PD-1 antibody. Thus, PD-1 immune checkpoint blockade affects the ovarian reserve through a mechanism possibly involving inflammation following CD3+ T-cell infiltration.