Diagnostic Value of Autoantibodies against Steroidogenic Enzymes and Hormones in Infertile Women with Premature Ovarian Insufficiency.

The objective of the study was to evaluate the profile and diagnostic significance of serum autoantibodies in infertile patients with premature ovarian insufficiency (POI). The pilot study included 26 patients of reproductive age with POI and diminished ovarian reserve who received complex treatment using new surgical technologies (Group 1) and 18 patients without POI (Group 2). The profile of serum autoantibodies, including anti-ovarian antibodies, antibodies against thyroid peroxidase (TPO), steroidogenic enzymes, and steroid and gonadotropic hormones, was studied using modified ELISAs and human recombinant steroidogenic enzymes (CYP11A1, CYP19A1, CYP21A2). Patients in Group 1 had higher levels of IgG autoantibodies against steroidogenic enzymes, estradiol, progesterone, and TPO than those in Group 2. Tests for IgG antibodies against CYP11A1, CYP19A1, and CYP21A2 exhibited high sensitivity (65.4-76.9%), specificity (83.3-89.9%), and AUC values (0.842-0.910) for POI, the highest in the first test. Three-antibodies panel screening showed higher diagnostic accuracy (84.1% versus 75-79.6%). The levels of these antibodies correlated with menstrual irregularities and a decrease in the antral follicle count. Thus, antibodies against CYP11A1, CYP19A1, and CYP21A2 have a high diagnostic value for POI. Three-antibody panel screening may improve the accuracy of POI diagnosis and be useful for identifying high-risk groups, early stages of the disease, and predicting POI progression.

Examining the causal relationship between sex hormone-binding globulin (SHBG) and infertility: A Mendelian randomization study.

BACKGROUND: The causal relationship between sex hormone-binding globulin (SHBG) and infertility has remained unclear. Thus, we used Mendelian randomization (MR) to investigate this relationship. METHODS: Risk factors for SHBG were extracted from European individuals within the UK Biobank using single-nucleotide polymorphism (SNP) data. Summary-level data for infertility outcomes were obtained from the FinnGen dataset. The causal relationship between SHBG and infertility was examined using inverse variance weighted, weighted model, weighted median, and MR-Egger regression analyses. Additionally, Cochran's Q test and Egger intercept tests were used to confirm the heterogeneity and pleiotropy of identified instrumental variables (IVs). RESULTS: Our findings revealed a significant negative association between sex hormone-binding globulin (SHBG) levels and infertility, particularly with anovulation, a specific form of female infertility. However, SHBG did not exert a causal impact on male infertility or on female infertility of tubal origin. CONCLUSIONS: SHBG expression offers protection against the development of certain types of female infertility, suggesting it is a potential therapeutic target for infertility.

Treating refractory thin endometrium through a novel way of activation and administration of Platelet-rich plasma in sexually active women: An interventional prospective cohort clinical study.

A prospective cohort study investigated the effectiveness of platelet-rich plasma (PRP) infusion for refractory thin endometrium in 38 infertile patients. Patients showed significant improvement in endometrial thickness post-PRP injection, leading to successful implantation and pregnancy. The study revealed a negative correlation between antimullerian hormone (AMH) levels and the need for PRP interventions, suggesting higher ovarian reserve may reduce the necessity for repeated treatments. This implies AMH levels could serve as a prognostic indicator for treatment outcomes, aiding clinicians in optimizing protocols and reducing patient burden. Further research is needed to confirm these findings in larger and more diverse populations, along with exploring long-term reproductive success rates post-PRP treatment.

Associations between a normal-range free thyroxine concentration and ovarian reserve in infertile women undergoing treatment via assisted reproductive technology.

BACKGROUND: Some recent studies have shown that female subclinical hypothyroidism (SCH) is associated with diminished ovarian reserve (DOR). In this study, we aimed to investigate whether serum-free thyroxine (fT4) concentrations within the reference range are associated with ovarian reserve in women. METHODS: This cross-sectional study included 4933 infertile women with normal-range fT4 concentrations who received assisted reproductive technology treatment in our clinic. The data of women in different fT4 concentration tertiles (namely 12-15.33, 15.34-18.67, and 18.68-22 pmol/L) were compared with ovarian reserve markers, namely the anti-Müllerian hormone (AMH) concentration, the antral follicle count (AFC), and the number of aspirated oocytes. The primary outcomes were the AMH concentration and the risk of DOR, diagnosed as an AMH concentration < 1.1 ng/mL. RESULTS: The average ages of women in the low-normal, middle-normal, and high-normal fT4 tertiles were 33.20 (standard deviation [SD]: 5.11), 32.33 (SD: 5.13), and 31.61 (SD: 5.10) years, respectively (p < 0.0001). AMH concentrations (adjusted mean: 3.32 [95% confidence interval {CI}: 3.16 to 3.50] vs. 3.51 [3.40 to 3.62] vs. 3.64 [3.50 to 3.80] ng/mL, p = 0.022) were significantly different between the fT4 concentration tertiles. The risk of DOR was significantly increased in the low-normal (adjusted odds ratio: 1.61 [95% CI: 1.01 to 2.58]) and middle-normal (1.47 [95% CI: 1.00 to 2.16]) tertiles compared with the high-normal tertile. Subgroup analysis showed that AMH concentrations were significantly different among the fT4 concentration tertiles in women aged < 35 years (adjusted mean: 3.94 [95% CI: 3.70 to 4.20] vs. 4.25 [4.11 to 4.39] vs. 4.38 [4.18 to 4.58], p = 0.028), whereas this difference was not significant in women aged ≥ 35 years (p = 0.534). The general additive models using fT4 as a continuous variable indicated that a lower fT4 concentration within the normal range was significantly associated with a lower AMH concentration (p = 0.027), a lower AFC (p = 0.018), a lower number of aspirated oocytes (p = 0.001), and a higher risk of DOR (p = 0.007). CONCLUSION: Low-normal fT4 concentrations are associated with lower ovarian reserve in infertile women.

Ovarian response to controlled stimulation and its predictors in a limited-resource setting.

BACKGROUND: Infertility remains a serious health concern for Ethiopian women. Most of its treatment approaches entail controlled ovarian stimulation, the responses of which vary. However, there are no data on ovarian response to stimulation or its predictors in our situation. Thus, the current study aimed to assess the ovarian response to controlled stimulation and identify predictors. METHODS: A retrospective follow-up study was undertaken from April 1, 2021, to March 31, 2022, among patients who had first-cycle controlled ovarian stimulation at St.Paul's Hospital Fertility Center in Addis Ababa, Ethiopia. Clinical data were extracted using a checklist. SPSS-26 for data analysis and Epidata-4.2 for data entry were employed. The binary logistic regression model was fitted. A p-value < 0.05 indicated a significant association. The ROC curve was used to determine cutoff values and identify accurate predictors. RESULTS: A total of 412 study participants were included in the final analysis. The patients had a mean age of 32.3 ± 5.1 years (range: 20 - 4). The good ovarian response rate was 67% (95% CI: 62.2-71.5). An anti-Mullerian hormone (AMH) concentration < 1.2ng/ml (AOR = 0.19, 95% CI (0.06-0.57)), an antral follicle count (AFC) < 5 (AOR = 0.16, 95% CI (0.05-0.56)), and an induction length < 10 days (AOR = 0.23, 95% CI (0.06-0.93)) were significantly associated with ovarian response. The prediction accuracies for the AFC and AMH concentrations were 0.844 and 0.719, respectively. The optimal cutoff point for prediction was 5.5 AFC, which had a sensitivity of 77.2% and a specificity of 72.8%. However, its positive and negative predictive values were 85.2% and 61.1%, respectively. For AMH, the optimal cutoff value was 0.71ng/mL, with a corresponding sensitivity and specificity of 65.2% and 66%. At this value, the positive and negative predictive values were 63.8% and 67.3%, respectively. CONCLUSION: Only two-thirds of our patients achieved a good ovarian response. Induction duration, AMH concentration, and AFC were found to be predictors, with the AFC being the strongest predictor. Therefore, the AFC should be performed on all of our patients, and the AMH is selectively employed. Future research must verify the best cutoff points and investigate additional factors affecting ovarian response.

Analysis of factors affecting pregnancy rate after laparoscopic surgery for infertility associated with endometriosis.

OBJECTIVE: To analyze the factors that might influence the pregnancy rate in patients with infertility related to endometriosis (EMs) after undergoing laparoscopic surgery, providing guidance for our clinical diagnostic and therapeutic decision-making. METHODS: A retrospective analysis was conducted on clinical records and 1-year postoperative pregnancy outcomes of 335 patients diagnosed with endometriosis-related infertility via laparoscopic surgery, admitted to our department from January 2018 to December 2020. RESULTS: The overall pregnancy rate for patients with endometriosis (EMs) related infertility 1-year post-surgery was 57.3 %, with the highest pregnancy rate observed between 3 to 6 months after surgery. Factors such as Body Mass Index (BMI) (P = 0.515), presence of dysmenorrhea (P = 0.515), previous pelvic surgery (P = 0.247), type of EMs pathology (P = 0.893), and preoperative result of serum carbohydrate antigen 125 (CA125)（P = 0.615）had no statistically significant effect on postoperative pregnancy rates. The duration of infertility (P = 0.029), coexistence of adenomyosis (P = 0.042), surgery duration (P = 0.015), intraoperative blood loss (P = 0.050), preoperative result of serum anti-Müllerian hormone (AMH) (P = 0.002) and age greater than 35 (P = 0.000) significantly impacted postoperative pregnancy rates. The post-surgery pregnancy rate in patients with mild (Stage I-II) EMs was notably higher than those with moderate to severe (Stage III-IV) EMs (P = 0.009). Age (P = 0.002), EMs stage (P = 0.018), intraoperative blood loss (P = 0.010) and adenomyosis (P = 0.022) were the factors that affected the postoperative live birth rate. CONCLUSION: For patients with EMs-related infertility undergoing laparoscopic surgery, factors such as age > 35 years, infertility duration > 3 years, concurrent adenomyosis, severe EMs, surgery duration ≥ 2 h, intraoperative blood loss ≥ 50 ml, and low AMH before surgery are detrimental for the pregnancy rate within the first postoperative year. However, BMI, dysmenorrhea, past history of pelvic surgery, EMs pathology types (ovarian, peritoneal, deep infiltrating),and preoperative result of serum CA125 barely show any statistical difference in their effect on postoperative pregnancy rates. In terms of postoperative live birth rate, age > 35 years, severe EMs, intraoperative blood loss ≥ 50 ml, and adenomyosis were adverse factors.

Platelet-rich plasma (PRP) treatment of the ovaries significantly improves fertility parameters and reproductive outcomes in diminished ovarian reserve patients: a systematic review and meta-analysis.

INTRODUCTION: The incidence of infertility caused by diminished ovarian reserve has become a significant problem worldwide. The beneficial effect of PRP treatment of the ovaries has already been described, but the high-level evidence of its effectiveness has not yet been proven. MATERIALS AND METHODS: A systematic search was performed in five databases, until March 12th, 2024. Both randomized and non-randomized studies that compared PRP treatment of the ovaries to self-control among women with diminished ovarian reserve were eligible for inclusion. Hormonal levels (Anti-Müllerian hormone (AMH), Follicle stimulating hormone (FSH), Luteinizing hormone (LH), Estradiol (E2), In-vitro fertilization parameters (Antral follicle count, oocyte, and embryo count), biochemical and spontaneous pregnancy and livebirth were measured. RESULTS: 38 eligible studies were identified reporting on 2256 women. The level of AMH rised, the level of FSH decreased significantly after the PRP treatment. AMH 1 month MD 0.20 (n = 856, p > 0.001, 95% CI: [0.12;0.28]), 2 months MD 0.26 (n = 910, p = 0.013, 95% CI: [0.07;0.44]), 3 months MD 0.36 (n = 881, p = 0.002,95% CI: [0.20;0.52]). FSH 1 month MD -10.20 (n = 796, p > 0.039, 95% CI: [-19.80;-0.61]), 2 months MD -7.02 (n = 910, p = 0.017, 95% CI: [-12.48; -1.57]), 3 months MD -8.87 (n = 809, p = 0.010, 95% CI: [-14.19; -3.55]). The antral follicle count elevated significantly MD 1.60 (n = 1418, p = < 0.001, 95% CI: [0.92; 2.27]). Significant improvement was observed in the number of retrieved oocytes MD 0.81 (n = 802, p = 0.002, 95% CI: [0.36; 1.26]), and embryos created MD 0.91 (n = 616, p = 0.001, 95% CI: [0.45;1.36]). The incidence of spontaneous pregnancy following PRP treatment showed a rate with a proportion of 0.07 (n = 1370, 95% CI: 0.04-0.12), the rate of biochemical pregnancy was 0.18 (n = 1800, 95% CI: 0.15-0.22), livebirth was 0.11 (n = 1482, 95% CI: 0.07-0.15). CONCLUSIONS: Our meta-analysis showed that based on protocolized analysis of the widest scientific literature search to date, containing predominantly observational studies, PRP treatment resulted in a statistically significant improvement in the main fertility parameters of diminished ovarian reserve women. Further multicenter, randomized trials, with large patient numbers and a longer follow-up period are needed to certify our results and develop the most effective treatment protocol.

Metabolic landscape and pathogenic insights: a comprehensive analysis of high ovarian response in infertile women undergoing in vitro fertilization.

BACKGROUND: In the realm of assisted reproduction, a subset of infertile patients demonstrates high ovarian response following controlled ovarian stimulation (COS), with approximately 29.7% facing the risk of Ovarian Hyperstimulation Syndrome (OHSS). Management of OHSS risk often necessitates embryo transfer cancellation, leading to delayed prospects of successful pregnancy and significant psychological distress. Regrettably, these patients have received limited research attention, particularly regarding their metabolic profile. In this study, we aim to utilize gas chromatography-mass spectrometry (GC-MS) to reveal these patients' unique serum metabolic profiles and provide insights into the disease's pathogenesis. METHODS: We categorized 145 infertile women into two main groups: the CON infertility group from tubal infertility patients and the Polycystic Ovary Syndrome (PCOS) infertility group. Within these groups, we further subdivided them into four categories: patients with normal ovarian response (CON-NOR group), patients with high ovarian response and at risk for OHSS (CON-HOR group) within the CON group, as well as patients with normal ovarian response (PCOS-NOR group) and patients with high ovarian response and at risk for OHSS (PCOS-HOR group) within the PCOS group. Serum metabolic profiles were analyzed using GC-MS. The risk criteria for OHSS were: the number of developing follicles > 20, peak Estradiol (E2) > 4000pg/mL, and Anti-Müllerian Hormone (AMH) levels > 4.5ng/mL. RESULTS: The serum metabolomics analysis revealed four different metabolites within the CON group and 14 within the PCOS group. Remarkably, 10-pentadecenoic acid emerged as a discernible risk metabolite for the CON-HOR, also found to be a differential metabolite between CON-NOR and PCOS groups. cysteine and 5-methoxytryptamine were also identified as risk metabolites for the PCOS-HOR. Furthermore, KEGG analysis unveiled significant enrichment of the aminoacyl-tRNA biosynthesis pathway among the metabolites differing between PCOS-NOR and PCOS-HOR. CONCLUSION: Our study highlights significant metabolite differences between patients with normal ovarian response and those with high ovarian response and at risk for OHSS within both the tubal infertility control group and PCOS infertility group. Importantly, we observe metabolic similarities between patients with PCOS and those with a high ovarian response but without PCOS, suggesting potential parallels in their underlying causes.

Association between blood lead levels and unfavorable IVF outcomes: potential involvement of endoplasmic reticulum stress response in granulosa cells.

PURPOSE: To investigate the relationship between blood lead levels (BLLs) and IVF clinical outcomes in infertile females and to further explore the possible involvement of granulosa cell (GC) endoplasmic reticulum (ER) stress in the process. METHODS: One hundred twenty-three infertile women undergoing IVF cycles were included in the current study. All participants were divided into three (low, medium, and high) groups determined by BLL tertiles. Gonadotropin releasing hormone (GnRH) agonist regimen for ovarian stimulation was used for all patients, with follicular fluids being collected on the day of oocyte retrieval. Lactate dehydrogenase (LDH) levels in follicular fluid and the endoplasmic reticulum stress-signaling pathway of granulosa cells (GCs) were examined. RESULTS: The oocyte maturation rate and high-quality embryo rate on cleaved stage decreased significantly as BLL increased. For lead levels from low to high, live birth rate (68.29%, 56.10%, 39.02%; P=0.028) showed negative correlations with BLLs. Also, follicular fluid Pb level and LDH level was significantly higher in the high lead group versus the low group. Binomial regression analysis revealed significant negative correlation between BLLs and live birth rate (adjusted OR, 0.38; 95% CI, 0.15-0.95, P=0.038). Further analysis of the endoplasmic reticulum stress (ER stress) signaling pathway of GCs found that expressions of GRP78, total JNK, phosphorylated JNK, and CHOP increased and BCL-2 decreased with increasing BLLs. CONCLUSIONS: BLLs are negatively associated with final clinical outcomes in IVF patients that may be related to increased ER stress response and GC apoptosis. Thus, reducing Pb exposure before IVF procedures may improve final success rates.

Associations between cytokines and the risk of female and male infertility: A two-sample Mendelian randomization analysis.

PURPOSE: Observational studies have linked cytokines to the occurrence of female and male infertility. However, it is not clear how biomarkers of inflammation are causally related to infertility. To explore whether genetic variants in circulating cytokines are associated with the pathogenesis of infertility, we performed two-sample Mendelian randomization (MR) analysis. METHODS: A total of 31,112 individuals of European ancestry were included in a genome-wide association study (GWAS) of 47 circulating cytokines as instrumental variables (IVs). Outcome data were female infertility, including four different subtypes, and male infertility, from the FinnGen consortium. Five MR methods, including inverse-variance weighted (IVW), MR-Egger, simple mode, weighted median, and weighted mode were employed to examine the genetic association between cytokines and the risk of female infertility and male infertility. The false discovery rate (FDR) was controlled using the Benjamini-Hochberg method. RESULTS: After FDR correction, cis-protein quantitative trait locus (cis-pQTL) instruments showed that the cytokines GROa and MCSF were positively associated with female infertility. In analyses of subtypes of female infertility, eotaxin and sICAM were inversely associated with ovulation-related infertility; MCP3 alone was positively associated with uterus-related infertility; GROa and MCSF were positively correlated with infertility of cervical, vaginal, and other or unspecified origin; and MIP1a was negatively correlated with tubal origin infertility. The cytokines HGF, IL-2ra, and RANTES were positively correlated with male infertility. Similar findings were obtained in sensitivity analyses. There was no evidence of pleiotropy or heterogeneity in the results. CONCLUSION: These findings contribute to current understanding of the role of cytokine biomarkers in the etiology of female and male infertility. Furthermore clinical experimental validation is required to evaluate the potential of these cytokines as biomarkers.

Effect of radiation on serum anti-Müllerian hormone during hysterosalpingography in female infertility.

RESEARCH QUESTION: Does radiation exposure during hysterosalpingography (HSG) negatively affect serum anti-Müllerian hormone (AMH) levels in infertile women? DESIGN: Prospective cohort study conducted at Songklanagarind Hospital, Thailand, between April 2021 and May 2023. Thirty-two infertile women and 34 control participants were enrolled. Serum AMH levels were assessed in the infertile group at baseline before the HSG procedure and at 1 and 3 months after the procedure. Control participants, who self-reported no medical conditions, underwent the same AMH level assessments. Changes in serum AMH levels were compared. RESULTS: Infertile women had a mean age of 32.4 ± 3.8 years, body mass index of 21.2 ± 2.0 kg/m2 and baseline mean AMH level of 3.66 ng/ml (95% CI 3.00 to 4.32), which did not significantly differ from the control group. One month after HSG, mean AMH level significantly declined (0.33 ng/ml, 95% CI -0.65 to -0.01; P = 0.045) in the infertile group. The change in serum AMH levels between baseline and 1 month was significantly different in the HSG group compared with controls (-0.33 ng/ml, 95% CI -0.65 to -0.01 versus 0.36 ng/ml, 95% CI 0.06 to 0.67; P = 0.002). Changes in serum AMH levels from baseline to 3 months did not differ between the two groups. CONCLUSIONS: One month after the HSG, infertile women experienced a significant decrease in serum AMH levels compared with controls. The change in serum AMH levels between baseline and 3 months after HSG did not significantly differ from that of the control group.

Antimüllerian hormone levels and IVF outcomes in polycystic ovary syndrome women: a scoping review.

Antimüllerian hormone (AMH) is a homodimeric glycoprotein secreted by granulosa cells from primary to large antral follicles, and it plays an important role in the regulation of early follicle growth. It is considered a reliable marker of ovarian reserve and a predictor of ovarian response to controlled stimulation. Polycystic ovary syndrome (PCOS) is an endocrine condition that affects women of reproductive age worldwide, and it is associated with high levels of AMH. PCOS patients may have worse maturation and fertilization rates compared to normo-ovulatory women. Some studies have demonstrated a positive correlation between AMH levels and qualitative aspects of assisted reproduction treatment; but it is not clear whether high levels of both serum and follicular fluid AMH in PCOS patients correlate with in vitro fertilization outcomes. We ran this scoping review of the literature to address this specific question. We comprehensively searched the databases PubMed and Cochrane Library until January 2023. We found that higher AMH levels are associated with higher oocyte yield, but PCOS patients tend to have fewer mature oocytes and impaired embryo quality and implantation rates. Pregnancy rates, however, are not affected by AMH levels or laboratorial outcomes. We also found that higher AMH levels are associated with worse PCOS features.

Association of serum uric acid with women's ovarian reserve: observational study and Mendelian randomization analyses.

OBJECTIVE: To investigate the association between serum uric acid and women's ovarian reserve. DESIGN: Retrospective observational study and Mendelian randomization study. SETTING: University-affiliated in vitro fertilization center. PATIENTS: Observational analyses were undertaken using data from 8,257 women with infertility who finished their first in vitro fertilization treatments between May 2017 and December 2021. Mendelian randomization analyses were based on genome-wide association summary statistics from several biobanks of predominantly European ancestries. INTERVENTIONS: Observational study involved testing log2 transformed serum uric acid levels (for linear, negative regression, and logistic regression analyses); original uric acid levels (for nonlinear association analyses). Mendelian randomization study involved testing genetically predicted uric acid levels. MAIN OUTCOME MEASURES: Biomarkers including antimüllerian hormone, basal antral follicle count, follicle-stimulating hormone, luteinizing hormone, ratio of follicle-stimulating hormone to luteinizing hormone, estradiol; indices of ovarian response to stimulation including poor ovarian response according to different criteria and oocyte yield. RESULTS: In retrospective observational study, all ovarian reserve-related outcomes demonstrated significant differences across serum uric acid quartiles. A two-fold uric acid increase was associated with increased antimüllerian hormone (adjusted ß = 0.69; 95% confidence interval [CI], 0.43-0.95), antral follicle count (adjusted incidence rate ratio = 1.10, 95% CI, 1.05-1.14), luteinizing hormone (adjusted ß = 0.53, 95% CI, 0.28-0.78), decreased risks of Bologna poor ovarian response (adjusted odds ratio = 0.97; 95% CI, 0.95-0.99) and groups 2-4 Poseidon poor ovarian response (group 2: 0.63, 0.56-0.71; group 3: 0.71, 0.65-0.78; group 4: 0.50, 0.46-0.55), whereas an increased risk of group 1 (1.26, 1.13-1.41). Nonlinear analyses showed a common inflection point at 320-340 µmol/L of uric acid. Interactions between uric acid and antimüllerian hormone and antral follicle count were presented in association with oocyte yield. Mendelian randomization results suggested a significant association between genetically predicted uric acid levels and antimüllerian hormone levels (ß = 0.08; 95% CI, 0.04-0.12) but none for uric acid in relation to polycystic ovarian syndrome or other related hormones. CONCLUSION: Higher uric acid levels were associated with better ovarian reserve and increased levels of antimüllerian hormone albeit an increased risk of unexpected poor ovarian response.

Effects of vitamin D supplementation on ovarian reserve markers in infertile women with diminished ovarian reserve.

ABSTRACT: The purpose of this study was to evaluate the effects of vitamin D supplementation on ovarian reserve markers, including serum anti-Mullerian hormone (AMH) level, follicle-stimulating hormone (FSH) level, and antral follicle count (AFC), in infertile women with diminished ovarian reserve and vitamin D deficiency.A prospective, nonrandomized, cross-sectional study was conducted. Women aged 18 to 41 years who were unable to become pregnant after 12 months of sexual intercourse and had normal tubal patency, partners with normal semen analysis, diminished ovarian reserve, and 25-hydroxyvitamin D [25(OH)D] deficiency were included. Eligible patients' AFC and serum levels of AMH, FSH, 25(OH)D, 1,25-dihydroxyvitamin D [1,25(OH)D], calcium, phosphate, alkaline phosphatase, and parathormone were assessed before and after administration of 300,000 IU of vitamin D ampules. Changes in the parameter values after vitamin D supplementation were compared with the initial levels.The study was conducted in 62 of the 142 participants. The AFC and AMH, 25(OH)D, 1,25(OH)D, phosphate (P < .01), and calcium levels (P < .05) were statistically significantly increased after vitamin D supplementation. Statistically significant decreases in FSH (P < .01) and alkaline phosphatase levels (P < .05) were observed after vitamin D supplementation. No statistically significant correlations were found between 25(OH)D level and AFC, 1,25(OH)D level, AMH level, and FSH level before and after supplementation (P > .05).As improvements in the ovarian reserve markers were obtained with vitamin D supplementation, vitamin D might be considered as a fertility treatment for patients with diminished ovarian reserve and vitamin D deficiency.

Chronic Estrus Disrupts Uterine Gland Development and Homeostasis.

Female mice homozygous for an engineered Gnrhr E90K mutation have reduced gonadotropin-releasing hormone signaling, leading to infertility. Their ovaries have numerous antral follicles but no corpora lutea, indicating a block to ovulation. These mutants have high levels of circulating estradiol and low progesterone, indicating a state of persistent estrus. This mouse model provided a unique opportunity to examine the lack of cyclic levels of ovarian hormones on uterine gland biology. Although uterine gland development appeared similar to controls during prepubertal development, it was compromised during adolescence in the mutants. By age 20 weeks, uterine gland development was comparable to controls, but pathologies, including cribriform glandular structures, were observed. Induction of ovulations by periodic human chorionic gonadotropin treatment did not rescue postpubertal uterine gland development. Interestingly, progesterone receptor knockout mice, which lack progesterone signaling, also have defects in postpubertal uterine gland development. However, progesterone treatment did not rescue postpubertal uterine gland development. These studies indicate that chronically elevated levels of estradiol with low progesterone and therefore an absence of cyclic ovarian hormone secretion disrupts postpubertal uterine gland development and homeostasis.

Impact of sleep patterns upon female neuroendocrinology and reproductive outcomes: a comprehensive review.

Sleep is vital to human bodily function. Growing evidence indicates that sleep deprivation, disruption, dysrhythmia, and disorders are associated with impaired reproductive function and poor clinical outcomes in women. These associations are largely mediated by molecular-genetic and hormonal pathways, which are crucial for the complex and time sensitive processes of hormone synthesis/secretion, folliculogenesis, ovulation, fertilization, implantation, and menstruation. Pathologic sleep patterns are closely linked to menstrual irregularity, polycystic ovarian syndrome, premature ovarian insufficiency, sub/infertility, and early pregnancy loss. Measures of success with assisted reproductive technology are also lower among women who engage in shift work, or experience sleep disruption or short sleep duration. Extremes of sleep duration, poor sleep quality, sleep disordered breathing, and shift work are also associated with several harmful conditions in pregnancy, including gestational diabetes and hypertensive disorders. While accumulating evidence implicates pathologic sleep patterns in impaired reproductive function and poor reproductive outcomes, additional research is needed to determine causality and propose therapeutic interventions.

Folate Levels and Pregnancy Rate in Women Undergoing Assisted Reproductive Techniques: a Systematic Review and Meta-analysis.

Maternal nutrition is believed to be closely related to reproductive success and the importance of folate in the reproductive process and its involvement in fundamental biological systems are well known. The present systematic review and meta-analysis will focus on two main aspects: level of folate in women undergoing infertility treatments and association between folate status and success rate in assisted reproductive techniques. Although the importance of folate in the preconceptional phase is known, available data regarding the levels of folate in women who undergo infertility treatments are scarce. Referring to the threshold values generally used for the general population or for supplement users, the concentration of folate in the serum and erythrocytes of infertile women is adequate in the majority of the population with differences related to the geographic origin of the study populations. However, using the red blood cells folate threshold specifically indicated to prevent neural tube defects, the majority of available studies do not offer sufficient data to conclude on the real folate situation. As for the probability of success of ART treatments based on folate levels, our review did not reveal a significant effect.

Metabolomic Profiling of Poor Ovarian Response Identifies Potential Predictive Biomarkers.

Objective: To characterize the serum metabolomic profile and its role in the prediction of poor ovarian response (POR). Patients: Twenty-five women with normal ovarian reserve (24-33 years, antral follicle count [AFC] ≥5, anti-Müllerian hormone [AMH] ≥1.2 ng/ml) as the control group and another twenty-five women with POR (19-35 years, AFC <5, AMH < 1.2 ng/ml) as the study group were collected in our study. The serum levels of the women in both groups were determined from their whole blood by untargeted liquid chromatography-mass spectrometry (LC-MS). Multivariate statistical analysis and cell signal pathways analysis were used to reveal the results. Results: A total of 538 different metabolites were finally identified in the two groups. Tetracosanoic acid, 2-arachidonoylglycerol, lidocaine, cortexolone, prostaglandin H2,1-naphthylamine, 5-hydroxymethyl-2-furancarboxaldehyde, 2,4-dinitrophenol, and D-erythrulose1-phosphate in POR were significantly different from control as were most important metabolites in support vector machines (p <0.05). Metabolomic profiling, together with support vector machines and pathway analysis found that the nicotinate and nicotinamide metabolism pathway, including L-aspartic acid, 6-hydroxynicotinate, maleic acid, and succinic acid semialdehyde, was identified to have significant differences in POR women compared to control women, which may be associated with ovarian reserve. Conclusion: This study indicated that LC-MS-based untargeted metabolomics analysis of serum provided biological markers for women with POR. The nicotinate and nicotinamide metabolism pathway may offer new insight into the complementary prediction and therapeutic potential of POR. The functional associations of these metabolites need further investigation.

MicroRNA signatures in plasma and plasma exosome during window of implantation for implantation failure following in-vitro fertilization and embryo transfer.

BACKGROUND: MicroRNAs (miRNAs) are small, non-coding RNAs that are dysregulated in many diseases and can act as biomarkers. Although well-studied in cancer, the role of miRNAs in embryo implantation is poorly understood. Approximately 70% of embryos fail to implant following in-vitro fertilization and embryo transfer, 10% of patients experienced recurrent implantation failure. However, there are no well-established biomarkers that can predict implantation failure. Our purpose is to investigate distinct miRNA profiles in plasma and plasma exosomes during the window of implantation between patients with failed implantation and successful implantation. METHODS: We select a nested case-control population of 12 patients with implantation failure or successfully clinical pregnancy using propensity score matching. RNA was extracted from plasma and plasma exosomes collected during the window of implantation (WOI). MicroRNA expression in all samples was quantified using microRNA sequencing. The intersection of differently expressed miRNAs in plasma and exosomes were further validated in the GEO dataset. Significantly altered microRNAs in both plasma and plasma exosomes were then subjected to target prediction and KEGG pathway enrichment analyses to search for key signaling pathways. WGCNA analysis was performed to identify hub miRNAs associated with implantation. RESULTS: 13 miRNAs were differentially expressed in both plasma and plasma exosomes in patients with implantation failure. Among them, miR-150-5p, miR-150-3p, miR-149-5p, and miR-146b-3p had consistent direction changes in endometrium of patients with recurrent implantation failure (RIF), miR-342-3p had consistent direction changes in blood samples of patients with RIF. Pathway enrichment analysis showed that the target genes of differentially expressed miRNAs are enriched in pathways related to embryo implantation. WGCNA analysis indicated that miR-150-5p, miR-150-3p, miR-146b-3p, and miR-342-3p are hub miRNAs. CONCLUSIONS: Implantation failure is associated with distinct miRNA profiles in plasma and plasma exosomes during WOI.

Ethnic and Sociocultural Differences in Ovarian Reserve: Age-Specific Anti-Müllerian Hormone Values and Antral Follicle Count for Women of the Arabian Peninsula.

Background: Anti-Müllerian hormone (AMH) and antral follicle count (AFC) age-specific reference values form the basis of infertility treatments, yet they were based upon studies performed primarily on Caucasian populations. However, they may vary across different age-matched ethnic populations. This study aimed to describe age-specific serum AMH and AFC for women native to the Arabian Peninsula. Methods: A retrospective large-scale study was performed including 2,495 women, aged 19 to 50 years, native to the Arabian Peninsula. AMH and AFC were measured as part of their fertility assessment at tertiary-care fertility centres. Age-specific values and nomograms were calculated. Results: 2,495 women were evaluated. Mean, standard deviation and median values were calculated for AMH and AFC by 1-year and 5-years intervals. Median age was 34.81 years, median AMH was 1.76ng/ml and median AFC was 11. From the total group, 40.60% presented with AMH levels below 1.3ng/mL. For women <45 years old, the decrease in AFC was between -0.6/-0.8 per year. Up to 36 years old, the decrease of AMH was 0.1ng/ml. However, from 36 to 40 years old, an accelerated decline of 0.23ng/ml yearly was noted. In keeping with local customs, 71.23% of women wore the hijab and 25.76% the niqab. AMH and AFC were significantly lower for niqab group compared with hijab group (p=0.02 and p=0.04, respectively). Conclusion: This is to-date the largest data set on age-specific AMH and AFC values in women from the Arabian Peninsula aiming to increase clinical awareness of the ovarian reserve in this population.