Downregulation of glucose-energy metabolism via AMPK signaling pathway in granulosa cells of diminished ovarian reserve patients.

Glucose metabolism plays a crucial role in the function of granulosa cells (GCs) and the development of follicles. In cases of diminished ovarian reserve (DOR), alterations in these processes can impact female fertility. This study aims to investigate changes in glucose-energy metabolism in GCs of young DOR patients aged 20 to 35 years and their correlation with the onset and progression of DOR. 72 DOR cases and 75 women with normal ovarian reserve (NOR) as controls were included based on the POSEIDON and Bologna criteria. Samples of GCs and follicular fluid (FF) were collected for a comprehensive analysis involving transcriptomics, metabolomics, RT-qPCR, JC-1 staining, and flow cytometry. The study identified differentially expressed genes and metabolites in GCs of DOR and NOR groups, revealing 7 common pathways related to glucose-energy metabolism, along with 11 downregulated genes and 14 metabolites. Key substances in the glucose-energy metabolism pathway, such as succinate, lactate, NADP, ATP, and ADP, showed decreased levels, with the DOR group exhibiting a reduced ADP/ATP ratio. Downregulation of genes involved in glycolysis (HK, PGK, LDH1), the TCA cycle (CS), and gluconeogenesis (PCK) was observed, along with reduced glucose content and expression of glucose transporter genes (GLUT1 and GLUT3) in DOR GCs. Additionally, decreased AMPK pathway activity and impaired mitochondrial function in DOR suggest a connection between mitochondrial dysfunction and disrupted energy metabolism. Above all, the decline in glucose-energy metabolism in DOR is closely associated with its onset and progression. Reduced glucose uptake and impaired mitochondrial function in DOR GCs lead to internal energy imbalances, hindering the AMPK signaling pathway, limiting energy production and supply, and ultimately impacting follicle development and maturation.

Effects of maternal taxane chemotherapy exposure on daughters' ovarian reserve and fertility potential.

OBJECTIVE: To investigate the long-term effects of in utero taxane exposure on exposed daughters' ovarian reserve and reproductive potential. DESIGN: Pregnant dams were treated with a single, human-relevant animal-equivalent dose of saline, docetaxel, or paclitaxel at embryonic day 16.5. In utero-exposed daughters were aged to multiple postnatal time points for ovarian and endocrine analysis or were bred to assess fertility and fecundity. Granddaughters of treated dams were assessed also for ovarian follicle composition and atresia. SETTING: Laboratory study. ANIMALS: C57BL/6 mice. INTERVENTION(S): In utero exposure to saline, docetaxel, or paclitaxel. MAIN OUTCOME MEASURE(S): Ovarian follicle composition, rates of follicle atresia, and rates of multioocyte follicles were analyzed in all exposure groups. Serum hormone levels and oocyte retrieval outcomes following ovarian hyperstimulation were also assessed. Finally, animals from all exposure groups were bred with the number of litters, pups per litter, live births, interlitter time interval, and age at the last litter analyzed. RESULT(S): We found that docetaxel and paclitaxel exposure in utero results in ovarian toxicity later in life, significantly affecting folliculogenesis as well as increasing the rate of follicular abnormalities, including follicle atresia and multioocyte follicles. Furthermore, viability staining indicates that the ovaries of daughters exposed to taxanes in utero demonstrate a significantly higher number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive follicles. Hormone measurements also revealed that serum follicle-stimulating hormone concentration was significantly altered in taxane-exposed daughters, with the ratio of luteinizing hormone to follicle-stimulating hormone significantly elevated, specifically after paclitaxel exposure, coincident with the inability of these animals to properly respond to ovarian stimulation. Breeding studies over the course of a year also suggest that these taxane-exposed mice are fertile, although the duration of their fertility is shortened and they produce significantly fewer litters. Finally, ovarian effects are apparent in granddaughters of mice treated with docetaxel, suggesting persistent and multigenerational effects of taxane exposure. CONCLUSION(S): Our studies demonstrate that in utero exposure to taxane-based therapy during late gestation has a significant effect on the long-term reproductive health of exposed daughters (as well as their daughters) and will be instrumental in helping clinicians better understand which chemotherapies for maternal malignancy are least detrimental to a developing fetus.

The senolytic drug ABT-263 accelerates ovarian aging in older female mice.

Previous studies have reported that senolytic drugs can reverse obesity-mediated accumulation of senescent cells in the ovary and protect against cisplatin-induced ovarian injury by removing senescent cells. Early intervention with ABT-263 has been shown to mitigate ovarian aging. However, it remains unknown whether treatment with ABT-263 could rejuvenate the aged ovary in reproductively old females. Therefore, the current study was aimed to investigate whether advanced age intervention with ABT-263 could ameliorate age-related decline in ovarian function. Fourteen 16-month-old mice with a C57/BL6 background were treated with ABT-263 (N = 7) or vehicle (N = 7) for two weeks. Mice were initially treated with ABT-263 (60 mg/kg/d) or vehicle for 7 consecutive days. After a 7-day break, the treatment was repeated for another 7 consecutive days. Six 2-month-old mice with C57BL/6 were used as a young control. The hormonal levels, estrus cycles, ovarian reserve, ovarian cell proliferation and apoptosis, ovarian fibrosis, and steroidogenic gene expression of ovarian stromal cells were evaluated. ABT-263 treatment did not rescue abnormal estrus cycles and sex hormonal levels, or inhibit the formation of multinucleated giant cells and ovarian stromal cell apoptosis in aged ovaries. However, it reduced ovarian fibrosis and preserved the steroidogenic gene expression of ovarian stromal cells in aged ovaries. Importantly, ABT-263 treatment further depleted ovarian follicles in aged mice. In conclusion, ABT-263 treatment accelerated the depletion of ovarian follicles in aged mice, suggesting that senolytic drugs for reproductively old female may adversely affect female fertility.

Air pollutants and ovarian reserve: a systematic review of the evidence.

Background: Growing evidence indicates an association between ambient air pollution and decreased human reproductive potential. This study aims to systematically review the association between air pollutants and female ovarian reserve. Methods: The literature was searched in six electronic databases through June 2024. Screening the 136 articles retrieved for inclusion criteria resulted in the selection of 15 human observational studies that evaluated the effect of environmental pollutants on ovarian reserve markers. The study protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO, registration code: CRD42023474218). Results: The study design of the selected studies was found to be cross-sectional (2 of 15), retrospective cohort (10 of 15), prospective cohort (2 of 15), and case-control (1 of 15). The study population was distributed as follows: Asians (53%, eight studies), Americans (33%, five studies), and Europeans (14%, two studies). The main findings showed a higher body of evidence for the environmental pollutants PM2.5, PM10, and NO2, while a low body of evidence for PM1, O3, SO2, and a very low body of evidence for benzene, formaldehyde, and benzo(a)pyrene, yet consistently showing significant inverse association data. The overall methodological quality of the selected studies was rated moderated across the 14 domains of the National Institutes of Health (NIH) toolkit. Conclusion: The data suggest that increased exposure to air pollutants seems to be associated with reduced ovarian reserve, with the most substantial evidence for pollutants such as PM2.5, PM10, and NO2. However, more evidence is needed to draw conclusions about causality.

Comparative Analysis of Electrosurgical Energy and Hemostatic Sealant for Hemostasis in Laparoscopic Ovarian Cystectomy: A Randomized Controlled Phase III Study.

STUDY OBJECTIVE: To evaluate the efficacy of hemostatic sealant versus elertrosurgical energy in achieving hemostasis and preserving postoperative ovarian reserve during laparoscopic ovarian cystectomy DESIGN: Randomized controlled trial SETTING: Single center study PATIENTS: A total of 121 patients undergoing laparoscopic ovarian cystectomy INTERVENTIONS: Patients were randomized to receive either hemostatic sealant or elertrosurgical energy for hemostasis during surgery MEASUREMENTS AND MAIN RESULTS: The primary outcome measured was the time required to achieve hemostasis. Secondary outcomes included operating time, estimated blood loss, and assessment of postoperative ovarian reserve through hormone levels (AMH, FSH, E2, Inhibin) at three follow-up intervals. The results showed comparable hemostasis times between the two groups. Postoperative hormone levels indicated no significant differences in the impact on ovarian reserve between the groups, except in cases of bilateral ovarian cystectomy (BOC), where the hemostatic sealant group exhibited a lesser decline in AMH levels. CONCLUSION: Both hemostatic sealant and electrosurgical energy showed equivalent effectiveness in achieving hemostasis during laparoscopic ovarian cystectomy, with comparable results in hemostasis time, blood loss, postoperative complications, and ovarian reserve preservation. However, in cases of bilateral ovarian cystectomy (BOC), the hemostatic sealant group exhibited a lesser decline in AMH levels, suggesting a potential advantage in preserving ovarian reserve in these specific cases.

Influence of sire plane of nutrition and targeted body weight gain on ewe lamb growth, glucose metabolism, and ovarian reserve.

Rambouillet rams were managed on either a positive (POS; gain 12% body weight [BW]; n = 8), maintenance (MAINT; maintain BW; n = 8), or negative (NEG; lose 12% BW; n = 8) plane of nutrition before breeding. Rams were bred to ewes (n = 10 per ram) that were managed similarly throughout gestation, and lambs were fed a common diet postnatally. Two ewe lambs (7.6 ± 0.02 months of age, BW = 47.1 ± 1.17 kg) from each sire were selected and within pair, randomly assigned to be managed for a moderate (MOD, 0.11 kg/d; n = 23) or accelerated (ACC, 0.20 kg/d; n = 22) rate of gain for 56 d. Ewe lamb BW was recorded on a weekly basis and blood was collected on d 0, 28, and 56 for analysis of insulin-like growth factor 1 (IGF-1), triiodothyronine (T3), thyroxine (T4), glucose, blood urea nitrogen (BUN), and non-esterified fatty acids (NEFA). Intravenous glucose tolerance tests (IVGTT) were conducted from d -7 to -4 and d 57 to 64. A unilateral ovariectomy was performed and ovarian follicles were staged and counted macro and microscopically. Sire treatment × day and ewe treatment × day interactions were present for BW (P ≤ 0.05), where POS had slower growth than MAINT and NEG, and tended (P = 0.10) to have reduced average daily gain (ADG) when managed at an accelerated rate of gain.By design, ACC had greater BW and ADG than MOD (P < 0.05). Concentrations of IGF-1 and T4 were greater in ACC than MOD (P ≤ 0.05), and NEG tended to have greater concentrations of IGF-1 than POS and MAINT (P = 0.08). At the first IVGTT, concentration of insulin was influenced by a sire treatment × time interaction (P ≤ 0.05), suggesting impaired secretion in NEG-sires ewes, but no differences in area under the curve (AUC) for glucose, insulin, or their ratio (P ≥ 0.11). No interactive effects of sire and ewe treatment (P ≥ 0.52) were observed at the second IVGTT, but insulin and insulin:glucose ratio were influenced by sire treatment × time (P ≤ 0.02), as NEG had greater insulin concentration at 60 min than MAINT (P = 0.03) and greater AUC than POS and MAINT (P ≤ 0.04). No differences in ovary size, weight, or total counts of macro and microscopic follicles were observed (P ≥ 0.23). Ewes fed ACC had a greater number of small surface follicles (P = 0.02), whereas MOD tended to have a greater number of large surface follicles and tertiary follicles (P < 0.06). These findings suggest that paternal plane of nutrition influences female offspring physiology, particularly at varying growth rates.

Dual trigger or hCG alone: A retrospective analysis on patients with diminished ovarian reserve under in vitro fertilization and embryo transfer (IVF-ET) treatment.

OBJECTIVE: With remarkable deficiency in both oocyte stock and competence, the prognosis of IVF-ET in diminished ovarian reserve (DOR) is obstinately poor, underscoring warranted optimization to current procedures. We compared the efficacy of dual-trigger (hCG plus GnRH-a) and hCG alone on the outcomes for DOR patients. STUDY DESIGN: A total of 381 couples and 857 controlled ovarian stimulation (COS) cycles, and 222 couples and 366 frozen embryo transfer (FET) ones were included. The intermediate outcomes during oocyte retrieval and in vitro culture were compared based on COS dataset, while outcomes after embryo transfer analyzed based on FET dataset. The marginal effect of all study factors and covariates were evaluated with a cluster-weighted GEE model. RESULTS AND CONCLUSION: Neither the intermediate nor implantation outcomes were improved by dual-trigger. The OR values were 1.08 (95 % CI: 0.41-2.78) for retrieval cancellation, 1.33 (95 % CI: 0.89-2.00) for oocyte harvest, 1.04(95 %CI: 0.94-1.15) for viable embryo and 1.03(95 %CI: 0.88-1.19) for top-quality embryo. Similarly, the ORs were 0.90 (95 %CI: 0.62-1.30) for implantation and 0.97 (95 %CI: 0.56-1.69) for clinical pregnancy. This equivalence remained unchanged after adjusting for the covariates such as age, BMI, controlled ovarian stimulation protocols, etc. Thus, dual-trigger cannot provide significant advantage over hCG in related to immediate or clinical outcomes of IVF-ET treatments in DOR patients.

Long Term Postoperative Recurrence Rates and Fertility Outcomes after Endometrioma CO2-Laser Vaporization: a 5 years follow-up experience.

STUDY OBJECTIVE: Although cystectomy remains the gold standard for the surgical treatments of endometriomas, concerns about the negative effect on ovarian reserve are rising. Laser-CO2 vaporization of endometriomas has showed encouraging data on ovarian reserve preservation, postoperative pregnancy rates and recurrency. The aim of this study was to assess postoperative recurrence rate and pregnancy rate in patients with endometriomas managed by CO2 fiber laser vaporization after at least 5 years following surgery. DESIGN: Retrospective study. SETTING: Italian tertiary center from October 2023 to February 2024. PATIENTS: We included women aged >18 years who underwent laparoscopic CO2 fiber laser vaporization for endometriomas. Age ≥ 40 years, previous ovarian surgery, previous salpingectomy or hysterectomy, negative histologic finding for endometriosis or any findings of malignancy at histology were exclusion criteria. INTERVENTION: Ovarian endometriomas were vaporized through laparoscopic CO2 fiber laser. After surgery, patients were included in a surveillance program with periodic clinical follow-up. MEASUREMENTS AND MAIN RESULTS: Seventy-eight patients were included. The mean age was 33.2±4.6 years, the basal AMH was 2.7 ± 1.9 ng/mL and the median diameter of the endometriomas was 4(3-5)cm. The median duration of follow-up was 72.5 months(67-84.5). After surgery, 65.5%(n=36) of women with reproductive desire achieved a pregnancy, 55.6% spontaneously and 44.4% through Assisted Reproduction Techniques, with a mean time to pregnancy of 17.7±18.1 months. A Kaplan-Meier curve for the 7 patients who experienced an ipsilateral recurrence showed that the median time to recurrence was 26 months and the estimated rate of disease-free patients was 91.03% at 100 months (95% CI 82.10%-95.62%). CONCLUSION: CO2 fiber laser vaporization is an effective and safe surgical treatment of ovarian endometriomas, combining the advantage of being an ovarian tissue-sparing technique with long-term post-operative recurrence rate comparable with that described in literature for the cystectomy.

A spotlight on factors influencing the in vitro folliculogenesis of isolated preantral follicles.

Female fertility preservation via complete in vitro folliculogenesis is still chimerical. Due to many factors affecting the efficiency of isolation and culture of preantral follicles, the improvement of techniques geared to fertility preservation in higher mammals seems to be at an impasse. We need an objective view of the current stand to understand how to progress further. As such, a survey was conducted to analyze the relative distribution of studies performed in ten mammalian species on preantral follicle culture available on PubMed. Using the bovine as a reference model, we explore some factors influencing data variation that contribute to the difficulty in reproducing studies. While years of research have enabled the recapitulation of folliculogenesis from as modest as the early antral follicle stage ex vivo, in vitro preantral folliculogenesis remains elusive. Herein, we revisit the classical evidence that laid the foundations for understanding preantral folliculogenesis and review the length, breadth, and depth of information that the era of big data has currently levied. Moving forward, we recognize the urgency of synthesizing the multi-disciplinary approaches to mimic folliculogenesis in vitro to achieve a translational landscape of infertility at individual and large-scale conservation levels.

Effect of body mass index on ovarian reserve and ART outcomes in infertile women: a large retrospective study.

BACKGROUND: Obesity poses a significant global health challenge, with profound implications for women's reproductive health. The relationship between ovarian reserve and body mass index (BMI) remains a subject of debate. While obesity is generally associated with poorer outcomes in assisted reproductive technology (ART), the evidence remains inconclusive. This study aimed to investigate the effect of pre-pregnancy BMI on ovarian reserve and ART outcomes in infertile patients. METHODS: We conducted a retrospective cohort study involving women who underwent in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) procedures at Tongji Hospital between 2016 and 2023. The study included 30,746 initial fresh cycles and 5,721 singleton deliveries. Patients were stratified by age and further categorized into four BMI groups: lean (< 18.5 kg/m²), normal weight (18.5-24.9 kg/m²), overweight (25.0-29.9 kg/m²), and obese (≥ 30.0 kg/m²). The primary endpoints of the study were pregnancy and perinatal outcomes. To explore the association between BMI and these outcomes, we adjusted for relevant confounding factors and utilized multivariate linear regression models, complemented by multifactorial logistic regression analyses. RESULTS: Anti-Müllerian hormone (AMH) levels were significantly lower in the overweight and obese groups compared to the normal weight group. After adjusting for age, a negative correlation was found between AMH and BMI in the age subgroups of 20-30 and 30-35 years. Among women aged 20-35 years, those in the overweight and obese groups had significantly fewer retrieved oocytes, mature oocytes, and two-pronuclear (2PN) embryos than their normal weight counterparts. Despite these differences, pregnancy outcomes in the overweight and obese groups were comparable to those in the normal weight group across all age categories. Additionally, obesity was linked to an increased risk of gestational diabetes mellitus, hypertensive disorders of pregnancy, and macrosomia. CONCLUSIONS: An age-related decrease in AMH levels was evident with increasing BMI. Although being overweight or obese is associated with poorer embryo and perinatal outcomes, it does not seem to have a substantial impact on fertility.

Advanced age woman with diminished ovarian reserve obtained live birth following a zero pronuclei-derived four-cell frozen-thawed embryo transfer on day 4: a case report.

Objective: Advanced maternal age and diminished ovarian reserve (DOR) are challenges in infertile patients for in vitro fertilization-embryo transfer (IVF-ET). This study aimed to investigate the pregnancy outcomes of women with advanced age and DOR undergoing low-quality embryo transfers. Case report: We report a rare case of successful pregnancy resulting from a zero pronuclei (0PN)-derived four-cell embryo transfer on day 4 (D4). An advanced age patient with DOR underwent five unsuccessful embryo transfers. A successful outcome was achieved when the patient underwent a hormone replacement FET cycle and received 0PN-derived four-cell frozen-thawed cleavage embryo transfer on D4. Fourteen days after the transfer, her serum ß-human chorionic gonadotropin level was 575.3 mIU/mL. Subsequent prenatal examinations were normal, and the patient delivered a full-term healthy baby girl by caesarean section. Achieving a successful pregnancy after 0PN-derived four-cell frozen-thawed embryo transfer on D4 is rare. This increasingly exhibits significance for advanced age patients with DOR. Conclusion: Selectively transferring embryos with slow growth but low fragments and no evident damage is beneficial for advanced age patients with DOR. For these individuals, obtaining embryos is challenging. Therefore, a personalized embryo transfer strategy should be considered to increase the possibility of pregnancy.

Conception vessel acupuncture research regularity in the treatment of diminished ovarian reserve: a multi-center, large-sample prospective cohort study protocol.

Background: Diminished ovarian reserve (DOR) refers to a decrease in the number or quality of oocytes in the ovarian cortex, which is a degenerative disease of the reproductive system, and can further develop into premature ovarian failure. There are few studies on acupuncture and moxibustion for DOR, which are still in the exploratory stage. Methods/design: This study was a real-world case registry study. According to whether the subjects received conception vessel acupuncture or not, they were divided into the basic treatment combined with conception vessel acupuncture group and the basic treatment group. A total of 1221 patients with DOR were enrolled and treated for 12 weeks. The percentage of patients with ≥30% improvement in anti-Müllerian hormone (AMH) was evaluated at the end of week 12. Secondary outcomes included Antral follicle count (AFC), modified Kupperman scale, basal FSH level, LH level, FSH/LH ratio, positive pregnancy, clinical pregnancy, early spontaneous abortion, ongoing pregnancy, and ectopic pregnancy. Discussion: This study provides clinical evidence and theoretical support for the treatment of DOR with conception vessel acupuncture and moxibustion, so as to guide and improve the efficacy of acupuncture and moxibustion. Trial registration: Acupuncture-Moxibustion Clinical Trial Registry ChiCTR2400080471. Registered on 30 January 2024.

Metabolic Risk in Patients with a Diminished Ovarian Reserve and Premature Ovarian Insufficiency.

Objective: Diminished ovarian reserve (DOR) and premature ovarian insufficiency (POI) represent conditions of different severity, characterized by an earlier-than-expected decrease in ovarian activity. The present study aims to compare metabolic disturbances between women with DOR and patients with POI from a different origin. Materials and methods: A total of 226 women (28 healthy women; 77 individuals with DOR, and 121 patients with POI/36 with Turner syndrome [TS] and 85 with non-TS POI/) have been studied retrospectively. Data concerning anthropometric indices, and metabolic parameters were collected. Results: Patients with DOR, non-TS POI, and TS had increased blood pressure and liver enzymes, pronounced insulin resistance, and worse lipid profiles than controls (p < 0.008 for all). TS patients had significantly higher ASAT, GGT, and TSH levels compared to non-TS POI and DOR individuals. The prevalence of type 2 diabetes tended to be higher in TS women compared to other groups. The prevalence of previously diagnosed polycystic ovarian syndrome was lower in the non-TS POI patients than in the DOR patients (p = 0.005). Conclusions: patients with decreased ovarian function suffer from insulin resistance, abnormal lipid profile, and subtle hepatic disturbances, irrespective of the severity of the condition and the presence of chromosomal aberrations.

Immune checkpoint inhibitor treatment does not impair ovarian or endocrine function in a mouse model of triple negative breast cancer.

Background: Representing 15-20% of all breast cancer cases, triple negative breast cancer (TNBC) is diagnosed more frequently in reproductive-age women and exhibits higher rates of disease metastasis and recurrence when compared with other subtypes. Few targeted treatments exist for TNBC, and many patients experience infertility and endocrine disruption as a result of frontline chemotherapy treatment. While they are a promising option for less toxic therapeutic approaches, little is known about the effects of immune checkpoint inhibitors on reproductive and endocrine function. Results: Our findings in a syngeneic TNBC mouse model revealed that therapeutically relevant immunotherapies targeting PD-1, LAG-3, and TIM-3 had no effect on the quality and abundance of ovarian follicles, estrus cyclicity, or hormonal homeostasis. Similarly, in a tumor-free mouse model, we found that ovarian architecture, follicle abundance, estrus cyclicity, and ovulatory efficiency remain unchanged by PD-1 blockade. Conclusions: Taken together, our results suggest that immunotherapy may be a promising component of fertility-sparing therapeutic regimens for patients that wish to retain ovarian and endocrine function after cancer treatment.

Association between sleep quality and ovarian reserve in women of reproductive age: a cross-sectional study.

OBJECTIVE: To evaluate the association between sleep quality and ovarian reserve among women of reproductive age. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): A total of 1,070 female participants aged 20-40 years enrolled from February 2023 to January 2024. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): A questionnaire was administered to the participants to collect baseline information related to reproductive and lifestyle factors. Pittsburgh Sleep Quality Index (PSQI) was used to measure sleep quality. The assessment was conducted on ovarian reserve, including total antral follicle count (AFC), antimüllerian hormone (AMH) level, and basal sex hormone level. RESULT(S): The study sample of 1,070 women had a mean age of 31.67 ± 4.41 years. A total of 314 participants (29.35%) were classified under the poor sleep group (PSQI score >5). Significant differences were observed in the follicle-stimulating hormone (FSH), luteinizing hormone, estradiol, testosterone, AFC, and AMH between the two groups. The poor sleep group exhibited significantly lower levels of AMH and AFC. The FSH levels in the poor sleep group were higher. After the adjustment for confounding factors, multivariate regression analysis results indicated that the per unit increase in PSQI score was associated with increased odds of diminished ovarian reserve (adjusted odds ratio [AOR] of 1.28 for AMH <1.1 ng/mL; 95% confidence interval [CI], 1.20-1.37; AFC <7; AOR, 1.34; 95% CI, 1.25-1.43; FSH ≥10 mIU/mL; AOR, 1.16; 95% CI, 1.08-1.25; AMH <1.1 ng/mL or AFC <7 or FSH ≥10 mIU/mL; AOR, 1.29; 95% CI, 1.22-1.37). Compared with the PSQI ≤5 group, subjects with PSQI >5 had increased odds of diminished ovarian reserve (odds ratio, 3.80; 95% CI, 2.82-5.13; AOR, 4.43; 95% CI, 3.22-6.14). After stratification by age and body mass index, compared with the PSQI ≤5 group, all subgroups of the PSQI >5 group had increased odds of diminished ovarian reserve, especially <35-year-old and body mass index ≤18.4 kg/m2 subgroups. CONCLUSION(S): Poor sleep quality is associated with diminished ovarian reserve in women of reproductive age.

Ovarian reserve does not influence natural conception: insights from infertile women.

PURPOSE: There is several albeit not univocal evidence suggesting that ovarian reserve is not related to the chance of natural pregnancy, provided that the remnant follicular pool is sufficient to ensure regular menstrual cycles. Nevertheless, available studies have some methodological limitations, and the issue cannot be considered definitively ascertained. METHODS: To further address this issue, we retrospectively selected infertile women whose infertility diagnostic work-up was unremarkable (unexplained infertility-cases) and matched them by age and study period to a group of infertile women who were diagnosed with severe male infertility (controls). If ovarian reserve impacts on natural fertility, one had to expect lower ovarian reserve among women with unexplained infertility. Tested biomarkers included AMH, AFC and day 2-3 serum FSH. The primary aim was the frequency of women with serum AMH < 0.7 ng/ml. RESULTS: Two-hundred fifty-two women with unexplained infertility and 252 women with male infertility were included. All biomarkers of ovarian reserve did not differ between the study groups. AMH levels < 0.7 ng/mL were observed in 26 (10%) women with unexplained infertility and 35 (14%) women with male infertility (p = 0.28). The adjusted OR was 0.76 (95% CI: 0.44-1.33). Significant differences did not also emerge when repeating this dichotomous analysis using other biomarkers and other thresholds for the definition of low-ovarian reserve. CONCLUSION: This study confirms that ovarian reserve is unremarkable to natural conception. Physicians and patients should be aware of this concept to avoid inappropriate counseling and undue clinical decisions.

Artificial intelligence in reproductive endocrinology: an in-depth longitudinal analysis of ChatGPTv4's month-by-month interpretation and adherence to clinical guidelines for diminished ovarian reserve.

OBJECTIVE: To quantitatively assess the performance of ChatGPTv4, an Artificial Intelligence Language Model, in adhering to clinical guidelines for Diminished Ovarian Reserve (DOR) over two months, evaluating the model's consistency in providing guideline-based responses. DESIGN: A longitudinal study design was employed to evaluate ChatGPTv4's response accuracy and completeness using a structured questionnaire at baseline and at a two-month follow-up. SETTING: ChatGPTv4 was tasked with interpreting DOR questionnaires based on standardized clinical guidelines. PARTICIPANTS: The study did not involve human participants; the questionnaire was exclusively administered to the ChatGPT model to generate responses about DOR. METHODS: A guideline-based questionnaire with 176 open-ended, 166 multiple-choice, and 153 true/false questions were deployed to rigorously assess ChatGPTv4's ability to provide accurate medical advice aligned with current DOR clinical guidelines. AI-generated responses were rated on a 6-point Likert scale for accuracy and a 3-point scale for completeness. The two-phase design assessed the stability and consistency of AI-generated answers over two months. RESULTS: ChatGPTv4 achieved near-perfect scores across all question types, with true/false questions consistently answered with 100% accuracy. In multiple-choice queries, accuracy improved from 98.2 to 100% at the two-month follow-up. Open-ended question responses exhibited significant positive enhancements, with accuracy scores increasing from an average of 5.38 ± 0.71 to 5.74 ± 0.51 (max: 6.0) and completeness scores from 2.57 ± 0.52 to 2.85 ± 0.36 (max: 3.0). It underscored the improvements as significant (p < 0.001), with positive correlations between initial and follow-up accuracy (r = 0.597) and completeness (r = 0.381) scores. LIMITATIONS: The study was limited by the reliance on a controlled, albeit simulated, setting that may not perfectly mirror real-world clinical interactions. CONCLUSION: ChatGPTv4 demonstrated exceptional and improving accuracy and completeness in handling DOR-related guideline queries over the studied period. These findings highlight ChatGPTv4's potential as a reliable, adaptable AI tool in reproductive endocrinology, capable of augmenting clinical decision-making and guideline development.

Therapeutic management in women with a diminished ovarian reserve: a systematic review and meta-analysis of randomized controlled trials.

IMPORTANCE: The clinical management of women with diminished ovarian reserve (DOR) is a challenge in the field of medically assisted reproduction. Several therapeutic strategies have been proposed, but with mixed results, mainly because the definition of DOR used was inconsistent among trials. OBJECTIVE: To investigate adjuvant treatments and protocols involving only women with DOR according to POSEIDON criteria. DATA SOURCES: We conducted a systematic search using the MEDLINE (PubMed), EMBASE, and ISI Web of Knowledge databases to identify relevant studies published up to June 2024. The review protocol was registered at http://www.crd.york.ac.uk/PROSPERO/ (registration number CRD42022346117). STUDY SELECTION AND SYNTHESIS: After duplication removal, the titles and abstracts of 4,806 articles were scrutinized, and 124 full-text articles were assessed for eligibility. In total, 38 randomized controlled trials were included in the qualitative/quantitative analysis. The following interventions were evaluated: dehydroepiandrosterone (n = 1,336), testosterone (n = 418), high- versus low-dose gonadotropin (n = 957), delayed-start protocol with GnRH antagonist (n = 398), letrozole (n = 612), clomiphene citrate (1,113), growth hormone (311), luteal phase stimulation (n = 57), dual triggering (n = 139), dual stimulation (168), luteinizing hormone (979), oestradiol pre-treatment (n = 552), and corifollitropin alfa (n = 561). RESULTS: Testosterone supplementation is associated with higher live birth rates compared with non-supplemented women among all interventions evaluated (OR 2.19, 95% CI 1.11-4.32, 4 studies, 368 patients; p = 0.02). Testosterone (WMD 0.88, 95% CI 0.03-1.72; 4 studies, n = 368 patients; p = 0.04), DHEA (WMD 0.60, 95% CI 0.07-1.13; 4 studies, n = 418 patients; p = 0.03), high-dose gonadotropin regimen (WMD -1.57, 95% CI -2.12 to -1.17; 2 studies, n = 905 patients; p < 0.0001) and delayed started protocol (WMD 1.32, 95% CI 0.74 to 1.89; 3 studies, n = 398 patients; p < 0.00001) significantly improved the total number of eggs collected. The other interventions did not produce significant improvements. CONCLUSION AND RELEVANCE: Specific interventions such as testosterone seem to correlate with a better live birth rate in women with diminished ovarian reserve; these findings should be further explored in randomized trials.

A Mega-Analysis of Anti-Müllerian Hormone Levels in Female Childhood Cancer Survivors Based on Treatment Risk, Time since Treatment, and Pubertal Status.

Purpose: Female childhood cancer survivors (CCSs) risk infertility due to gonadotoxic chemotherapy/radiation. Anti-Müllerian hormone (AMH) helps evaluate ovarian reserve, and the 2020 Oncofertility Pediatric Initiative Network (O-PIN) risk stratification is utilized to counsel risk of gonadal dysfunction/infertility. This study analyzed how AMH levels after cancer treatment differ with age and correlate AMH with O-PIN risk level and clinical outcomes. Methods: A literature review and mega-analysis of individual patient data were performed. Females ages 0-20 years at the time of cancer diagnosis with AMH values post-treatment were included. AMH outcomes were compared by O-PIN risk stratification, age at diagnosis, cyclophosphamide equivalent dose (CED), and hematopoietic stem cell transplant (HSCT). Multivariable random effects mixed models correlated AMH with diminished ovarian reserve (DOR), premature ovarian insufficiency (POI), and pregnancy. Results: In 13 studies with 608 CCSs, the median age (years) at diagnosis was 12.0 (interquartile range [IQR] 5.2-16.2) and 21.1 (IQR 17.1-30.0) at AMH measurement. AMH values were higher with time since treatment and correlated with the O-PIN risk level. Patients with HSCT had very low/undetectable AMH levels regardless of CED; when stratified by CED, AMH levels were lower if treated peripubertally or older. AMH was detectable in 54% (34/63) of patients with POI on hormone replacement. Pregnancy did not correspond to the gonadotoxicity risk level (p = 0.70). Conclusion: This study supports utilizing the O-PIN risk stratification system in estimating risk of DOR in CCSs and its categorization by pubertal status. AMH levels may return over time even after receiving the highest risk therapy. These findings may help counsel cancer patients pre- and post-therapy.

Anti-Müllerian hormone as a predictor of the number of oocytes obtained during in vitro fertilization treatments.

OBJECTIVE: To evaluate the correlation between serum anti-Müllerian hormone (AMH) and the number of oocytes retrieved after controlled ovarian stimulation for in vitro fertilization treatments and determine cut-off values predictive of poor and high response to stimulation. METHODS: It was performed a retrospective observational study that included 1003 cycles of controlled ovarian stimulation carried between February 2017 and December 2023 at a Medically Assisted Procreation Centre. The exclusion criteria were the following: serum AMH levels obtained more than 6 months prior to the start of the ovarian stimulation, the presence of a single ovary, non-Caucasian ethnicity, a controlled ovarian stimulation cycle performed for the purpose of oocyte donation or fertility preservation, a documented diagnosis of endometriosis, a documented history of ovarian surgery and the absence of essential data for the study in the medical records (absence of the number of oocytes obtained or the AMH value). Poor response to stimulation was defined as ≤ 3 oocytes retrieved, and high response was defined as > 15 oocytes. The correlation between variables was calculated using Spearman's correlation test and cut-off values were determined using ROC (Receiver Operating Characteristic) curves. RESULTS: AMH exhibited a significantly positive correlation with the number of oocytes retrieved (Spearman's correlation coefficient = 0.60, p<0.01). The predictive cut-off for poor ovarian response was 0.72 ng/mL (specificity of 95.13%, sensitivity of 43.23%), and the predictive cut-off for high ovarian response was 4.77 ng/mL (specificity of 89.86%, sensitivity of 38.22%). CONCLUSIONS: Serum AMH proved to be a good predictor of the ovarian response to controlled ovarian stimulation for in vitro fertilization treatments, which makes it useful in supporting clinical decision-making. However, it should not be used as an absolute discriminator of poor or high ovarian response.