The functional role of lncRNAs as ceRNAs in both ovarian processes and associated diseases.

Long non-coding RNAs (lncRNAs) have attracted significant scientific attention due to their central role in regulating gene expression and their profound impact on the intricate mechanisms of ovarian function. These versatile molecules exert their influence through various mechanisms, including the coordination of transcription processes, modulation of post-transcriptional events, and the shaping of epigenetic landscapes. Furthermore, lncRNAs function as competitive endogenous RNAs (ceRNAs), engaging in intricate interactions with microRNAs (miRNAs) to finely adjust the expression of target genes. The intricate lncRNA-miRNA-mRNA network serves as a crucial determinant in governing the multifaceted physiological functions of the ovaries. It holds substantial potential in unraveling the causes and progression of reproductive disorders and, importantly, in identifying new therapeutic targets and diagnostic markers for these conditions. A comprehensive comprehension of lncRNAs and their ceRNA activities within the domain of ovarian biology could potentially lead to groundbreaking advancements in clinical interventions and management strategies. This exploration of lncRNAs and their intricate involvement in the regulatory framework provides an extensive platform for deciphering the complex nature of ovarian physiology and pathology. The ongoing progress in this field, which encompasses in-depth investigations into the functional roles of specific lncRNAs, the elucidation of their complex interactions with miRNAs, and the comprehensive profiling of their expression patterns, holds the promise of making significant contributions to our understanding of ovarian biology and reproductive disorders. Ultimately, these breakthroughs will have wide-ranging translational implications, paving the way for the development of precision therapies and personalized medicine strategies to address the myriad challenges in the realm of reproductive health.

Human ovarian gross morphology and subanatomy across puberty: insights from tissue donated during fertility preservation.

Objective: To study ovarian gross morphologic and subanatomic features across pubertal development. Design: Prospective cohort study. Setting: An academic medical center with specimens collected from 2018-2022. Patients: Tissue was obtained from prepubertal and postpubertal participants (0.19-22.96 years) undergoing ovarian tissue cryopreservation before treatment that put them at a significantly or high increased risk of developing premature ovarian insufficiency. Most participants (64%) had not received chemotherapy at tissue collection. Interventions: None. Main Outcome Measures: Ovaries procured for fertility preservation were weighed and measured. Ovarian tissue fragments released during processing, biopsies used for pathology, and hormone panels were analyzed for gross morphology, subanatomic features, and reproductive hormones. Graphical analysis of best-fit lines determined age at maximum growth velocity. Results: Prepubertal ovaries were significantly (1.4-fold and 2.4-fold) smaller than postpubertal ovaries by length and width and 5.7-fold lighter on average. Length, width, and weight grew in a sigmoidal pattern with age. Prepubertal ovaries were less likely to display a defined corticomedullary junction (53% vs. 77% in postpubertal specimens), less likely to have a tunica albuginea (22% vs. 93% in postpubertal specimens), contained significantly more (9.8-fold) primordial follicles, and contained primordial follicles at significantly deeper depths (2.9-fold) when compared with postpubertal ovaries. Conclusions: Ovarian tissue cryopreservation is a resource to study human ovarian biology and pubertal development. Maximum growth velocity occurs late within the pubertal transition (Tanner 3+) after changes in subanatomic features. This ovarian morphology model adds to foundational knowledge of human ovarian development and supports ongoing transcriptomics research.

Slowest first passage times, redundancy, and menopause timing.

Biological events are often initiated when a random "searcher" finds a "target," which is called a first passage time (FPT). In some biological systems involving multiple searchers, an important timescale is the time it takes the slowest searcher(s) to find a target. For example, of the hundreds of thousands of primordial follicles in a woman's ovarian reserve, it is the slowest to leave that trigger the onset of menopause. Such slowest FPTs may also contribute to the reliability of cell signaling pathways and influence the ability of a cell to locate an external stimulus. In this paper, we use extreme value theory and asymptotic analysis to obtain rigorous approximations to the full probability distribution and moments of slowest FPTs. Though the results are proven in the limit of many searchers, numerical simulations reveal that the approximations are accurate for any number of searchers in typical scenarios of interest. We apply these general mathematical results to models of ovarian aging and menopause timing, which reveals the role of slowest FPTs for understanding redundancy in biological systems. We also apply the theory to several popular models of stochastic search, including search by diffusive, subdiffusive, and mortal searchers.

Understanding the Ovarian Interrelationship with Low Antral Follicle Counts (AFC) in the In Vivo Bos indicus Cow Model: Unilateral and Bilateral Main AFC as Possible Biomarkers of Ovarian Response to Hormonal Synchronisation.

The antral follicle count (AFC) is a test in which the number of oocyte-containing follicles that are developing in both ovaries are visually counted. The count of these follicles strongly relates to the population of the growing follicle reserve on the ovaries. However, the importance of the main number of antral follicle populations (mAFC) in mono-ovulatory animal species has yet to be completely elucidated. Moreover, the investigation of the ovarian interrelationship with unilateral mAFC (main number of antral follicle populations appearing on only one side of the ovary) and bilateral mAFC (main number of antral follicle populations appearing in equivalent numbers on both sides of the ovary) and how understanding this interrelationship can offer possible indicators of ovarian response to hormonal induction have not yet been investigated in mono-ovulatory Bos indicus beef cows. The aim of this study is to investigate the different ovarian interrelationships of mAFC (unilateral and bilateral mAFC) at the time of exogenous hormonal stimulation on the total number of AFC (left and right ovaries) at the beginning of the hormonal protocol for ovarian stimulation and ovarian response at the completion of exogenous hormonal stimulation as well as their usefulness as possible biomarkers of successful hormonal stimulation in Bos indicus beef cattle. Beef cows (n = 104) with low total numbers of AFC (4.7 ± 2.4 follicles) were stimulated with a gonadotropin-releasing hormone-progesterone-prostaglandin F2α-based protocol. At the beginning of the hormonal protocol, ovarian ultrasound scans were performed to evaluate AFC from both ovaries of cows. Beef cows were divided into two groups, unilateral (n = 74) and bilateral mAFC (n = 30), according to the ovarian interrelationship. At the completion of the hormonal stimulation, ovarian ultrasound scans were performed to evaluate the dominant follicle (DF) and cows with DF > 8.5 mm in diameter emerging on their ovaries were defined as having experienced a response to hormonal stimuli. There was a difference of 19.1% between Bos indicus cows bearing unilateral mAFC that produced an increase in ovarian response (odds ratio = 2.717, p < 0.05) compared to the responsive rate of cows displaying bilateral mAFC (82.4% vs. 63.3%). In unilateral mAFC, cows bearing mAFC ipsilateral to the ovary of dominant follicle (DF) had a higher responsive rate than cows bearing mAFC contralateral to the DF ovary (50.0% vs. 32.4%, p < 0.05). In mAFC ipsilateral to the DF ovary, pregnancy rates were greatest in cows bearing mAFC and DF on the right ovary compared with cows bearing mAFC and DF on the left ovary (25.0% vs. 9.1%, p < 0.05). In primiparous and multiparous cows, unilateral mAFC occurs with a greater (p < 0.05) frequency than bilateral mAFC (69.0% and 72.0% vs. 31.0% and 28.0%, respectively). In unilateral mAFC, primiparous cows bearing mAFC ipsilateral to the DF ovary had a greater responsive rate than primiparous cows bearing mAFC contralateral to the DF ovary (55.0% vs. 20.0%, p < 0.05). In mAFC ipsilateral to the DF ovary, responsive and pregnancy rates were greatest (p < 0.05) in multiparous cows bearing mAFC and DF on the right ovary compared with multiparous cows bearing mAFC and DF on the left ovary (58.1% and 22.6% vs. 25.8% and 3.2%, respectively). Furthermore, there was a positive correlation between the mean diameter of AFC at the time of the exogenous hormonal trigger and the mean diameter of DF at the completion of hormonal synchronisation (p < 0.05). Our findings emphasise that the ovarian interrelationship with unilateral mAFC at the time of the hormonal trigger might be a promising biomarker for predicting success in ovarian response to hormonal stimulation of mono-ovulatory Bos indicus beef cows with low AFCs.

Shorter telomere length of white blood cells is associated with higher rates of aneuploidy among infertile women undergoing in vitro fertilization.

OBJECTIVE: To evaluate whether the telomere length of white blood cells (WBC) and cumulus cells (CC) in an infertile population is associated with ovarian and embryonic performance. DESIGN: Prospective cohort study. SETTING: Academic-affiliated private practice. PATIENTS: A total of 175 infertile women undergoing in vitro fertilization (IVF) at a single center between July 2017 and December 2018. INTERVENTIONS: On the day of oocyte retrieval, genomic DNA was isolated from WBC and CC samples. Telomere length assessment was performed for both tissue types using quantitative real-time polymerase chain reaction. Telomere lengths were normalized using an AluYa5 sequence as an endogenous control, and linear regressions were applied. MAIN OUTCOME MEASURES: This study assessed the relationship between relative telomere length of WBC and CC samples and measures of ovarian and embryonic performance. Specifically, patient age, antimüllerian hormone (AMH) level, peak estradiol (E2) level, number of oocytes retrieved, number of mature (MII) oocytes retrieved, blastulation rate, and aneuploidy rate were assessed. RESULTS: There was a statistically significant relationship between WBC relative telomere length and patient age as well as rates of embryonic aneuploidy, with shorter WBC relative telomere length associated with increasing patient age (P<.01) and higher rates of aneuploidy (P=.01). No statistically significant relationships were observed between WBC relative telomere length and the other outcome measures. No significant associations were noted between CC relative telomere length and any outcomes assessed in this study. CONCLUSION: The relationship between WBC relative telomere length and aneuploidy warrants further investigation, particularly because significant overlap exists between increasing maternal age and rates of embryonic aneuploidy.

Low Molecular Weight Hyaluronan Induces an Inflammatory Response in Ovarian Stromal Cells and Impairs Gamete Development In Vitro.

The ovarian stroma, the microenvironment in which female gametes grow and mature, becomes inflamed and fibrotic with age. Hyaluronan is a major component of the ovarian extracellular matrix (ECM), and in other aging tissues, accumulation of low molecular weight (LMW) hyaluronan fragments can drive inflammation. Thus, we hypothesized that LMW hyaluronan fragments contribute to female reproductive aging by stimulating an inflammatory response in the ovarian stroma and impairing gamete quality. To test this hypothesis, isolated mouse ovarian stromal cells or secondary stage ovarian follicles were treated with physiologically relevant (10 or 100 µg/mL) concentrations of 200 kDa LMW hyaluronan. In ovarian stromal cells, acute LMW hyaluronan exposure, at both doses, resulted in the secretion of a predominantly type 2 (Th2) inflammatory cytokine profile as revealed by a cytokine antibody array of conditioned media. Additional qPCR analyses of ovarian stromal cells demonstrated a notable up-regulation of the eotaxin receptor Ccr3 and activation of genes involved in eosinophil recruitment through the IL5-CCR3 signaling pathway. These findings were consistent with an age-dependent increase in ovarian stromal expression of Ccl11, a major CCR3 ligand. When ovarian follicles were cultured in 10 or 100 µg/mL LMW hyaluronan for 12 days, gametes with compromised morphology and impaired meiotic competence were produced. In the 100 µg/mL condition, LMW hyaluronan induced premature meiotic resumption, ultimately leading to in vitro aging of the resulting eggs. Further, follicles cultured in this LMW hyaluronan concentration produced significantly less estradiol, suggesting compromised granulosa cell function. Taken together, these data demonstrate that bioactive LMW hyaluronan fragments may contribute to reproductive aging by driving an inflammatory stromal milieu, potentially through eosinophils, and by directly compromising gamete quality through impaired granulosa cell function.

Cumulus cells have longer telomeres than leukocytes in reproductive-age women.

OBJECTIVE: To investigate whether telomere length (TL) in granulosa cells (GC) or cumulus cells (CC) correlates with TL in leukocytes (L). DESIGN: Prospective noninterventional study. SETTING: Private assisted reproductive technology center. PATIENT(S): Thirty-five egg donors were included in the study. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): Average relative leukocyte telomere length (LTL), cumulus cell telomere length (CCTL), and granulosa cell telomere length (GCTL) measurements from each study subject. RESULT(S): Participants had a mean age of 25.43 ± 4.57 years, antimüllerian hormone level of 1.90 ± 0.92 ng/mL, antral follicle count of 23.29 ± 5.11, and the mean number of mature oocytes retrieved was 23.29 ± 9.13. No significant association between these variables and GCTL, CCTL, or LTL was found. In addition, no correlation was observed between TL measurements of L vs. CC, L vs. GC, or CC vs. GC. Interestingly, CCTL was significantly higher than LTL (1.54-fold), although no significant differences were found between GCTL vs. CCTL or GCTL vs. LTL. CONCLUSION(S): CC from mature follicles have significantly longer telomeres than L, suggesting that the follicular environment could possess different mechanisms to cope against telomere shortening compared with other somatic tissues. Furthermore, these data do not support the utility of telomere DNA measurement in L as an estimate of TL in follicular cells.