High-altitude hypoxia exposure alters follicular metabolome and oocyte developmental potential in women.

PURPOSE: To explore the effects of high-altitude hypoxia on the microenvironment of oocyte development and fertilization potential, we compared the metabolomic patterns of follicular fluid from women living in different altitude areas and traced their oocyte maturation and subsequent development. METHODS: A total of 315 clinical cases were collected and divided into three groups according to their residence altitudes: 138 cases in low-altitude (< 2300 m) group, 100 cases in middle-altitude (2300-2800 m) group and 77 cases in high-altitude (> 2800 m) group. The clinical outcomes were statistically estimated, including hormonal level, oocyte maturation, in vitro fertilization, and embryo development. Meanwhile, a metabolomic analysis was performed on the follicular fluid of women from different groups using ultra-high-performance liquid chromatography and high-resolution mass spectrometry and differential metabolites were analyzed through the KEGG pathway. RESULTS: The clinical data indicated that the physical condition and reproductive hormone secretion were similar among different groups. Although personalized gonadotropin-releasing hormone strategies were applied, the numbers of antral follicles and obtained oocytes were not impacted by the residence altitude change. In in vitro culture, the maturing rate, fertility rate and cleavage rate of high-altitude group were compared with the other groups. However, the rates of high-quality embryo, formative blastocyst, and available blastocyst were gradually decreased with the rise of residence altitude. Metabolome analysis identified 1193 metabolites in female follicular fluid. Differential analysis indicated that metabolic components in follicular fluid were remarkably changed with the elevation of residence altitude. These differential metabolites were closely related with amino acid metabolism, protein digestion and absorption, oocyte meiosis and steroid biosynthesis. CONCLUSION: The residence altitude alters the microenvironment of follicular fluid, which could damage the oocyte developmental potential. This study provides diagnostic basis and therapeutic targets for research on female oocyte and embryo development.

Which is the current knowledge on man-made endocrine- disrupting chemicals in follicular fluid? An overview of effects on ovarian function and reproductive health.

The increase in female reproductive disorders, such as polycystic ovary syndrome, endometriosis, and diminished ovarian reserve that lead to subfertility and infertility, has encouraged researchers to search and discover their underlying causes and risk factors. One of the crucial factors that may influence the increasing number of reproductive issues is environmental pollution, particularly exposure to man-made endocrine-disrupting chemicals (EDCs). EDCs can interfere with the ovarian microenvironment, impacting not only granulosa cell function but also other surrounding ovarian cells and follicular fluid (FF), which all play essential roles for oocyte development, maturation, and overall reproductive function. FF surrounds developing oocytes within an ovarian follicle and represents a dynamic milieu. EDCs are usually found in biological fluids, and FF is therefore of interest in this respect. This narrative review examines the current knowledge on specific classes of EDCs, including industrial chemicals, pesticides, and plasticizers, and their known effects on hormonal signaling pathways, gene expression, mitochondrial function, oxidative stress induction, and inflammation in FF. We describe the impact of EDCs on the development of reproductive disorders, oocyte quality, menstrual cycle regulation, and their effect on assisted reproductive technique outcomes. The potential transgenerational effects of EDCs on offspring through animal and first-human studies has been considered also. While significant progress has been made, the current understanding of EDCs' effects on ovarian function, particularly in humans, remains limited, underscoring the need for further research to clarify actions and effects of EDCs in the ovary.

COVID-19 and Female Fertility: An Observational Prospective Multicenter Cohort Study: Upholding Reproductive Rights in Emergency Circumstances.

OBJECTIVES: Currently available research data points to COVID-19-related multi-organ system damage. This study aims to evaluate the impact of SARS-CoV-2 on the reproductive health, that is, plasma levels of FSH, LH, estradiol, AMH, and antral follicular count, of women undergoing level II ART techniques. METHODS: This is a multicenter, prospective, and observational study by the reproductive medicine centers of Palermo's Ospedali Riuniti Villa Sofia-Cervello Hospital and Vanvitelli University. From September 2022 to March 2024, 203 patients aged 24-43 were enrolled, all with diagnosed infertility and a history of SARS-CoV-2 infection. Symptomatic women, patients testing positive for HIV or other liver viruses, and patients with a history of ovarian cancer or who had taken gonadotoxic drugs were excluded. Plasma measurements of FSH, LH, estradiol, AMH, and antral follicular count were performed before and after infection. RESULTS: The analysis accounting for the concentration of anti-Müllerian hormone (AMH) before and after COVID-19 infection shows an average concentration decrease from 1.33 ng/mL before SARS-CoV-2 infection to 0.97 ng/mL after infection. Average decrease after infection was -27.4%; average reduction of 1 follicle (95% CI: from -0.74 to -1.33) was reported following SARS-CoV-2 infection. Levels of E2 before and after SARS-CoV-2 infection did not vary significantly. Average FSH and LH levels before and after SARS-CoV-2 infection pointed to an increase. CONCLUSIONS: SARS-CoV-2 infection damages female reproductive health, causing significant reductions in AMH (-27.4%) and AFC (-1 antral follicle) values and an increase in FSH (+13.6%) and LH (+13.4%) values. No effect on E2 levels was reported. The pandemic has also affected the ability of infertile patients to access ART procedures, and that calls for a novel, updated blueprint designed to enhance our preparedness in the event that similar circumstances should occur again.

Exploring stem cell technology: Pioneering new pathways for female fertility preservation and restoration.

The fertility of women is crucial for the well-being of individuals and families. However, various factors such as chemotherapy, lifestyle changes, among others, may lead to a decline in female fertility, thus emphasizing the significance of preserving and restoring fertility. Stem cells, with their unique capacity for self-renewal and pluripotent differentiation, have made significant strides in areas such as ovarian tissue cryopreservation, in vitro culture of frozen-thawed ovarian tissue, and construction of ovarian-like organs. This review aims to summarize the latest findings in these fields, highlighting the pivotal role, mechanisms, and future prospects of stem cell technology in preserving and restoring female fertility. Additionally, the importance of interdisciplinary collaboration is underscored, as personalized stem cell therapy regimens tailored through interdisciplinary cooperation between reproductive medicine and stem cell fields hold promise in providing reliable solutions for the preservation and restoration of female fertility.

Myosuppressin signaling deficiency affects ovarian development via repression of 20-hydroxyecdysone biosynthesis in Grapholita molesta.

The steroid 20-hydroxyecdysone (20E) is crucial in regulating ovarian development. However, the neuropeptidergic mechanisms underlying ovarian development via 20E are underexplored. In this study, we investigated myosuppressin (MS) signaling in the dominant fruit pest Grapholita molesta and revealed that MS signaling is necessary for 20E biosynthesis during ovarian maturation. Pharmacological and molecular docking analyses confirmed that the GmMS mature peptide could activate its receptor GmMSR. Additionally, transcript expression analyses of GmMS and GmMSR showed different distribution patterns in adults. Notably, GmMSR was also detected in the ovaries of sexually mature females. RNAi-mediated dysfunction of GmMS or GmMSR specifically decreased fertility in females. Furthermore, GmMS or GmMSR knockdown decreased vitellogenin synthesis and uptake, thereby delaying ovarian development. RNA-seq, gene expression validation, and hormone quantification further revealed that GmMS signaling depletion blocked 20E biosynthesis in the ovary. Finally, exogenous MS rescued most dsGmMS- or dsGmMSR-induced ovarian defects and 20E titers. These results suggest that MS/MSR-to-20E signaling regulates ovarian development through vitellogenesis, providing a new perspective on the development of neuroendocrine targets that suppress pest field populations.

Building a Human Ovarian Antioxidant ceRNA Network "OvAnOx": A Bioinformatic Perspective for Research on Redox-Related Ovarian Functions and Dysfunctions.

The ovary is a major determinant of female reproductive health. Ovarian functions are mainly related to the primordial follicle pool, which is gradually lost with aging. Ovarian aging and reproductive dysfunctions share oxidative stress as a common underlying mechanism. ROS signaling is essential for normal ovarian processes, yet it can contribute to various ovarian disorders when disrupted. Therefore, balance in the redox system is crucial for proper ovarian functions. In the present study, by focusing on mRNAs and ncRNAs described in the ovary and taking into account only validated ncRNA interactions, we built an ovarian antioxidant ceRNA network, named OvAnOx ceRNA, composed of 5 mRNAs (SOD1, SOD2, CAT, PRDX3, GR), 10 miRNAs and 5 lncRNAs (XIST, FGD5-AS1, MALAT1, NEAT1, SNHG1). Our bioinformatic analysis indicated that the components of OvAnOx ceRNA not only contribute to antioxidant defense but are also involved in other ovarian functions. Indeed, antioxidant enzymes encoded by mRNAs of OvAnOx ceRNA operate within a regulatory network that impacts ovarian reserve, follicular dynamics, and oocyte maturation in normal and pathological conditions. The OvAnOx ceRNA network represents a promising tool to unravel the complex dialog between redox potential and ovarian signaling pathways involved in reproductive health, aging, and diseases.

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.

The Effect of Nutrient Supplementation on Female Fertility: A Systematic Review.

Assisted reproductive technologies (ART) have improved infertility treatment but reproductive outcomes remain challenging. Nutrient supplementation is being explored to enhance pregnancy rates, increase live birth rates, and reduce miscarriage rates in females undergoing ART. Nutrients like folic acid, omega-3 fatty acids, and antioxidants have shown potential benefits, yet conflicting results exist. Live birth rates may also be influenced by nutrient supplementation, with coenzyme Q10 and vitamin D showing promise. Miscarriage rates may be reduced with nutrients such as vitamin D, omega-3 fatty acids, and antioxidants, although more research is needed for definitive conclusions. Scientific and medical literature databases such as Cochrane Library, PubMed, and Web of Science were queried to identify relevant English publications adhering to predetermined inclusion and exclusion criteria. Various reproductive metrics, encompassing biochemical pregnancy rate, clinical pregnancy rate, ongoing pregnancy rate, implantation rate, live birth rates, and miscarriage rates, were assessed as clinical endpoints. The study population included 996 female subjects receiving ART. Two studies performed investigations on subjects diagnosed with unexplained infertility, two studies specifically included polycystic ovary syndrome patients, and five studies did not provide any specific information on the type of infertility or subfertility. All studies reported on the clinical/ongoing pregnancy rate, among which four included studies observed a significantly higher rate. Out of the four studies that reported on implantation rates, three found significantly higher rates in treatment groups. Out of the three studies that reported on biochemical pregnancy rates, two studies found significantly higher rates in treatment groups. With respect to the clinical outcomes that were studied in this analysis, variable effects of nutritional supplementation on reproductive parameters were observed. Some studies reported significantly higher rates of clinical/ongoing pregnancy, implantation, biochemical pregnancy, and live birth, while no significant difference was found in miscarriage rates.

Calcium signaling in oocyte quality and functionality and its application.

Calcium (Ca2+) is a second messenger for many signal pathways, and changes in intracellular Ca2+ concentration ([Ca2+]i) are an important signaling mechanism in the oocyte maturation, activation, fertilization, function regulation of granulosa and cumulus cells and offspring development. Ca2+ oscillations occur during oocyte maturation and fertilization, which are maintained by Ca2+ stores and extracellular Ca2+ ([Ca2+]e). Abnormalities in Ca2+ signaling can affect the release of the first polar body, the first meiotic division, and chromosome and spindle morphology. Well-studied aspects of Ca2+ signaling in the oocyte are oocyte activation and fertilization. Oocyte activation, driven by sperm-specific phospholipase PLCζ, is initiated by concerted intracellular patterns of Ca2+ release, termed Ca2+ oscillations. Ca2+ oscillations persist for a long time during fertilization and are coordinately engaged by a variety of Ca2+ channels, pumps, regulatory proteins and their partners. Calcium signaling also regulates granulosa and cumulus cells' function, which further affects oocyte maturation and fertilization outcome. Clinically, there are several physical and chemical options for treating fertilization failure through oocyte activation. Additionally, various exogenous compounds or drugs can cause ovarian dysfunction and female infertility by inducing abnormal Ca2+ signaling or Ca2+ dyshomeostasis in oocytes and granulosa cells. Therefore, the reproductive health risks caused by adverse stresses should arouse our attention. This review will systematically summarize the latest research progress on the aforementioned aspects and propose further research directions on calcium signaling in female reproduction.

Impact of Bisphenol A and its alternatives on oocyte health: a scoping review.

BACKGROUND: Bisphenol A (BPA) is an endocrine disrupting chemical released from plastic materials, including food packaging and dental sealants, persisting in the environment and ubiquitously contaminating ecosystems and human populations. BPA can elicit an array of damaging health effects and, alarmingly, 'BPA-free' alternatives mirror these harmful effects. Bisphenol exposure can negatively impact female fertility, damaging both the ovary and oocytes therein. Such damage can diminish reproductive capacity, pregnancy success, and offspring health. Despite global government regulations in place to indicate 'safe' BPA exposure levels, these policies have not considered the effects of bisphenols on oocyte health. OBJECTIVE AND RATIONALE: This scoping review was conducted to evaluate evidence on the effects of BPA and BPA alternatives on standardized parameters of oocyte health. In doing so, this review addresses a critical gap in the literature providing a comprehensive, up-to-date synthesis of the effects of bisphenols on oocyte health. SEARCH METHODS: This scoping review was conducted in accordance with PRISMA guidelines. Four databases, Medline, Embase, Scopus, and Web of Science, were searched twice (23 February 2022 and 1 August 2023) to capture studies assessing mammalian oocyte health post-bisphenol exposure. Search terms regarding oocytes, ovarian follicles, and bisphenols were utilized to identify relevant studies. Manuscripts written in English and reporting the effect of any bisphenol on mammalian oocyte health from all years were included. Parameters for toxicological studies were evaluated, including the number of bisphenol concentrations/doses tested, dosing regimen, biological replicates and/or animal numbers, and statistical information (for human studies). Standardized parameters of oocyte health including follicle counts, oocyte yield, oocyte meiotic capacity, morphology of oocyte and cumulus cells, and oocyte meiotic spindle integrity were extracted across the studies. OUTCOMES: After screening 3147 studies, 107 studies of either humans or mammalian animal models or humans were included. Of the in vitro exposure studies, 96.3% (26/27) and 94.1% (16/17) found at least one adverse effect on oocyte health using BPA or BPA alternatives (including BHPF, BPAF, BPB, BPF, and BPS), respectively. These included increased meiotic cell cycle arrest, altered morphology, and abnormal meiotic spindle/chromosomal alignment. In vivo, 85.7% (30/35) of studies on BPA and 92.3% (12/13) on BPA alternatives documented adverse effects on follicle development, morphology, or spindle/chromosome alignment. Importantly, these effects were recorded using levels below those deemed 'safe' for human exposure. Over half (11/21) of all human observational studies showed associations between higher urinary BPA levels and reduced antral follicle counts or oocyte yield in IVF patients. Recommendations are presented based on the identified shortcomings of the current evidence, incorporating elements of FDA requirements for future research in the field. WIDER IMPLICATIONS: These data highlight the detrimental impacts of low-level BPA and BPA alternative exposure, contributing to poor oocyte quality and reduced fertility. These outcomes are valuable in promoting the revision of current policies and guidelines pertaining to BPA exposure internationally. This study serves as a valuable resource to scientists, providing key recommendations on study design, reporting elements, and endpoint measures to strengthen future studies. Ultimately, this review highlights oocyte health as a fundamentally important endpoint in reproductive toxicological studies, indicating an important direction for future research into endocrine disrupting chemicals to improve fertility outcomes.

Evolutionary Analysis of the Mammalian IL-17 Cytokine Family Suggests Conserved Roles in Female Fertility.

PROBLEM: The interleukin-17 (IL-17) family includes pro-inflammatory cytokines IL-17A-F with important roles in mucosal defence, barrier integrity and tissue regeneration. IL-17A can be dysregulated in fertility complications, including pre-eclampsia, endometriosis and miscarriage. Because mammalian subclasses (eutherian, metatherian, and prototherian) have different related reproductive strategies, IL-17 genes and proteins were investigated in the three mammalian classes to explore their involvement in female fertility. METHOD OF STUDY: Gene and protein sequences for IL-17s are found in eutherian, metatherian and prototherian mammals. Through synteny and multiple sequence protein alignment, the relationships among mammalian IL-17s were inferred. Publicly available datasets of early pregnancy stages and female fertility in therian mammals were collected and analysed to retrieve information on IL-17 expression. RESULTS: Synteny mapping and phylogenetic analyses allowed the classification of mammalian IL-17 family orthologs of human IL-17. Despite differences in their primary amino acid sequence, metatherian and prototherian IL-17s share the same tertiary structure as human IL-17s, suggesting similar functions. The analysis of available datasets for female fertility in therian mammals shows up-regulation of IL-17A and IL-17D during placentation. IL-17B and IL-17D are also found to be over-expressed in human fertility complication datasets, such as endometriosis or recurrent implantation failure. CONCLUSIONS: The conservation of the IL-17 gene and protein across mammals suggests similar functions in all the analysed species. Despite significant differences, the upregulation of IL-17 expression is associated with the establishment of pregnancy in eutherian and metatherian mammals. The dysregulation of IL-17s in human reproductive disorders suggests them as a potential therapeutic target.

Redox Balance and Inflammatory Response in Follicular Fluids of Women Recovered by SARS-CoV-2 Infection or Anti-COVID-19 Vaccinated: A Combined Metabolomics and Biochemical Study.

To date, not many studies have presented evidence of SARS-CoV-2 infecting the female reproductive system. Furthermore, so far, no effect of the administration of anti-COVID 19 vaccines has been reported to affect the quality of oocytes retrieved from women who resorted to assisted reproduction technology (ART). The FF metabolic profiles of women who had been infected by SARS-CoV-2 before IVF treatments or after COVID-19 vaccination were examined by 1H NMR. Immunochemical characterization of proteins and cytokines involved in the redox and inflammatory pathways was performed. The increased expression of SOD2 and NQO1, the lack of alteration of IL-6 and CXCL10 levels, as well as the increased expression of CD39, suggested that, both sharing similar molecular mechanisms or proceeding along different routes, the redox balance is controlled in the FF of both vaccinated and recovered women compared to controls. The lower amount of metabolites known to have proinflammatory activity, i.e., TMAO and lipids, further supported the biochemical results, suggesting that the FF microenvironment is controlled so as to guarantee oocyte quality and does not compromise the outcome of ART. In terms of the number of blastocysts obtained after ICSI and the pregnancy rate, the results are also comforting.

Association between the Exposure to Phthalates and the Risk of Endometriosis: An Updated Review.

Endometriosis is a chronic gynecological disease, primarily associated with pelvic pain and infertility, that affects approximately 10% of the women of reproductive age. Estrogen plays a central role in endometriosis, and there is growing evidence that endocrine disruptors, such as phthalates, may contribute to its development. This review aimed to determine whether there is a causal relationship between phthalate exposure and the development of endometriosis, as well as the possible effects of phthalates on fertility, by analyzing epidemiological data. After a literature search with a combination of specific terms on this topic, we found that although there are limitations to the current studies, there is a clear association between phthalate exposure and endometriosis. Phthalates can interfere with the cellular processes of the endometrium; specifically, they can bind to PPAR and ER-α and activate TGF-ß, promoting different signaling cascades that regulate the expression of specific target genes. This may lead to inflammation, invasion, cytokine alteration, increased oxidative stress, and impaired cell viability and proliferation, culminating in endometriosis. Nevertheless, future research is important to curb the progression and development of endometriosis, and strategies for prevention, diagnosis, and treatment are a priority. In this regard, public policies and recommendations to reduce exposure to phthalates and other endocrine disruptors should be promptly implemented.

Autophagy and Female Fertility: Mechanisms, Clinical Implications, and Emerging Therapies.

Autophagy, an evolutionarily conserved cellular mechanism essential for maintaining internal stability, plays a crucial function in female reproductive ability. In this review, we discuss the complex interplay between autophagy and several facets of female reproductive health, encompassing pregnancy, ovarian functions, gynecologic malignancies, endometriosis, and infertility. Existing research emphasizes the crucial significance of autophagy in embryo implantation, specifically in the endometrium, highlighting its necessity in ensuring proper fetal development. Although some knowledge has been gained, there is still a lack of research on the specific molecular impacts of autophagy on the quality of oocytes, the growth of follicles, and general reproductive health. Autophagy plays a role in the maturation, quality, and development of oocytes. It is also involved in reproductive aging, contributing to reductions in reproductive function that occur with age. This review explores the physiological functions of autophagy in the female reproductive system, its participation in reproductive toxicity, and its important connections with the endometrium and embryo. In addition, this study investigates the possibility of emerging treatment approaches that aim to modify autophagy, using both natural substances and synthetic molecules, to improve female fertility and reproductive outcomes. Additionally, this review intends to inspire future exploration into the intricate role of autophagy in female reproductive health by reviewing recent studies and pinpointing areas where current knowledge is lacking. Subsequent investigations should prioritize the conversion of these discoveries into practical uses in the medical field, which could potentially result in groundbreaking therapies for infertility and other difficulties related to reproduction. Therefore, gaining a comprehensive understanding of the many effects of autophagy on female fertility would not only further the field of reproductive biology but also open new possibilities for diagnostic and treatment methods.

Beyond defence: Immune architects of ovarian health and disease.

Throughout the individual's reproductive period of life the ovary undergoes continues changes, including cyclic processes of cell death, tissue regeneration, proliferation, and vascularization. Tissue-resident leucocytes particularly macrophages, play a crucial role in shaping ovarian function and maintaining homeostasis. Macrophages crucially promote angiogenesis in the follicles and corpora lutea, thereby supporting steroidogenesis. Recent research on macrophage origins and early tissue seeding has unveiled significant insights into their role in early organogenesis, e.g. in the testis. Here, we review evidence about the prenatal ovarian seeding of leucocytes, primarily macrophages with angiogenic profiles, and its connection to gametogenesis. In the prenatal ovary, germ cells proliferate, form cysts, and undergo changes that, following waves of apoptosis, give rice to the oocytes contained in primordial follicles. These follicles constitute the ovarian reserve that lasts throughout the female's reproductive life. Simultaneously, yolk-sac-derived primitive macrophages colonizing the early ovary are gradually replaced or outnumbered by monocyte-derived fetal macrophages. However, the cues indicating how macrophage colonization and follicle assembly are related are elusive. Macrophages may contribute to organogenesis by promoting early vasculogenesis. Whether macrophages contribute to ovarian lymphangiogenesis or innervation is still unknown. Ovarian organogenesis and gametogenesis are vulnerable to prenatal insults, potentially programming dysfunction in later life, as observed in polycystic ovary syndrome. Experimental and, more sparsely, epidemiological evidence suggest that adverse stimuli during pregnancy can program defective folliculogenesis or a diminished follicle reserve in the offspring. While the ovary is highly sensitive to inflammation, the involvement of local immune responses in programming ovarian health and disease remains to be thoroughly investigated.

SIK2 and SIK3 Differentially Regulate Mouse Granulosa Cell Response to Exogenous Gonadotropins In Vivo.

Salt-inducible kinases (SIKs), a family of serine/threonine kinases, were found to be critical determinants of female fertility. SIK2 silencing results in increased ovulatory response to gonadotropins. In contrast, SIK3 knockout results in infertility, gonadotropin insensitivity, and ovaries devoid of antral and preovulatory follicles. This study hypothesizes that SIK2 and SIK3 differentially regulate follicle growth and fertility via contrasting actions in the granulosa cells (GCs), the somatic cells of the follicle. Therefore, SIK2 or SIK3 GC-specific knockdown (SIK2GCKD and SIK3GCKD, respectively) mice were generated by crossing SIK floxed mice with Cyp19a1pII-Cre mice. Fertility studies revealed that pup accumulation over 6 months and the average litter size of SIK2GCKD mice were similar to controls, although in SIK3GCKD mice were significantly lower compared to controls. Compared to controls, gonadotropin stimulation of prepubertal SIK2GCKD mice resulted in significantly higher serum estradiol levels, whereas SIK3GCKD mice produced significantly less estradiol. Cyp11a1, Cyp19a1, and StAR were significantly increased in the GCs of gonadotropin-stimulated SIK2GCKD mice. However, Cyp11a1 and StAR remained significantly lower than controls in SIK3GCKD mice. Interestingly, Cyp19a1 stimulation in SIK3GCKD was not statistically different compared to controls. Superovulation resulted in SIK2GCKD mice ovulating significantly more oocytes, whereas SIK3GCKD mice ovulated significantly fewer oocytes than controls. Remarkably, SIK3GCKD superovulated ovaries contained significantly more preantral follicles than controls. SIK3GCKD ovaries contained significantly more apoptotic cells and fewer proliferating cells than controls. These data point to the differential regulation of GC function and follicle development by SIK2 and SIK3 and supports the therapeutic potential of targeting these kinases for treating infertility or developing new contraceptives.

Potential mechanisms and therapeutic strategies for LPS-associated female fertility decline.

As a major component of the outer membrane of Gram-negative bacteria, lipopolysaccharide (LPS) can be recognized by toll-like receptors (TLRs) and induce inflammation through MyD88 or the TIR domain-containing adapter-inducing interferon-ß (TRIF) pathway. Previous studies have found that LPS-associated inflammatory/immune challenges were associated with ovarian dysfunction and reduced female fertility. However, the etiology and pathogenesis of female fertility decline associated with LPS are currently complex and multifaceted. In this review, PubMed was used to search for references on LPS and fertility decline so as to elucidate the potential mechanisms of LPS-associated female fertility decline and summarize therapeutic strategies that may improve LPS-associated fertility decline.

Drinking water quality impacts oocyte viability and embryo development.

Normal reproductive function and fertility is considered a "sixth vital sign" because disruptions to this sensitive physiological system can forewarn other health issues, including exposure to environmental toxicants. We found that female mice exhibited profound loss of embryos during pre-implantation and fetal development coincident with a change to the source of their drinking water. When female mice were provided with tap water from the building in which they were housed (Water 2), instead of tap water from a neighboring building which was their previous supply (Water 1), ovulated oocytes were degenerated or had impaired meiotic maturation, and failed to form embryos. The harmful effects of Water 2 exposure were not reversible even following a recovery period; however, carbon-filtration of Water 2 removed the toxic contaminant. Water composition analysis to identify the responsible toxicant(s) found that trace elements were present at expected levels and phthalates were undetectable. Per- and Poly-fluoroalkyl Substances (PFAS), a family of persistent organic pollutants were detected at ∼4 ng/L. To investigate further, female mice were given drinking water categorized by level of PFAS contamination (0.6 ng/L, 2.8 ng/L, or 4.4 ng/L) for 9 weeks. Compared to mice consuming purified MilliQ water, mice consuming PFAS-contaminated water had decreased oocyte quality, impaired embryogenesis and reduced cell numbers in blastocysts. PFAS concentration in the drinking water was negatively correlated with oocyte viability. Importantly, the levels of PFAS detected in the tap water are within current "safe level" guidelines, and further research is needed to determine whether PFAS are responsible for the observed reproductive toxicity. However, this research demonstrating that water deemed suitable for human consumption has detrimental effects on mammalian embryo development has important implications for public health and water quality policies.

Environmental factors affecting female fertility.

INTRODUCTION: Over the recent years, scientific community has increased its interest on solving problems of female fertility pathology. Many factors acting separately or in combination affect significantly the reproductive life of a woman. This review summarizes current evidence regarding the direct and/or indirect action of environmental factors and endocrine disrupting chemicals (EDCs; i.e. heavy metals, plasticizers, parabens, industrial chemicals, pesticides, or medications, by-products, anti-bacterial agents, perfluorochemicals) upon assisted and non-assisted female fertility, extracted from in vivo and in vitro animal and human published data. Transgenerational effects which could have been caused epigenetically by the action of EDCs have been raised. METHODS: This narrative review englobes and describes data from in vitro and in vivo animal and human studies with regard to the action of environmental factors, which include EDCs, on female fertility following the questions for narrative reviews of the SANRA (a scale for the quality assessment of narrative review articles). The identification of the studies was done: through the PubMed Central and the PubMed of the MEDLINE, the Google Scholar database and the Cochrane Library database until December 2023 combining appropriate keywords ("specific environmental factors" including "EDCs" AND "specific negative fertility outcomes"); by manual scanning of references from selected articles and reviews focusing on these subjects. It includes references to EDCs-induced transgenerational effects. RESULTS: From the reported evidence emerge negative or positive associations between specific environmental factors or EDCs and infertility outcomes such as infertility indices, disrupted maturation of the oocytes, anovulation, deranged transportation of the embryo and failure of implantation. CONCLUSION: The revealed adverse outcomes related to female fertility could be attributed to exposure to specific environmental factors such as temperature, climate, radiation, air pollutants, nutrition, toxic substances and EDCs. The recognition of fertility hazards related to the environment will permit the limitation of exposure to them, will improve female fertility and protect the health potential of future generations.