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Polycystic ovary syndrome (PCOS) is one of the most common gynecological endocrine disorders. Most pathophysiological changes of PCOS begin in the peripubertal phase, and these pathophysiological changes will continuously affect women's health in the later stages of their lives. The pathogenic mechanisms of PCOS remain unclear, involving key aspects such as the regulation of hypothalamic-pituitary function, ovarian cellular functions, androgen levels, and insulin resistance. Herein, we summarized the latest findings on the pathogenesis of PCOS from the perspectives of the genetic background, intrauterine development, neuroendocrine function, inflammatory factors, gut microbiome, and environmental factors. This review will help provide new ideas for a deeper understanding of the disease, as well as its clinical diagnosis and treatment.

Vitamin D levels and lipid profiles in patients with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women. Dyslipidemia is a prevalent metabolic abnormality in individuals with PCOS. Moreover, vitamin D deficiency is widespread across all societal strata, with a particularly heightened prevalence observed in patients afflicted with PCOS. The present study aimed to investigate the level of vitamin D and its correlation with lipid profiles in Iranian women diagnosed with PCOS. METHODS: This cross-sectional study was carried out at the PCOS and infertility clinic of Arash Women's Hospital in Tehran. The study encompassed the medical records of PCOS patients who attended the clinic from March 2021 to December 2023. All patients underwent blood tests, which included assessments of fasting blood sugar levels, lipid profiles, and 25-hydroxyvitamin D (25(OH)D) levels. The investigation focused on evaluating the relationship between vitamin D levels and lipid profiles. Statistical analyses, including the chi-square test and Spearman's correlation coefficient, were employed to analyze the data. RESULTS: A total of 1004 women diagnosed with PCOS were included in the study. The age range of the participants was 14 to 46 years. The majority of the participants had a body mass index (BMI) within the normal range (n = 555, 55.3%). The median vitamin D level among the participants was 26.00 (IQR: 19.00-34.00). The relationship between vitamin D levels and lipid profile parameters was assessed, revealing no significant correlation between vitamin D levels and low-density lipoprotein (LDL) (r = 0.021, p = 0.505), high-density lipoprotein (HDL) (r = 0.011, p = 0.719), or triglyceride (TG) (r = -0.026, p = 0.417) levels, both in non-adjusted and age-adjusted analyses. CONCLUSION: According to the present study, there was no significant correlation between serum 25(OH)D deficiency and elevated TG or LDL levels or decreased HDL levels in PCOS patients. Nevertheless, further prospective studies are needed to determine whether there is a causal relationship between vitamin D deficiency and lipid profile alterations, specifically among PCOS patients.

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.

Performance of grayscale combined with contrast-enhanced ultrasound in differentiating benign and malignant pediatric ovarian masses.

OBJECTIVES: To evaluate grayscale US combined with contrast-enhanced ultrasound (CEUS) in the preoperative differentiation between benign and malignant ovarian masses in a pediatric population. MATERIALS AND METHODS: This retrospective study enrolled patients who underwent grayscale US and CEUS before surgery because of ovarian masses between July 2018 and September 2023, with available histopathologic or follow-up results. Two senior radiologists summarized the grayscale US and CEUS characteristics of all ovarian masses, including percentage of solidity, ascites, vascularity, and enhanced vessel morphology. These characteristics were then independently reviewed by radiologists with different experience to assess interobserver agreement. Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUC), while interobserver agreement was evaluated by intraclass correlation coefficient (ICC). RESULTS: A total of 26 children (median age: 10.1 [7.5, 11.7] years; age range: 0-14 years; benign: 15 patients) were included. The main characteristics of malignant ovarian tumors were abundant blood flow and twisted blood vessels within the mass, enhanced portion of the mass over 50 percent (all p < 0.001). The grayscale US combined with CEUS showed better diagnostic performance than the grayscale US alone (AUC = 0.99 [95% CI: 0.95, 1.00] vs AUC = 0.70 [95% CI: 0.50, 0.90] p < 0.001). A statistically significant AUC before and after CEUS was also shown between two junior radiologists (0.75 vs 0.92 and 0.69 vs 0.86, respectively, both p < 0.05). ICC of CEUS was better than that of grayscale US among radiologists. CONCLUSION: The combination of grayscale US and CEUS might improve the diagnostic accuracy in differentiating benign and malignant pediatric ovarian masses. CLINICAL RELEVANCE STATEMENT: Grayscale ultrasound combined with contrast-enhanced ultrasound can improve the diagnostic performance in the preoperative differentiation of benign and malignant ovarian lesions in a pediatric population. KEY POINTS: Correctly distinguishing benign from malignant ovarian masses in pediatric patients is critical for determining treatments. Grayscale combined with contrast-enhanced ultrasound (CEUS) differentiated benign and malignant pediatric ovarian masses better than grayscale US alone. Junior radiologists' diagnostic performances could be and were significantly improved with the application of CEUS.

Identification of potential diagnostic genes for atherosclerosis in women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS), which is the most prevalent endocrine disorder among women in their reproductive years, is linked to a higher occurrence and severity of atherosclerosis (AS). Nevertheless, the precise manner in which PCOS impacts the cardiovascular well-being of women remains ambiguous. The Gene Expression Omnibus database provided four PCOS datasets and two AS datasets for this study. Through the examination of genes originating from differentially expressed (DEGs) and critical modules utilizing functional enrichment analyses, weighted gene co-expression network (WGCNA), and machine learning algorithm, the research attempted to discover potential diagnostic genes. Additionally, the study investigated immune infiltration and conducted gene set enrichment analysis (GSEA) to examine the potential mechanism of the simultaneous occurrence of PCOS and AS. Two verification datasets and cell experiments were performed to assess biomarkers' reliability. The PCOS group identified 53 genes and AS group identified 175 genes by intersecting DEGs and key modules of WGCNA. Then, 18 genes from two groups were analyzed by machine learning algorithm. Death Associated Protein Kinase 1 (DAPK1) was recognized as an essential gene. Immune infiltration and single-gene GSEA results suggest that DAPK1 is associated with T cell-mediated immune responses. The mRNA expression of DAPK1 was upregulated in ox-LDL stimulated RAW264.7 cells and in granulosa cells. Our research discovered the close association between AS and PCOS, and identified DAPK1 as a crucial diagnostic biomarker for AS in PCOS.

Identification of Key Genes Associated with Polycystic Ovarian Syndrome and Endometrial and Ovarian Cancer through Bioinformatics.

Background: Polycystic ovary syndrome (PCOS), a common endocrine disorder, is linked to increased risks of endometrial cancer (EC) and ovarian cancer (OC). Our study utilises bioinformatics analysis to identify shared gene signatures and elucidate biological processes between EC and OC and PCOS. Aim: The objective of this research is to unveil the common molecular landscape shared by PCOS and EC and OC. Settings and Design: An observational computational bioinformatics analysis. Materials and Methods: Gene expression profiles for PCOS (GSE199225), EC (GSE215413) and OC (GSE174670) were obtained from the Gene Expression Omnibus database. Hub genes were identified through functional enrichment analysis and protein-protein interaction. Drug identification analyses were employed to find drugs targeting the hub genes. Results: Key hub genes linking PCOS and EC includes RECQL4, RAD54L, ATR, CHTF18, WDHD1, CDT1, PLK1, PKMYT1, RAD18 and RPL3; for PCOS and OC, they include HMOX1, TXNRD1, NQO1, GCLC, GSTP1, PRDX1, SOD1, GPX3, BOP1 and BYSL. Gene Ontology analysis revealed DNA metabolic process in PCOS and EC, while in PCOS and OC, it identified the removal of superoxide radicals. Kyoto Encyclopaedia of Genes and Genomes pathway analysis highlighted cell cycle in PCOS and EC and hepatocellular carcinoma in PCOS and OC. Potential drugs for PCOS and EC include quercetin, calcitriol and testosterone; for PCOS and OC, eugenol and 1-chloro-2,4-dinitrobenzene are identified. Conclusion: These findings offer insights into potential therapeutic targets and pathways linking PCOS with EC and OC, enhancing our understanding of the molecular mechanisms involved in these associations.

Pure large-cell neuroendocrine carcinoma of the ovary with a somatic BRCA1 mutation: The first reported case and the review of the literature.

Pure large-cell neuroendocrine carcinomas of the ovary are extremely rare, so there is a lack of molecular information on this type of cancer. Herein, we presented a pure primary large-cell neuroendocrine carcinomas of the ovary in a 72-year-old female with a pathogenic somatic mutation at the c.5332+1g>a splice site of the BRCA1 gene and with no TP53 mutation. She was uneventful 32 months after the operation and chemotherapies. To the best of our knowledge, this is the first report of a BRCA1 somatic mutation in the ovary large-cell neuroendocrine carcinomas. Testing BRCA1/2 mutations in patients with large ovarian cell neuroendocrine carcinomas might provide an opportunity for their future target treatments. It would expand our understanding.

European survey of diagnosis and management of the polycystic ovary syndrome: full report on the ESE PCOS Special Interest Group's 2023 Questionnaire.

BACKGROUND: Although polycystic ovary syndrome (PCOS) is a very common endocrinopathy, there are several issues related to this disorder which perplex clinicians in their everyday practice. OBJECTIVE: To determine the current state of knowledge among European endocrinologists concerning the full spectrum of PCOS. METHODS: An online survey comprising 41 items covering various aspects of PCOS diagnosis and management was distributed to members of the European Society of Endocrinology. RESULTS: A total of 505 European endocrinologists (64% females), with a mean age of 47 ± 11.6 years, participated in the survey. The Rotterdam criteria were the primary diagnostic tool for 85% of respondents. Most referrals (87.1%) occurred between ages 20 and 40 years. Twenty-five percent of physicians have access to mass spectrometry for the evaluation of androgen levels. While an extended metabolic profile was commonly employed as part of the workup, there was uncertainty regarding chronic anovulation diagnosis. Diabetes, including gestational or type 2, was recognized as a significant risk factor with universal screening irrespective of BMI status. Lifestyle modification and metformin were considered as standard interventions by all participants alongside oral contraceptives, though there was significant discrepancy in treatment duration. CONCLUSIONS: The Rotterdam diagnostic criteria are widely adopted for PCOS diagnosis among European endocrinologists. The current updated survey shows an emphasis on steroid profiling as an important part of diagnostic workup and a strong position held for recognition of PCOS as a metabolic condition with potentially serious implications. Current therapy thus shifted to the demand for prioritizing lifestyle interventions and metabolic therapies, either as monotherapy or in combination with standard hormone compounds.

Monodermal teratoma: Three case reports and review of literature.

BACKGROUND: The incidence of monodermal teratomas of the reproductive system is low, and most doctors lack adequate understanding, which can easily lead to missed diagnoses and/or misdiagnosis. Therefore, it is important to fully understand the clinical characteristics, diagnosis, differential diagnosis, and treatment of monodermal teratomas of the reproductive system. CASE SUMMARY: Case 1: A 14-year-old boy was admitted to the hospital with a right testicular mass for 1 wk and underwent surgical resection. He was finally diagnosed with right testicular monodermal teratoma with no special postoperative discomfort. Case 2: A 40-year-old woman was admitted to the hospital for uterine abnormalities indicated by ultrasound 20 d prior and underwent laparoscopic surgery. She was finally diagnosed with a left ovarian monodermal teratoma with a satisfactory postoperative quality of life. Case 3: A 49-year-old woman was admitted to the hospital with a pelvic mass that was discovered on B-ultrasound a week prior and underwent laparoscopic resection of the left adnexa. She was finally diagnosed with left ovarian monodermal teratoma, and her postoperative quality of life was satisfactory. CONCLUSION: Monodermal teratoma is a rare tumor whose clinical manifestations are primarily benign. Simple surgical resection of the tumor is effective.

Metabolic characteristics of different phenotypes in reproductive-aged women with polycystic ovary syndrome.

Objective: Polycystic ovary syndrome (PCOS) is an endocrine metabolic disorder in reproductive-aged women. The study was designed to investigate the metabolic characteristics of different phenotypes in women with PCOS of reproductive age. Methods: A total of 442 women with PCOS were recruited in this cross-sectional study. According to different phenotypes, all women were divided into three groups: the chronic ovulatory dysfunction and hyperandrogenism group (OD-HA group, n = 138), the chronic ovulatory dysfunction and polycystic ovarian morphology group (OD-PCOM group, n = 161), and the hyperandrogenism and polycystic ovarian morphology group (HA-PCOM group, n = 143). The metabolic risk factors and prevalence rates of metabolic disorders among the three groups were compared. Results: The body mass index (BMI), waist circumference, and waist-to-hip ratio (WHR) of women from the OD-HA group and HA-PCOM group were significantly higher than those of women from the OD-PCOM group (p < 0.05). The serum insulin concentration and homeostasis model assessment of insulin resistance (HOMA IR) at 2 h and 3 h after oral glucose powder in women from the OD-HA group and HA-PCOM group were significantly higher than those from the OD-PCOM group (p < 0.05). The serum total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) in women from the OD-HA group and HA-PCOM group were significantly higher than those in women from the OD-PCOM group (p < 0.05). The prevalence rates of impaired glucose tolerance (IGT), type 2 diabetes mellitus (T2DM), insulin resistance (IR), metabolic syndrome (MS), nonalcoholic fatty liver disease (NAFLD), and dyslipidemia of women with PCOS were 17.9%, 3.6%, 58.4%, 29.4%, 46.6%, and 43.4%, respectively. The prevalence rates of IGT, IR, MS, NAFLD, and dyslipidemia of women in the OD-HA group and HA-PCOM group were significantly higher than those of women in the OD-PCOM group (p < 0.05). T concentration (>1.67 nmol/L) and Ferriman-Gallwey (F-G) score (>3) significantly increased the risk of metabolic disorders in women with PCOS (p < 0.05). Conclusion: The phenotypes of OD-HA and HA-PCOM in women with PCOS were vulnerable to metabolic disorders compared to OD-PCOM. Thus, the metabolic disorders in women with PCOS especially those with the HA phenotype should be paid more attention in order to reduce long-term complications.

Surgical outcomes and complications associated with ovariectomy in the southern stingray Hypanus americanus.

Southern stingrays (Hypanus americanus) are relatively large rays that are common and popular in public aquariums because of their size and gentle nature. In aquariums, as well as in the wild, female southern stingrays are fecund. They have a short gestation cycle and can sustain multiple pregnancies each year, each culminating with 2-10 young. This reproductive rate could quickly outpace capacity in managed care and result in a ray surplus. To prevent overpopulation, many aquaria have resorted to single sex groups with a preference for female-only populations. This is an effective way to control population growth, but forces the maintenance of two separated populations of rays; for females this interrupts normal reproductive cycling and replaces it with a protracted non-pregnant condition. An additional consideration is development of reproductive disease in females which is recognized by an enlarged, misshapen, and congested ovary with an abundance of cystic structures and an enlarged uterus with a thickened wall that is often filled with histotroph despite a non-pregnant status. There are no effective long-lasting medical treatments for this type of reproductive disease and mortality is often the result. This report describes a surgical technique for ovariectomy in southern stingrays including outcomes and complications. Ovariectomy as a surgical method prevents unwanted reproduction and has the benefit of reducing reproductive pathologies commonly observed in southern stingrays as they age. Seven stingrays 1-5.2 years old and 42-83.5 cm disc width underwent ovariectomy. After anesthesia, the ovary and a small amount of epigonal was excised via a left para-lumbar incision. Four of the seven rays survived five or more years post-procedure. Two rays died acutely of coelomitis and one ray died of complications unrelated to the procedure. This report details a surgical procedure for ovariectomy in southern stingrays including outcomes, complications, and recommendations.

Sigmoido-ovarian fistula complicating ovarian carcinosarcoma: a case report.

Introduction: Ovarian cancer is the leading cause of death from gynecological cancer. Ovarian carcinosarcomas represent a rare, aggressive entity with a poor prognosis. Spontaneous fistulization of ovarian cancer into the digestive tract is a rare phenomenon. Presentation of case: A 67-year-old woman with a significant history of cardiac rhythm disorders was consulted for abdominal pain. Examination revealed tachycardia and abdominal guarding. Biology pictured elevated inflammatory markers and low prothrombin time. The abdominal computed tomography scan suggested a perforated sigmoid tumor with a peri-colonic abscess and pneumoperitoneum. She was rushed to the operating theater. Upon exploration, it was an ovarian tumor fistulized to sigmoid with peritonitis. She had an en-bloc resection with a terminal stoma. Control radiological study revealed diffuse lymph node metastasis. She was scheduled for chemotherapy. Discussion: This complication worsens the prognosis. The fistulous communication in the digestive lumen leads to the overflow of its microbial deposit. The tumor, therefore, becomes superinfected and may result in pelvic peritonitis in case of secondary rupture. On the other hand, the patient is deprived of the benefit of undergoing neoadjuvant chemotherapy, which will decrease the chances of complete macroscopic cytoreduction. Through a literature review, we aim to shed light on this rare entity in order to clarify its pathophysiological consequences and make adequate therapeutic measures. Conclusion: Fistulization to the large intestine worsens the prognosis of ovarian carcinosarcomas. Surgery is mandatory and should comply with oncological requirements. Adjuvant therapy is mostly needed, although more studies should be conducted to delineate the regimen accurately.

Liraglutide improves follicle development in polycystic ovary syndrome by inhibiting CXCL10 secretion.

BACKGROUND: At present, a number of clinical trials have been carried out on GLP-1 receptor agonist liraglutide in the treatment of polycystic ovary syndrome (PCOS). However, the effect of liraglutide on follicle development and its specific mechanism are still unclear. METHODS: RNA sequencing was used to explore the molecular characteristics of granulosa cells from patients with PCOS treated with liraglutide. The levels of C-X-C motif chemokine ligand 10 (CXCL10) in follicular fluid were detected by ELISA, the expression levels of ovulation related genes and inflammatory factor genes in follicles and granulosa cells were detected by qPCR and the protein levels of connexin 43 (Cx43), Janus Kinase 2 (JAK2) and phosphorylated JAK2 were detected by Western blot. The mouse ovarian follicles culture system in vitro was used to detect the status of follicle development and ovulation. RESULTS: In the present study, we found that liraglutide inhibited the secretion of inflammatory factors in PCOS granulosa cells, among which CXCL10 was the most significant. In addition, CXCL10 was significantly higher in granulosa cells and follicular fluid in PCOS patients than in non-PCOS patients. We applied in vitro follicle culture and other techniques to carry out the mechanism exploration which revealed that CXCL10 disrupted the homeostasis of gap junction protein alpha 1 (GJA1) between oocyte and granulosa cells before physiological ovulation, thus inhibiting follicular development and ovulation. Liraglutide inhibited CXCL10 secretion in PCOS granulosa cells by inhibiting the JAK signaling pathway and can improved dehydroepiandrosterone (DHEA)-induced follicle development disorders, which is reversed by CXCL10 supplementation. CONCLUSIONS: The present study suggests that liraglutide inhibits CXCL10 secretion in granulosa cells through JAK signaling pathway, thereby improving the homeostasis of GJA1 between oocyte and granulosa cells before physiological ovulation and ultimately improving the follicular development and ovulation of PCOS, which provides more supportive evidence for the clinical application of liraglutide in the treatment of ovulatory disorders in PCOS. TRIAL REGISTRATION: Not applicable.

Adolescent exposure to a mixture of per- and polyfluoroalkyl substances (PFAS) depletes the ovarian reserve, increases ovarian fibrosis, and alters the hippo pathway in adult female mice.

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals known for their environmental persistence and resistance to biodegradation. This study investigated the impact of adolescent exposure to a PFAS mixture on adult ovarian function. Female CD-1 mice were orally exposed to vehicle control or a PFAS mixture (comprised of perfluorooctanoic acid [PFOA], perfluorooctanesulfonic acid [PFOS], undecafluoro-2-methyl-3-oxahexanoic acid [GenX/HFPO-DA], and perfluorobutanesulfonic acid [PFBS]) for 15 days. After a 42-day recovery period, reproductive hormones, ovarian fibrosis, and ovarian gene and protein expression were analyzed using ELISA, Picrosirius red (PSR) staining, qPCR, and immunoblotting, respectively. Results revealed that PFAS exposure did not affect adult body or organ weight, although ovarian weight slightly decreased. PFAS exposed mice exhibited a disturbed estrous cycle, with less time spent in proestrus than control mice. Follicle counting indicated a reduction in primordial and primary follicles. Serum analysis revealed no changes in steroid hormones, follicle-stimulating hormone, or anti-Müllerian hormone, but a significant increase in luteinizing hormone was observed in PFAS-treated mice. Ovaries collected from PFAS treated mice had increased mRNA transcripts for steroidogenic enzymes and fatty acid synthesis-related genes. PFAS exposure also increased collagen content in the ovary. Additionally, serum tumor necrosis factor-α levels were higher in PFAS treated mice. Finally, transcripts and protein abundance for Hippo pathway components were upregulated in the ovaries of the PFAS treated mice. Overall, these findings suggest that adolescent exposure to PFAS can disrupt ovarian function in adulthood.

Tamoxifen-induced alterations in the expression of connexin 43 in the chicken ovary.

Connexin 43 (Cx43) is a gap junction protein that participates in small molecule exchange between adjacent cells. It is a predominant Cx within the mammalian ovary, where is associated with proper follicle development. The expression and regulation of Cx43 in the chicken ovary is largely unknown. The aim of the present study was to examine the expression of the Cx43 gene (GJA1) and protein as well as the immunolocalization of Cx43 in the laying hen ovary in relation to follicle development, and to examine how tamoxifen (TMX; an estrogen receptor modulator) treatment affects these factors. qRT-PCR and western blotting demonstrated differences in Cx43 mRNA transcript and protein abundances in ovarian white follicles, yellowish follicles, small yellow follicles, and the largest yellow preovulatory follicles (F3-F1). In general, Cx43 was more abundant in hierarchical than prehierarchical follicles and in granulosa cells compared with theca cells. Further, the response to TMX treatment depended on the stage of follicle development and the layer of the follicular wall. Ovarian regression following TMX treatment was accompanied by an increase in Cx43 expression in most ovarian tissues, which may impact the formation and function of Cx43 hemichannels. Overall, our results showed, for the first time, the differences in Cx43 mRNA and protein levels between ovarian follicles, suggesting the potential involvement of this gap junction protein in the regulation of ovarian follicle development and function. In addition, the results indicate a possible role for estradiol in regulation of Cx43 transcription and/or translation in the chicken ovary. Understanding the contribution of Cx43 in mechanisms underlying ovarian follicle development may be of considerable importance for poultry egg production.

SFRP4 promotes autophagy and blunts FSH responsiveness through inhibition of AKT signaling in ovarian granulosa cells.

BACKGROUND: Secreted frizzled-related proteins (SFRPs) comprise a family of WNT signaling antagonists whose roles in the ovary are poorly understood. Sfrp4-null mice were previously found to be hyperfertile due to an enhanced granulosa cell response to gonadotropins, leading to decreased antral follicle atresia and enhanced ovulation rates. The present study aimed to elucidate the mechanisms whereby SFRP4 antagonizes FSH action. METHODS: Primary cultures of granulosa cells from wild-type mice were treated with FSH and/or SFRP4, and effects of treatment on gene expression were evaluated by RT-qPCR and RNAseq. Bioinformatic analyses were conducted to analyse the effects of SFRP4 on the transcriptome, and compare them to those of FSH or a constitutively active mutant of FOXO1. Additional granulosa cell cultures from wild-type or Sfrp4-null mice, some pretreated with pharmacologic inhibitors of specific signaling effectors, were used to examine the effects of FSH and/or SFRP4 on signaling pathways, autophagy and apoptosis by western blotting and TUNEL. RESULTS: Treatment of cultured granulosa cells with recombinant SFRP4 was found to decrease basal and FSH-stimulated mRNA levels of FSH target genes. Unexpectedly, this effect was found to occur neither via a canonical (CTNNB1-dependent) nor non-canonical WNT signaling mechanism, but was found to be GSK3ß-dependent. Rather, SFRP4 was found to antognize AKT activity via a mechanism involving AMPK. This lead to the hypophosphorylation of FOXO1 and a decrease in the expression of a portion of the FSH and FOXO1 transcriptomes. Conversely, FSH-stimulated AMPK, AKT and FOXO1 phosphorylation levels were found to be increased in the granulosa cells of Sfrp4-null mice relative to wild-type controls. SFRP4 treatement of granulosa cells also induced autophagy by signaling via AKT-mTORC1-ULK1, as well as apoptosis. CONCLUSIONS: This study identifies a novel GSK3ß-AMPK-AKT signaling mechanism through which SFPR4 antagonizes FSH action, and further identifies SFRP4 as a novel regulator of granulosa cell autophagy. These findings provide a mechanistic basis for the phenotypic changes previously observed in Sfrp4-null mice, and broaden our understanding of the physiological roles of WNT signaling processes in the ovary.

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.

A metabolome-wide Mendelian randomization study prioritizes causal circulating metabolites for reproductive disorders including primary ovarian insufficiency, polycystic ovary syndrome, and abnormal spermatozoa.

BACKGROUND: Accumulating studies have highlighted the significant role of circulating metabolomics in the etiology of reproductive system disorders. However, the causal effects between genetically determined metabolites (GDMs) and reproductive diseases, including primary ovarian insufficiency (POI), polycystic ovary syndrome (PCOS), and abnormal spermatozoa (AS), still await thorough clarification. METHODS: With the currently most comprehensive genome-wide association studies (GWAS) data of metabolomics, systematic two-sample Mendelian randomization (MR) analyses were conducted to disclose causal associations between 1,091 blood metabolites and 309 metabolite ratios with reproductive disorders. The inverse-variance weighted (IVW) method served as the primary analysis approach, and multiple effective MR methods were employed as complementary analyses including MR-Egger, weighted median, constrained maximum likelihood (cML-MA), contamination mixture method, robust adjusted profile score (MR-RAPS), and debiased inverse-variance weighted method. Heterogeneity and pleiotropy were assessed via MR-Egger intercept and Cochran's Q statistical analysis. Outliers were detected by Radial MR and MR-PRESSO methods. External replication and metabolic pathway analysis were also conducted. RESULTS: Potential causal associations of 63 GDMs with POI were unearthed, and five metabolites with strong causal links to POI were emphasized. Two metabolic pathways related to the pathogenesis of POI were pinpointed. Suggestive causal effects of 70 GDMs on PCOS were detected, among which 7 metabolites stood out for strong causality with elevated PCOS risk. Four metabolic pathways associated with PCOS mechanisms were recognized. For AS, 64 GDMs as potential predictive biomarkers were identified, particularly highlighting two metabolites for their strong causal connections with AS. Three pathways underneath the AS mechanism were identified. Multiple assessments were conducted to further confirm the reliability and robustness of our causal inferences. CONCLUSION: By extensively assessing the causal implications of circulating GDMs on reproductive system disorders, our study underscores the intricate and pivotal role of metabolomics in reproductive ill-health, laying a theoretical foundation for clinical strategies from metabolic insights.