Effect of Mitochondrial Function of Ovarian Granulosa Cells on In Vitro Fertilization and Embryo Transfer Outcomes in Obese Polycystic Ovary Syndrome Patients

Objective:To investigate the effect of abnormal ovarian granulosa cell metabolism on in vitro fertilization and embryo transfer(IVF-ET)outcomes in obese polycystic ovary syndrome(PCOS)patients.Methods:Patients with PCOS who met the study criteria were screened according to the inclusion criteria.A total of 32 patients with obese PCOS were recruited into the study group,and 39 patients with non-obese PCOS were recruited into the control group.The general data(age,body mass index,and years of infertility),insulin resistance index(HOMA-IR),follicle-stimulating hormone(FSH),luteinizing hormone(LH),granulosa cell mitochondrial function,and IVF-ET outcome of patients in the study group and control group were retrospectively analyzed.Results:The differences in age and years of infertility between the study group and the control group were insignificant(P>0.05),and the body mass index(BMI)of the study group and control group was 30.5±1.24 kg/m2 and 22.3±1.12 kg/m2,respectively,in which the difference was statistically significant(P<0.05);the HOMA-IR of the study group was significantly higher than that of the control group(P<0.05);the reactive oxygen species(ROS)in the study group was significantly higher than that in the control group(P<0.05),and the ATP content in the study group was significantly lower than that in the control group(P<0.05);comparing the FSH and LH levels between the two groups,the difference was not statistically significant(P>0.05);the rate of IVF-ET failure was significantly higher in the study group than in the control group.Conclusion:PCOS is a complex endocrine disorder,and obesity is one of the independent risk factors for the development of PCOS.

Reprogramming of ovarian granulosa cells by YAP1 leads to development of high-grade cancer with mesenchymal lineage and serous features

Understanding the cell-of-origin of ovarian high grade serous cancer(HGSC)is the prerequisite for efficient prevention and early diagnosis of this most lethal gynecological cancer.Recently,a mesenchymal type of ovarian HGSC with the poorest prognosis among ovarian cancers was identified by both TCGA and AOCS studies.The cell-of-origin of this subtype of ovarian cancer is unknown.While pursuing studies to understand the role of the Hippo pathway in ovarian granulosa cell physiology and pathology,we unexpectedly found that the Yes-associated protein 1(YAP1),the major effector of the Hippo signaling pathway,induced dedifferentiation and reprogramming of the ovarian granulosa cells,a unique type of ovarian follicular cells with mesenchymal lineage and high plasticity,leading to the development of high grade ovarian cancer with serous features.Our research results unveil a potential cell-of-origin for a subtype of HGSC with mesenchymal features.

Knockdown of the Premature Ovarian Insufficiency Candidate Gene NUP107 in Ovarian Granulosa Cells Affects Cell Functions, Including Receptor Expression and Estrogen Synthesis

Objective:Mutations in NUP107 have been discovered in patients with premature ovarian insufficiency and may have tissue-specific effects in ovarian development.However,the role of NUP107 in human granulosa cell(GC)function and female fertility still remains unknown.In this study,we used RNA interference to investigate how NUP107 dysfunction influences GCs and ovarian development.Methods:Immunohistochemical staining was used to detect the expression of NUP107 in ovaries.Cell counting kit-8 assay,real-time cell analysis,and flow cytometry were used to explore cell proliferation and apoptosis,and an enzyme-linked immunosorbent assay was used to assess the estrogen concentrations.Quantitative real-time reverse transcription-quantitative polymerase chain reaction and Western blot analyses were used to determine the expression of NUP107 and functional receptors.Results:Knockdown of NUP107 expression had little effect on the growth and number of GCs.Further study confirmed that knockdown of NUP107 may interfere with estrogen synthesis in GCs and their sensitivity to the regulation of follicle-stimulating hormone(FSH)by decreasing the expression of estrogen synthesis-related genes AR,CYP17A1,CYP19A1,STAR,and NR5A1.Moreover,knockdown of NUP107 decreased the expression of AMHR2,FSHR,LHR,and ESR1 in GCs,but had no effect on the expression of ESR2.Conclusions:These data revealed that NUP107 may impede follicle growth and maturation by regulating hormone synthesis,sensitivity to follicle-stimulating hormone,and expression of functional receptors in GCs,and may,therefore,interfere with female fertility.

DENND1A desensitizes granulosa cells to FSH by arresting intracellular FSHR transportation

Polycystic ovary syndrome(PCOS)is a complex disorder.Genome-wide association studies(GWAS)have identified several genes associated with this condition,including DENND1A.DENND1A encodes a clathrin-binding protein that functions as a guanine nucleotide exchange factor involved in vesicular transport.However,the specific role of DENND1A in reproductive hormone abnormalities and follicle development disorders in PCOS remain poorly understood.In this study,we investigated DENND1A expression in ovarian granulosa cells(GCs)from PCOS patients and its correlation with hormones.Our results revealed an upregulation of DENND1A expression in GCs from PCOS cases,which was positively correlated with testosterone levels.To further explore the functional implications of DENND1A,we generated a transgenic mouse model overexpressing Dennd1a(TG mice).These TG mice exhibited subfertility,irregular estrous cycles,and increased testosterone production following PMSG stimulation.Additionally,the TG mice displayed diminished responsiveness to FSH,characterized by smaller ovary size,less well-developed follicles,and abnormal expressions of FSH-priming genes.Mechanistically,we found that Dennd1a overexpression disrupted the intracellular trafficking of follicle stimulating hormone receptor(FSHR),promoting its internalization and inhibiting recycling.These findings shed light on the reproductive role of DENND1A and uncover the underlying mechanisms,thereby contributing valuable insights into the pathogenesis of PCOS and providing potential avenues for drug design in PCOS treatment.

Clinicopathological Evaluation of Ovarian Juvenile Granulosa Cell Tumor: Is Fertility-Sparing Surgery Safe?

Objective:To retrospectively investigate the clinicopathological characteristics of ovarian juvenile granulosa cell tumors(JGCTs)and to evaluate the safety of fertility-sparing surgery.Methods:In this study,surgically treated patients with JGCTs diagnosed between January 2004 and October 2018 in our center were identified.Clinicopathological data,survival outcomes,and recurrence rates were examined in these patients.Results:A total of 8 patients were included.All patients were premenarchal girls or young women(age range,9-32 years).Irregular vaginal bleeding was the most common presenting symptom.Of them,seven patients were classified with Stage I JGCTs,and they underwent fertility-sparing surgery.One patient who had Stage IIIC JGCT and had completed childbearing underwent complete surgery.Seven patients received adjuvant chemotherapy.The median follow-up duration in the total cohort was 64 months(range,2-117 months).The overall survival rate in the fertility-sparing group was 100%,whereas the patient with Stage IIIC JGCT died 1 month after the treatment.Conclusions:Fertility-sparing surgery might not show a negative impact on oncologic outcomes.Fertility sparing could be considered a modified option for patients with Stage I JGCTs.However,due to the limited number of patients,the conclusion must be interpreted with caution,and larger or multicenter studies are needed before conclusions can be drawn.