Polycystic ovary syndrome(PCOS)is the leading cause of anovulatory infertility.Inadequate understanding of the ovulation drivers hinders PCOS intervention.Herein,we report that follicle stimulating hormone(FSH)control...Polycystic ovary syndrome(PCOS)is the leading cause of anovulatory infertility.Inadequate understanding of the ovulation drivers hinders PCOS intervention.Herein,we report that follicle stimulating hormone(FSH)controls follicular fluid(FF)glutamine levels to determine ovulation.Murine ovulation starts from FF-exposing granulosa cell(GC)apoptosis.FF glutamine,which decreases in pre-ovulation porcine FF,elevates in PCOS patients FF.High-glutamine chow to elevate FF glutamine inhibits mouse GC apoptosis and induces hormonal,metabolic,and morphologic PCOS traits.Mechanistically,follicle-development-driving FSH promotes GC glutamine synthesis to elevate FF glutamine,which maintain follicle wall integrity by inhibiting GC apoptosis through inactivating ASK1-JNK apoptotic pathway.FSH and glutamine inhibit the rapture of cultured murine follicles.Glutamine removal or ASK1-JNK pathway activation with metformin or AT-101 reversed PCOS traits in PCOS models that are induced with either glutamine or EsR1-KO.These suggest that glutamine,FSH,and ASK1-JNK pathway are targetable to alleviate PCOS.展开更多
Objective::Altered bile acid transformation induces low-grade chronic inflammation and may play an important role in the pathophysiology of polycystic ovary syndrome (PCOS). Liquiritincan regulate bile acid metabolism...Objective::Altered bile acid transformation induces low-grade chronic inflammation and may play an important role in the pathophysiology of polycystic ovary syndrome (PCOS). Liquiritincan regulate bile acid metabolism and anti-inflammatory properties;however, limited information is available regarding its therapeutic potential in PCOS.Methods::Female C57BL/6 mice were randomly assigned into four groups ( n = 6 mice/group): the control, letrozole or dehydroepiandrosterone-induced PCOS groups, PCOS + 20 mg/kg liquiritin group, and control + liquiritin groups. After 21 days of treatment, the mice were euthanized, and the associated metabolism indications were investigated. Ovarian histological examinations were performed, and serum hormone concentration was measured. The expression of key genes involved in steroid hormone synthesis, ovarian follicle development, and ovulation was assessed. Results::Liquiritin reduced fasting blood glucose levels and increased insulin sensitivity compared to the PCOS group. Liquiritin also significantly decreased serum levels of total testosterone ( P < 0.001) and dehydroepiandrosterone sulfate ( P < 0.05) in the PCOS group. Histomorphological inspection of ovaries from the liquiritin group revealed fewer cystic dilated follicles than in the PCOS group. Moreover, liquiritinsignificantly ( P < 0.01) decreased Cyp17a1, Cyp19a1, Fshr, Hsd3b2, Runx2, and Ccn2 mRNA expression compared to letrozole-induced PCOS. Conclusion::Liquiritin may be safe and helpful in ameliorating PCOS-associated hyperandrogenemia and hyperglycemia. However, clinical trials investigating different liquiritin dosages are needed to confirm these findings.展开更多
基金State Key Development Programs of China(Nos.2018YFA0800300)(S.M.Z),2018YFA0801300(W.X)National Natural Science Foundation of China(Nos.92253305)(S.M.Z),31821002(S.M.Z),32230054(S.M.Z),31930062(S.M.Z),91857000(S.M.Z),92157001(S.M.Z),32171298(W.X),81971449(Y.Y.Y),82171672(Y.Y.Y)+1 种基金Program of Shanghai Academic Research Leader(21XD1423000)(W.X)China postdoctoral science foundation(2022M721954)(K.H.Z).
文摘Polycystic ovary syndrome(PCOS)is the leading cause of anovulatory infertility.Inadequate understanding of the ovulation drivers hinders PCOS intervention.Herein,we report that follicle stimulating hormone(FSH)controls follicular fluid(FF)glutamine levels to determine ovulation.Murine ovulation starts from FF-exposing granulosa cell(GC)apoptosis.FF glutamine,which decreases in pre-ovulation porcine FF,elevates in PCOS patients FF.High-glutamine chow to elevate FF glutamine inhibits mouse GC apoptosis and induces hormonal,metabolic,and morphologic PCOS traits.Mechanistically,follicle-development-driving FSH promotes GC glutamine synthesis to elevate FF glutamine,which maintain follicle wall integrity by inhibiting GC apoptosis through inactivating ASK1-JNK apoptotic pathway.FSH and glutamine inhibit the rapture of cultured murine follicles.Glutamine removal or ASK1-JNK pathway activation with metformin or AT-101 reversed PCOS traits in PCOS models that are induced with either glutamine or EsR1-KO.These suggest that glutamine,FSH,and ASK1-JNK pathway are targetable to alleviate PCOS.
基金This work was supported by the Shanghai Commission of Science and Technology Planning(22ZR1409100)to F.Zthe Shanghai Municipal Commission of Health and Family Planning(2017ZZ01016)to C.X.
文摘Objective::Altered bile acid transformation induces low-grade chronic inflammation and may play an important role in the pathophysiology of polycystic ovary syndrome (PCOS). Liquiritincan regulate bile acid metabolism and anti-inflammatory properties;however, limited information is available regarding its therapeutic potential in PCOS.Methods::Female C57BL/6 mice were randomly assigned into four groups ( n = 6 mice/group): the control, letrozole or dehydroepiandrosterone-induced PCOS groups, PCOS + 20 mg/kg liquiritin group, and control + liquiritin groups. After 21 days of treatment, the mice were euthanized, and the associated metabolism indications were investigated. Ovarian histological examinations were performed, and serum hormone concentration was measured. The expression of key genes involved in steroid hormone synthesis, ovarian follicle development, and ovulation was assessed. Results::Liquiritin reduced fasting blood glucose levels and increased insulin sensitivity compared to the PCOS group. Liquiritin also significantly decreased serum levels of total testosterone ( P < 0.001) and dehydroepiandrosterone sulfate ( P < 0.05) in the PCOS group. Histomorphological inspection of ovaries from the liquiritin group revealed fewer cystic dilated follicles than in the PCOS group. Moreover, liquiritinsignificantly ( P < 0.01) decreased Cyp17a1, Cyp19a1, Fshr, Hsd3b2, Runx2, and Ccn2 mRNA expression compared to letrozole-induced PCOS. Conclusion::Liquiritin may be safe and helpful in ameliorating PCOS-associated hyperandrogenemia and hyperglycemia. However, clinical trials investigating different liquiritin dosages are needed to confirm these findings.