Synergistic Role of Fisetin and Dapagliflozin in Ameliorating Oxidative Damage & Insulin Resistance in Dehydroepiandrosterone Induced Polycystic Ovarian Syndrome in Rats.

Background: Polycystic ovarian syndrome (PCOS) is a syndrome defined by ovarian dysfunction which is marked primarily by elevated hormone levels and the presence of polycystic ovaries discovered on ultrasonography. Polycystic ovarian syndrome is an extremely prevalent lifestyle disorder that affects 6 out of 10 women. The management of polycystic ovarian syndrome is largely unclear. This study examines the possible use of Banana Blossom an herbal therapy in a rat model of polycystic ovarian syndrome caused by the medication mifepristone. Methods: For 13 days, female Wistar rats were given 20mg/kg b.w. of mifepristone daily to induce PCOS, which was verified by the sustained estrous cycle. The rats received treatment with Banana Blossom extract orally for 21 days at a dosage of 200, 400 and 800mg/kg b.w. after PCOS induction and standard treatment was metformin. Physical, biochemical parameter and oxidative stress marker was carried out using standard procedure. Result: The PCOS rats reported a significant decline (P˂0.001) in uterine weight, HDL, SOD as well as GSH levels along with a significant rise (P˂0.001) in body weight, periovarian fat, LDL, triglycerides, MDA and glucose level. Banana Blossom extract reversed these effects, with the 800mg/kg b.w. dose providing the most significant improvements in oxidative stress markers and biochemical parameters. Conclusion: After analysing the data, one can conclude that the banana blossom ethanolic extract exhibited an improved therapeutic effect on mifepristone induced polycystic ovarian syndrome in female Wistar rats.

The study designed to evaluate influence of kisspeptin on polycystic ovary syndrome in female rats, First experiment (Induction of polycystic ovary): thirtieth virgin female rats divided randomly into two groups first group via used ten rats serves as control group . While the second group twenty female rat (PCOS-induce group) were orally administered with letrozole at a dose of 1 mg/kg/21 days. The Second Experiment Effect of treatments with kisspeptin on PCOS : Animals were divided as follows: first group (negative control) .Second group (Positive control) .While animals in third and fourth groups (PCOS+Kisspeptin): five animal in each group PCOS-induced rats administrated of 20 and 40 nmol/rat S/C 21 days Kisspeptin daily respectively .The result show in first experiment a significant increase in serum activity of LH, FSH, estrogen and testosterone and significant decrease progesteron concentration in serum of female rats treated with letrozole. While in the second experiment there was significant decrease in FSH in the C+ compared with C and PCOS treated group. A significant increase in the LH in C+ compared with C and treated group 20 and 40 nmol/rat Kisspeptin . Also the results showed that there was a significant decrease in serum estrogen concentration was observed in PCOS nontreated group compared with control. On other hand a significant increase in serum estrogen in T1(20 nmol/kg B.W) compared with T2(40 nmol/kg B.W). The results of the histopathological study of ovary after treatment PCOS with kisspeptin 20 nmol/kg show partial return of follicular cyst to normal ovarian tissue, but the treated with 40 nmol/kg show semicomplete treated and return follicular cyst to normal ovarian tissue. On conclusions, the present study confirmed that PCOS affect the female reproductive hormonal balance and kisspeptin 40 nmol/rat daily S/C injection show effect in normal restoring of female reproductive hormonal and histological balance of PCOS rats.

Objective: To investigate the combined therapeutic potential of Gymnema (G.) sylvestre and Pergularia (P.) daemia on letrozole-induced polycystic ovarian syndrome (PCOS) in rats. Methods: Thirty six healthy female Wistar rats with regular estrus cycles were randomly divided into six groups each of 6. Group I received 1 mL of 0.5% carboxyl methyl cellulose orally and served as the vehicle control group, while groups II to VI were treated with letrozole (1 mg/kg body weight p. o.) for 21 days to induce PCOS. After induction of PCOS, group II served as the PCOS control group, without treatment; group III received metformin (20 mg/kg body weight p. o.) as the standard group, and groups IV to VI received G. sylvestre (100 mg/kg body weight p. o.), P. daemia (300 mg/kg body weight p. o.), and the combination of G. sylvestre and P. daemia, respectively, for 28 days. Vaginal smears were collected from all rats daily throughout the study to determine the phases of the estrus cycle. After completing the treatment schedule, oral glucose tolerance test, serum lipid profile and reproductive hormonal analysis were carried out. Subsequently, the rats were sacrificed to collect ovary and uterus for histopathological examination. Results: The PCOS control rats showed a significant irregularity in the estrus cycle, hyperglycemia, and the altered serum lipid profile such as the increased low and very low density lipoprotein, triglyceride, and decreased high density lipoproteins. In addition, the PCOS control rats showed a significant increase in serum luteinizing hormone, testosterone, and estrogen, and decrease in follicle stimulating hormone and progesterone. These changes were significantly revoked in all the treatment groups. The test drugs also significantly reduced the gained ovary weight (P<0.001), and histopathology of the ovary showed almost normal ovary. Among the treatment groups, the group of combination treatment of G. sylvestre and P. daemia showed superior ameliorative results in PCOS parameters. Conclusions: Combination of G. sylvestre and P. daemia presents potent synergistic activity against hyperandrogenism, hyperinsulinemia, anovulation and follicular cysts in letrozole-induced PCOS rats.

This study aims to explore the therapeutic effect of Yuzhi Zhixue Granules on polycystic ovary syndrome(PCOS) in rats and explain the underlying mechanism by metabolomics. Rats were randomized into normal, model, low-, medium-, and high-dose(0.5, 1.5, and 4.5 g·kg~(-1)·d~(-1)) Yuzhi Zhixue Granules, and positive control(metformin, 0.2 g·kg~(-1)·d~(-1)) groups. The rats in other groups except the normal group were administrated with 1 mg·kg~(-1)·d~(-1) letrozole and fed with a high-sugar and high-fat diet for the modeling of PCOS. After 40 days of modeling, the normal and model groups received distilled water and letrozole+distilled water, respectively, and other groups received letrozole and corresponding drugs, once a day for 50 days. The oral glucose tolerance test(OGTT) was carried out and enzyme-linked immunosorbent assay(ELISA) was conducted to detect insulin release, and the radioimmunoassay was employed to measure the serum levels of follicle-stimulating hormone(FSH), luteinizing hormone(LH), estradiol(E_2), and testosterone(T). The serum levels of high density lipoprotein-cholesterol(HDL-C), low density lipoprotein-cholesterol(LDL-C), and triglyceride(TG) were determined by an automatic biochemical analyzer. The pathological changes in the ovary were observed by hematoxylin-eosin(HE) staining. The protein levels of phosphatidylinositol 3-kinase(PI3K), protein kinase B(Akt), and their phosphorylated forms in the ovary were determined by Western blot. Ultra-high performance liquid chromatography-tandem mass spectrometry(LC-MS/MS) was employed to study the fecal and serum metabolites in the rat model of PCOS. The results showed that compared with the model group, drug administration repaired the impaired glucose tolerance, enhanced the insulin sensitivity, elevated the serum levels of HDL-C and E_2, lowered the serum levels of TG and T, ameliorated the pathological changes in the ovarian tissue, and up-regulated the protein levels of p-PI3K and p-Akt in the ovarian tissue. A total of 46 differential metabolites and 10 metabolic pathways in the fecal samples were screened out, which were mainly related to the biosynthesis of unsaturated fatty acids and tyrosine metabolism. In terms of the serum metabolism, 34 differential metabolites and 15 metabolic pathways were screened out, mainly related to the biosynthesis of unsaturated fatty acids and aminoacyl-tRNA. In conclusion, Yuzhi Zhixue Granules can alleviate the disorders of glucose, lipids, and sex hormones and improve the ovarian status in the rat model of PCOS by regulating the serum and fecal metabolism and activating the PI3K/Akt pathway.

This study investigated the effects of proanthocyanidins (PCs) on ovarian fibrosis in letrozole-induced polycystic ovary syndrome (PCOS) in rats. The administration of PCs effectively reduced the body weight (BW) and relative ovarian weight in PCOS rats. ELISA results revealed that PCs significantly reduced the level of serum T, LH, LH/FSH in the PCOS group. In addition, qRT-PCR results revealed that treatment with PCs significantly increased the main antioxidant enzymes (Cat, Sod2, Gpx3, Mgst1, Gsta4, Sod1 and Prdx3) in PCOS rats. Also, the expression analysis of proteins by Western blotting revealed that PCs significantly decreased the level of TGF-βR1, p-Smad3, p-Smad2 and Smad4 and reversed the downregulation of Smad7 in PCOS rats. The study suggested that PCs improved ovarian fibrosis in PCOS rats by regulating the serum hormone level, inhibiting oxidative stress and suppressing the activation of the TGF-β1/Smads signaling pathway. PRACTICAL APPLICATIONS: Currently, plant extracts are being widely used to treat female reproductive and metabolic disorders. Particularly, proanthocyanidins (PCs), the well-known natural polyphenolic compounds, which are a significant source of antioxidants present in many colored fruits, are consumed as fruits as well as a dietary supplement to prevent many disorders. Recent pharmacological studies have reported that PCs have many health beneficial properties, such as antioxidant activity, improving cholesterol homeostasis, blood lipid regulatory properties, microcirculation improvement effect, antitumor activity and anti-aging activity. Despite these properties of PCs, the antifibrosis effect of PCs has not been studied to date. The main purpose of this study was to research the role and the mechanisms of PCs in ovarian fibrosis in PCOS rats.

Objectives: To evaluate the therapeutic potential of Gymnema sylvestre (GS) leaf ethanolic extract against letrozole induced polycystic ovarian syndrome (PCOS) in rats. Methods: Thirty female virgin rats (180 - 250g) with regular estrus cycles were used and divided into five groups of six animals each. Group-I serves as normal control receives 1ml of 0.5% carboxyl methyl cellulose orally; group-II to V were treated with letrozole (1mg/kg/b.w. p.o.) for 21 days to induce PCOS. Induction of PCOS was confirmed by measuring menstrual irregularity. After induction of PCOS, group-II serves as PCOS control, group-III receives metformin (20 mg/kg/b.w. p.o.) as standard, and group- IV to V treated with G. sylvestre ethanolic extract 200mg/kg/b.w. and 400mg/kg/b.w. p.o. respectively for 28 days. After completion of the treatment schedule oral glucose tolerance test was carried out, followed by serum lipid profile (LDL, VLDL, HDL, and TG), and hormonal analysis was carried out. Then the animals have sacrificed and the ovaries were then processed for histological examination. Results: The results of this study exhibited irregularity in the estrus cycle, a significant increase in serum blood glucose, and an altered serum lipid profile in PCOS control. In addition, the PCOS control rats showed a significant increase in serum luteinizing hormone, testosterone, and a decrease in estrogen, follicle-stimulating hormone, and progesterone. These changes were significantly reversed by G. sylvestre in a dose dependent manner. Histopathology of the ovary also showed an almost normal ovary in the treatment groups. Conclusion: In conclusion, the treatment of ethanolic leaf extract of Gymnema sylvestre reduces insulin resistance by improving glucose utilization, regularize menstrual irregularity and promote ovulation by correcting the hormonal irregularities and improve the development of follicles in PCOS condition.

Objective To explore the role of isorhamnetin on polycystic ovary syndrome (PCOS) in rats. Methods Sprague Dawley (SD) rats were subcutaneously injected with dehydroepiandrosteron (DHEA) to establish PCOS model. Hematoxylin and eosin (H&E) staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) were used to measure histological changes and apoptosis of ovary tissues. The levels of serum hormones and inflammatory factors in ovary tissues were measured by enzyme-linked immuno sorbent assay (ELISA). Results In DHEA-induced PCOS rats, the levels of serum glucose, insulin, testosterone and luteinizing hormone (LH) were enhanced, estradiol (E2), sex hormone-binding globulin (SHBG), follicle stimulating hormone (FSH) levels were decreased, inflammatory levels and apoptosis of ovary tissues were increased. Additionally, DHEA increased the body weight, ovary weight, and ovary volume, cystic follicles, and decreased corpus luteum. Moreover, the tumor necrosis factor (TNF) signaling pathway was activated in PCOS rats. The levels of TNF receptor superfamily member 1 A (TNFR1), TNF-α, and fas cell surface death feceptor (FAS) were enhanced in ovary tissues of DHEA induced PCOS rats. Isorhamnetin (ISO) treatment after DHEA modeling markedly reduced serum levels of glucose, insulin, testosterone and LH, increased E2, SHBG, FSH level, decreased inflammatory levels, and inhibited apoptosis and decreased body weight, ovary weight, and ovary volume. The levels of TNFR1, TNF-α, and FAS were markedly decreased after ISO treatment in PCOS rats. Additionally, ISO alone had no significant effect on rats. Conclusion Isorhamnetin inhibits inflammatory response to alleviate DHEA-induced PCOS in rats by inactivating the TNF signaling pathway.

Numerous inducers of polycystic ovarian syndrome (PCOS) at different doses have been proposed in several experimental animals but there is no consensus on an appropriate dose(s) that should ideally reproduce the key biochemical and clinical features of PCOS similar to those of humans. Therefore, this study was aimed at investigating an appropriate dose(s) for the induction of PCOS in female Wistar rats. Twenty-four female albino rats (190.00 ± 13.00 g) with 4-5 days of estrus cyclicity were completely randomized into 4 groups (A - D) of six animals each. Animals in group A (control) were subcutaneously administered 0.2 ml of pure olive oil, while those in groups B, C and D were subcutaneously administered same volume corresponding to 5.0, 7.5 and 10.0 mg of mifepristone in olive oil for 9 days starting from the day of estrus (Day 1). The estrus cycle, serum testosterone (T), estradiol (E), prolactin (Pr), follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P), insulin (Is), weight of the animals, fasting blood glucose (FBS) and ovarian morphology were monitored/evaluated/examined. The 5.0 mg of mifepristone extended the estrus stage for four days, increased (p<0.05) the levels of serum E, P, Pr, FSH, T, triacylglycerides (TAG), and total cholesterol (TC) as well as decreased the concentrations of LH and high density lipoprotein-cholesterol (HDL-C). There was no significant difference (p<0.05) in the Is concentration, animal body weights and FBS at day 10 in rats administered 5.0 mg of mifepristone. The 7.5 mg of mifepristone produced irregular estrus cycle, increased Pr, TAG, T, and TC concentrations and FBS whereas it decreased E, P, HDL-C, and LH. The Is, FSH and body weights of the animals were not significantly altered at 7.5 mg of mifepristone. The 10.0 mg of mifepristone produced irregular estrus cycle, increased the levels of E, TAG, Is, LH, T as well as decreased the levels of P and HDL-C. The levels of Pr, FSH, TC, body weights and FBS were not significantly altered at this dose. There was no ovarian follicular growth and atresia in the 5.0 and 7.5 mg mifepristone-treated rats whereas the 10 mg of mifepristone produced these histopathological features. Overall, the study concluded that subcutaneous administration of mifepristone (RU486) induces polycystic ovarian syndrome in rats through deprivation of progesterone with the 10 mg producing majority of the key biochemical and clinical features associated with PCOS in humans. The study, therefore, recommends the subcutaneous administration of mifepristone (RU486) on daily basis for 9 days as a good model for inducing PCOS in animals.

This study was undertaken to study the effects of melatonin on metabolic and reproductive aspects of polycystic ovary syndrome (PCOS) in rats. PCOS was induced by daily subcutaneous administration of testosterone (20 mg/kg) to 21-day-old female rats for 35 days. Rats were given metformin (500 mg/kg), melatonin (1 mg/kg) or melatonin (2 mg/kg) along with testosterone. One group served as vehicle control. On the 36th day, the animals were euthanised, and anthropometrical, biochemical (glucose, insulin, lipids, testosterone, C reactive protein (CRP)), oral glucose tolerance test, and histopathological evaluation of ovaries, uterus and intraabdominal fat (IAF), were carried out. Daily colpocytological examination was carried out from 14(th) day of study until termination. Both the doses of melatonin significantly reduced body weight, body mass index, IAF, insulin and CRP. A favourable lipid profile, normal glucose tolerance and a decrease in the percentage of estrus smears were observed. Histopathological examination of ovary, uterus and IAF revealed a decrease in the number of cystic follicles, decrease in neoplastic endometrial glands, and decrease in adipocyte hypertrophy, respectively. The effects observed with melatonin were comparable to that with metformin. The study provides evidence of the potential beneficial effects of melatonin in PCOS.

Objective:The effect of trans-anethole and metformin on biochemical and hormonal changes of testosterone-induced Polycystic ovary syndrome (PCOS) in rats was investigated.Materials and Methods:Female Wister rats (n=48) were randomly divided into six groups: control; PCOS; PCOS+metformin (300 mg/kg); and PCOS+trans-anethole (20, 40, and 80 mg/kg). PCOS was induced by intraperitoneal injection of testosterone (1 mg/kg/day) for 35 days. After induction of PCOS, trans-anethole and metformin were given orally for 30 days. Finally, blood sugar, insulin, lipid profile, and testosterone and dehydroepiandrosterone (DHEAS) as well as animals’ weight, and water and food intake were determined.Results:In all treated and untreated PCOS groups, serum testosterone levels were significantly increased compared to the control group (p<0.001 for all groups). Treatment of rats with trans-anethole or metformin significantly reduced serum levels of cholesterol, insulin, triglycerides, testosterone and DHEAS (only in PCOS+trans-anethole groups) compared to the PCOS group (p<0.01-p<0.001). Weight gain in the PCOS animals increased significantly compared to the control group (p<0.001), while in the metformin- and trans-anethole (40 and 80)-treated animals it decreased significantly compared to the PCOS group (p<0.01-p<0.001).Conclusion:These results showed that trans-anethole significantly decreased serum levels of insulin, DHEAS and blood lipids. It can be concluded that trans-anethole ameliorates PCOS biochemical and hormonal change in PCOS rats; therefore, it might be suggested as a beneficial remedy for further clinical evaluations in PCOS patients.

Contamination by fungi and the toxins they secrete is a worldwide health concern. One such toxin is zearalenone (Zea), which is structurally similar to the hormone estrogen, interferes with its action on the reproductive system, and is therefore classified as an endocrine disruptor. This study aims to determine the effectiveness of hispidin and magnesium nanoparticles (MgONPs) against zearalenone-induced myotoxicity, which causes polycystic ovary syndrome (PCOS) in rats. A three-month exposure study was performed using female Wistar rats (n = 42) with an average weight of 100–150 g. The animals were divided into six groups (I to VI) of seven rats each. Group I was administered distilled water as a negative control. Group II was exposed to Zea 0.1 mg/kg b.w. through gavage daily. Group III was treated with 0.1 mg/kg of hispidin through gavage daily. Group IV was given 150 µg/mL MgONPs orally each day. Group V was treated with Zea 0.1 mg/kg b.w. + 0.1 mg/kg hispidin orally each day. Group VI was treated with Zea 0.1 mg/kg b.w. and the combination treatment of 0.1 mg/kg hispidin + 150 µg/mL MgONPs through gavage every day. The effectiveness of hispidin and MgONPs against Zea toxicity was evaluated in terms of ovarian histological changes, gene expression, oxidative stress biomarkers, biochemical variables, and hormone levels. The findings showed that exposure to Zea promotes PCOS in rats, with Zea-treated rats displaying hyper-ovulation with large cysts; elevated testosterone, luteinizing hormone, insulin, and glucose; and reduced sex hormone-binding globulin. In addition, qRT-PCR for aromatase (Cyp19α1) showed it to be downregulated. Treatment with hispidin improved the histopathological and hormonal situation and rescued expression of Cyp19α. Our data indicate the potential therapeutic effects of hispidin against Zea-induced Fungal Toxicity.

The relationship between apoptosis of granulosa cells and follicle development arrest in polycystic ovarian syndrome (PCOS) rats, and the contribution of tumor necrosis factor related apoptosis inducing ligand (TRAIL) in apoptosis of granulosa cells were explored. By using sodium prasterone sulfate rat PCOS model was induced. The apoptosis of granulosa cells in ovaries of rats was observed by TdT-mediated dUTP-biotin nick end-labeling (TUNEL), and the expression of TRAIL protein and mRNA in granulosa cells was detected by using immunohistochemical staining and reverse transcription polymerase chain reaction (RT-PCR) respectively. The apoptotic rate and the expression of protein TRAIL in granulosa cells were significantly higher in antral follicles from the PCOS rats than in those from the control rats (P<0.01, P<0.05). There was no significant difference in apoptotic rate and the expression of TRAIL protein in granulosa cells of preantral follicles between the PCOS rats and the control rats (P>0.05). No apoptosis and the expression of TRAIL protein in granulosa cells of primordial follicles were found in the two groups. The expression of TRAIL mRNA was significantly stronger in granulosa cells from the PCOS rats than in those from the control rats (P<0.01). It was suggested that the apoptotic rate in granulosa cells was significantly higher in antral follicle from the PCOS rats than in those from the control rats. TRAIL played a role in regulating the apoptosis of granulosa cells in PCOS rats.

ObjectiveTo identify the association between the phosphorylated Janus kinase 2/phosphorylated signal transducer and activator of transcription (p-JAK2/p-STAT3) signaling pathway and follicular development in polycystic ovary syndrome (PCOS) rats, and explore the underlying mechanism. To evaluate the role of exogenous JAK2 inhibitor AG490 in the model and the associations among luteinizing hormone/choriogonadotropin receptor (LHCGR), follicle-stimulating hormone receptor (FSHR), cytochrome P450 17α (CYP17a), cytochrome P450 19 (CYP19), and PCOS. ResultsRat models of PCOS was established. PCOS rats were intraperitoneally treated with double-distilled water (ddH2O)/DMSO/AG490. The rate of ovarian morphological recovery in the AG490 group was significantly higher compared with the DMSO group (83.3 % vs 9.1 %, X2 = 12.68, P < 0.001). Moreover, the short in the time the estrous cycle was resumed in the AG490 group (hazard ratio = 16.32, P < 0.001) compared with the DMSO group. Compared with the controls, p-JAK2, p-STAT3, LHCGR, and CYP17a expression levels were increased whereas that of FSHR and CYP19 were decreased in the ovaries of PCOS rats. However, an opposite trend was observed after treatment with AG490. Software prediction revealed that the p-STAT3 bound to the promoter regions of LHCGR, FSHR, CYP17a, and CYP19 genes. This finding was confirmed by results of correlation analysis (R = 0.834, −0.836, 0.875 and −0.712, respectively, all P < 0.001). ConclusionThis study demonstrated that the p-JAK2/p-STAT3 signaling pathway was involved in follicular development in PCOS rats by upregulating LHCGR and CYP17a expression, and downregulating that of FSHR and CYP19. AG490 treatment exerted beneficial effects. LHCGR, FSHR, CYP17a, and CYP19 are candidate genes associated with follicular development in PCOS rats.

Polycystic ovarian syndrome (PCOS) is one of the common causes or female infertility. Phyllanthus muellerianus (Euphorbiaceae) is a plant used to treat various ailments including frequent menstruation and anovulation. We investigated the effects of P. muellerianus extracts on estrus cyclicity, lipid profile, oxidative stress-related markers, sex hormones, and ovarian architecture in letrozole-induced PCOS in rats. After induction of PCOS using letrozole (1 mg/kg/day), normal (n=6), and PCOS (n=108; distributed into 18 groups of 6 animals/group) rats were treated orally for 7 or 14 days with distilled water (10 ml/kg/day), clomiphene citrate (2 mg/kg/day), metformin (500 mg/kg/day), and aqueous or methanolic extract of P. muellerianus (30, 60, and 120 mg/kg). Estrus cyclicity, body, and sexual organ (ovaries and uterus) weights, biochemical and histological parameters were measured. There were letrozole-induced PCOS characterized by irregular estrus cyclicity, elevated (p<0.05-0.01) glycaemia, ovarian weight, triglycerides, total cholesterol, LDL cholesterol, VLDL cholesterol, malondialdehyde, luteinizing hormone (LH), and testosterone concentrations, but there were low (p<0.05-0.001) HDL cholesterol, estradiol, progesterone, catalase, peroxidase, and superoxide dismutase levels, compared with control. PCOS rats had multiple cysts compared with control. These reproductive, biochemical, and structural alterations were alleviated by P. muellerianus extracts. For instance, P. muellerianus restored the estrus cyclicity with a remarkable effect after 14 days of treatment. Moreover, P. muellerianus significantly decreased (p<0.001) LH and testosterone (both extracts; 30, 60, and 120 mg/kg) levels, but increased (p<0.01) estradiol (aqueous extract; 60 mg/kg) concentration. Cystic follicles were also decreased after plant application. P. muellerianus alleviated reproductive, hormonal, and structural alterations in PCOS rats. This plant could be useful in the management/treatment of reproductive and metabolic disorders related to PCOS.

Fisetin, a polyphenolic flavonoid, exhibits numerous pharmacological activities against metabolic syndromes. The present research aims to explore the therapeutic efficacy of fisetin in experimental polycystic ovary syndrome (PCOS). Female Sprague-Dawley rats were administered mifepristone (20mg/kg/day) to induce PCOS. PCOS rats were treated with fisetin (20mg/kg and 40mg/kg) and further compared with metformin HCl, the conventional drug for PCOS. The mechanism of fisetin was explored using dorsomorphin (an AMPK inhibitor). Then, rats were sacrificed for further analysis of biochemical and histological parameters. PCOS rats exhibited irregular estrous cycles, increased serum testosterone (4.72 ± 0.139ng/ml), estradiol (750.2 ± 16.56pg/ml), LH (30.33 ± 1.563 mIU/ml), HOMA-IR (1.115 ± 0.049), TNF-α (86.59 ± 3.93pg/ml), IL-6 (55.34 ± 4.432pg/ml), and TBARS (3.867 ± 0.193µmol/mg) along with declined progesterone (11.67 ± 1.54ng/ml), FSH (13.33 ± 1.256 mIU/ml), GSH (33.47 ± 1.348µmol/mg) levels, and SOD (2.163 ± 0.298 U/mg) activity as compared to normal control group. Fisetin high dose significantly lowers testosterone (3.014 ± 0.234ng/ml), estradiol (533.7 ± 15.39pg/ml), LH (16.67 ± 1.62 mIU/ml), HOMA-IR (0.339 ± 0.20), TNF-α (46.02 ± 2.66pg/ml), IL-6 (31.77 ± 3.47pg/ml), and TBARS (1.747 ± 0.185µmol/mg) and enhances progesterone (33.17 ± 1.447ng/ml), FSH (27.17 ± 1.42 mIU/ml), GSH (60.35 ± 1.1.102µmol/mg) levels, and SOD (4.513 ± 0.607 U/mg) activity. The histology of ovarian tissues shows a significant increase in cystic follicles in PCOS rats compared with the normal control group. These alterations were attenuated with fisetin treatment. Administration of dorsomorphin with fisetin can reverse the beneficial effects of fisetin in PCOS rats. Altogether, these present findings highlight the potential of fisetin as a promising therapeutic intervention for the management of PCOS by modulating AMPK/SIRT1 signaling in rats.