Letrozole-induced Polycystic Ovary Syndrome Research Articles

Gallic acid reverses ovarian disturbances in mice with letrozole-induced PCOS via modulating Adipo R1 expression

Research questionWomen are increasingly suffering from polycystic ovary syndrome (PCOS). Its pathophysiology is still unknown, though. The purpose of this study was to ascertain how gallic acid affected the pathophysiology of the ovary in an animal model of polycystic ovary syndrome. We also showed the potential mechanism of adiponectin involvement in endocrine metabolic changes in PCOS mice and the function of adiponectin, which appear to be frequent factors in PCOS. DesignEighteen adult female Parkes strain mice (Age: 4–5 weeks) having body weight of 16–21 g were separated into three groups at random with 6 animals in each group as follows: Group I serving the control, received water and normal diet for 81 days; group II received oral gavage administration of letrozole (LETZ)(6 mg/kg b.w.daily), which was dissolved in 0.9 % NaCl solution for 21 days for the induction of PCOS and left untreated for 60 days; Group III received oral gavage administration of LETZ (6 mg/kg) for first 21 days followed by the administration of gallic acid (GA) (75 mg/kg b.w. orally daily) for 60 days. ResultsWe found LETZ-treated mice experienced PCOS-like symptoms, including increased Serum testosterone, LH/FSH ratio, body and ovarian weight, blood glucose, serum insulin levels and inflammatory Cytokines. We also found decreased serum estrogen, oxidant capacity and enzyme activity and altered ovarian cytoarchitecture, with multiple cysts apart from irregular estrous cycle. Furthermore, mRNA expression levels CYP11a, CYP19a1, Kitl, PTGS2 and Adipo R1 were decreased. Furthermore, LETZ-induced PCOS mice when treated with GA we observed decrease in testosterone, LH, LH/FSH ratio, blood glucose, serum insulin and inflammatory cytokines. GA treatment in PCOS mice also increased estrogen levels, and oxidant capacity as well as enzyme activity. Furthermore mRNA expression levels of CYP11a1, CYP19a1, KITL, PTGS2 and Adipo R1 were also increased in LETZ+GA treated mice. These changes were linked to lower levels of circulating adiponectin and were altered when the mice were administered with gallic acid. ConclusionGallic acid might be a potential therapy in treating PCOS by regulating endocrine and metabolic abnormalities that are brought on by a drop in adiponectin levels along with hyperandrogenism. Additionally, adiponectin seems to be a frequent factor in PCOS. In addition to reducing inflammation-related comorbidities linked to LETZ-induced PCOS, GA enhances mRNA expression levels CYP11a, CYP19a1, Kitl and PTGS2 and hence reduces endocrine and metabolic abnormalities.

Metformin ameliorates polycystic ovary syndrome in a rat model by decreasing excessive autophagy in ovarian granulosa cells via the PI3K/AKT/mTOR pathway.

Polycystic ovary syndrome (PCOS) is a common gynecological disease accompanied by a variety of clinical features, including anovulation, hyperandrogenism, and ovarian abnormalities, resulting in infertility. PCOS affects approximately 6%-15% of all reproductive-age women worldwide. Metformin, a popular drug used to treat PCOS in patients, has beneficial effects in reducing hyperandrogenism and inducing ovulation; however, the mechanisms by which metformin ameliorates PCOS are not clear. Hence, we aimed to explore the mechanisms of metformin in treating PCOS. In the present study, we first treated a letrozole-induced PCOS rat model with metformin, detected the pathological recovery of PCOS, and then assessed the effects of metformin on H2O2-induced autophagy in ovarian granulosa cells (GCs) by detecting the level of oxidative stress and the expression of autophagy-associated proteins and key proteins in the PI3K/AKT/mTOR pathway. We demonstrated that metformin ameliorated PCOS in a rat model by downregulating autophagy in GCs, and metformin decreased the levels of oxidative stress and autophagy in H2O2-induced GCs and affected the PI3K/AKT/mTOR signaling pathway. Taken together, our results indicate that metformin ameliorates PCOS in a rat model by decreasing excessive autophagy in GCs via the PI3K/AKT/mTOR pathway, and this study provides evidence for targeted reduction of excessive autophagy of ovarian granulosa cells and improvement of PCOS.

Pharmacological efficacy of the traditional Chinese medicinal formula Kun-Tai-1A in the treatment of letrozole-induced polycystic ovary syndrome

Pharmacological efficacy of the traditional Chinese medicinal formula Kun-Tai-1A in the treatment of letrozole-induced polycystic ovary syndrome

New alternative herbal remedies for treatment of letrozole-induced polycystic ovary syndrome in rats

New alternative herbal remedies for treatment of letrozole-induced polycystic ovary syndrome in rats

Cysteine-Cysteine Motif Chemokine Receptor 5 Expression in Letrozole-Induced Polycystic Ovary Syndrome Mice.

Polycystic ovary syndrome (PCOS), which affects 5–10% of women of reproductive age, is associated with reproductive and metabolic disorders, such as chronic anovulation, infertility, insulin resistance, and type 2 diabetes. However, the mechanism of PCOS is still unknown. Therefore, this study used a letrozole-exposed mouse model in which mice were orally fed letrozole for 20 weeks to investigate the effects of letrozole on the severity of reproductive and metabolic consequences and the expression of cysteine–cysteine motif chemokine receptor 5 (CCR5) in letrozole-induced PCOS mice. The letrozole-treated mice showed a disrupted estrous cycle and were arrested in the diestrus phase. Letrozole treatment also increased plasma testosterone levels, decreased estradiol levels, and caused multicystic follicle formation. Furthermore, histological analysis of the perigonadal white adipose tissue (pgWAT) showed no significant difference in the size and number of adipocytes between the letrozole-treated mice and the control group. Further, the letrozole-treated mice demonstrated glucose intolerance and insulin resistance during oral glucose and insulin tolerance testing. Additionally, the expression of CCR5 and cysteine-cysteine motif ligand 5 (CCL5) were significantly higher in the pgWAT of the letrozole-treated mice compared with the control group. CCR5 and CCL5 were also significantly correlated with the homeostasis model assessment of insulin resistance (HOMA-IR). Finally, the mechanisms of insulin resistance in PCOS may be caused by an increase in serine phosphorylation and a decrease in Akt phosphorylation.

Ficus deltoidea ameliorates biochemical, hormonal, and histomorphometric changes in letrozole-induced polycystic ovarian syndrome rats

BackgroundInsulin resistance and hormonal imbalances are key features in the pathophysiology of polycystic ovarian syndrome (PCOS). We have previously shown that Ficus deltoidea var. deltoidea Jack (Moraceae) can improve insulin sensitivity and hormonal profile in PCOS female rats. However, biological characteristics underpinning the therapeutic effects of F. deltoidea for treating PCOS remain to be clarified. This study aims to investigate the biochemical, hormonal, and histomorphometric changes in letrozole (LTZ)-induced PCOS female rats following treatment with F. deltoidea.MethodsPCOS was induced in rats except for normal control by administering LTZ at 1 mg/kg/day for 21 days. Methanolic extract of F. deltoidea leaf was then orally administered to the PCOS rats at the dose of 250, 500, or 1000 mg/kg/day, respectively for 15 consecutive days. Lipid profile was measured enzymatically in serum. The circulating concentrations of reproductive hormone and antioxidant enzymes were determined by ELISA assays. Ovarian and uterus histomorphometric changes were further observed by hematoxylin and eosin (H&E) staining.ResultsThe results showed that treatment with F. deltoidea at the dose of 500 and 1000 mg/kg/day reduced insulin resistance, obesity indices, total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL), malondialdehyde (MDA), testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) to near-normal levels in PCOS rats. The levels of high-density lipoprotein cholesterol (HDL), estrogen, and superoxide dismutase (SOD) are also similar to those observed in normal control rats. Histomorphometric measurements confirmed that F. deltoidea increased the corpus luteum number and the endometrial thickness.ConclusionsF. deltoidea can reverse PCOS symptoms in female rats by improving insulin sensitivity, antioxidant activities, hormonal imbalance, and histological changes. These findings suggest the potential use of F. deltoidea as an adjuvant agent in the treatment program of PCOS.

Differential expression and interaction of melatonin and thyroid hormone receptors with estrogen receptor α improve ovarian functions in letrozole-induced rat polycystic ovary syndrome

AimsThe objective of the present study was to investigate the effect of melatonin and L-thyroxine (T4) on the expression of various receptors, and some metabolic, reproductive, and gonadotropic hormones in letrozole-induced polycystic ovary syndrome (PCOS) in rats. Material and methodsAssessment of gravimetric, hormonal profile and thyroid histology and relative expression of melatonin receptors (MT1, MT2) and estrogen receptor α (Erα) in thyroid and ovary, and type II iodothyronine deiodinase (Dio2) and thyroid hormone receptor α (TRα) in the ovary were performed using standard protocols. Key findingsA significant increase in thyroid follicles numbers was noted in the hyperthyroid rat. T4 treatment to PCOS showed the expected increment in the circulating level of triiodothyronine (T3) and T4. Melatonin and T4 treatment of PCOS rats resulted in a significant decrease in the circulating level of T3 and T4. Hyperthyroid rats showed a decrement in plasma melatonin levels. However, T4 treatment to PCOS rats showed increased circulating melatonin levels, and a decrease in the circulating level of gonadotropins (LH and FSH), and testosterone. Melatonin treatment to PCOS-hyperthyroid rats resulted in the normal expression of ovarian and thyroid MT1 and ERα, receptors, which had been altered in PCOS and hyperthyroid rats, without any significant change in the MT2 receptor. SignificanceThe present findings suggest a fine interplay and cross-talk via melatonin and its two receptors with ERα, TRα, and Dio2in thyroid and ovarian tissue during PCOS and hyperthyroidism pathogenicity.

Effects of Soy Isoflavones, Resistant Starch and Antibiotics on Polycystic Ovary Syndrome (PCOS)-Like Features in Letrozole-Treated Rats.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women. Recently, various dietary interventions have been used extensively as a novel therapy against PCOS. In the present study, we show that soy isoflavone metabolites and resistant starch, together with gut microbiota modulations, were successful in decreasing the severity of PCOS-like reproductive features while increasing the expression of gut barrier markers and butyric acid in the gut. In the letrozole-induced PCOS model rats, the intake of both 0.05% soy isoflavones and 11% resistant starch, even with letrozole treatment, reduced the severity of menstrual irregularity and polycystic ovaries with a high concentration of soy isoflavones and equol in plasma. Antibiotic cocktail treatment suppressed soy isoflavone metabolism in the gut and showed no considerable effects on reducing the PCOS-like symptoms. The mRNA expression level of occludin significantly increased with soy isoflavone and resistant starch combined treatment. Bacterial genera such as Blautia, Dorea and Clostridium were positively correlated with menstrual irregularity under resistant starch intake. Moreover, the concentration of butyric acid was elevated by resistant starch intake. In conclusion, we propose that both dietary interventions and gut microbiota modulations could be effectively used in reducing the severity of PCOS reproductive features.

Effect of Green Tea extract (Camellia sinensis) on Polycystic Ovary Syndrome-Induced by Letrozole in Adult Female Wistar Rats

Green tea (Camellia sinensis), has always been a focus of interest in traditional medicine for its biochemical and medicinal properties as an antioxidant agent. Polycystic ovary syndrome (PCOS) is a common endocrinopathy among women of reproductive age. In the present study, the effects of green tea extract on letrozole-induced PCOS were evaluated. 48 adult female Wistar rats were assigned to eight groups in random: healthy control group (no treatment), PCOS control group (letrozole at 1 mg/kg by gavage), three healthy experimental groups (green tea extract at 50, 100 and 200 mg/kg body weight by gavage), and three experimental PCOS groups (green tea extract at 50, 100 and 200 mg/kg body weight + letrozole at 1 mg/kg by gavage). On the 28th day (at the end of the experiment), the rats were euthanized, and the antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) and lipid peroxidation were assessed in the ovarian tissue homogenates. The results indicated that the green tea extract significantly increased the activities of the antioxidant enzymes and decreased lipid peroxidation significantly (p<0.001). Our results showed that the green tea extract was also effective in treating letrozole-induced PCOS in the rats by increasing the activities of the antioxidant enzymes.

Effects of Metformin on Reproductive, Endocrine, and Metabolic Characteristics of Female Offspring in a Rat Model of Letrozole-Induced Polycystic Ovarian Syndrome With Insulin Resistance.

The beneficial effects of metformin, especially its capacity to ameliorate insulin resistance (IR) in polycystic ovary syndrome (PCOS), explains why it is widely prescribed. However, its effect on the offspring of patients with PCOS remains uncertain. This study investigated the impact of metformin treatment on the first- and second-generation female offspring born to letrozole-induced PCOS-IR rats. Forty-five female Wistar rats were implanted with continuous-release letrozole pellets or placebo and treated with metformin or vehicle control. Rats exposed to letrozole showed PCOS-like reproductive, endocrine, and metabolic phenotypes in contrast to the controls. Metformin significantly decreased the risk of body weight gain and increased INSR expression in F1 female offspring in PCOS-IR rats, contributing to the improvement in obesity, hyperinsulinemia, and IR. Decreased FSHR expression and increased LHCGR expression were observed in F1 female rats of the PCOS-IR and PCOS-IR+Metformin groups, suggesting that FSHR and LHCGR dysfunction might promote the development of PCOS. Nevertheless, we found no significant differences in INSR, FSHR, and LHCGR expression or other PCOS phenotypes in F2 female offspring of PCOS-IR rats. These findings indicated widespread reproductive, endocrine, and metabolic changes in the PCOS-IR rat model, but the PCOS phenotypes could not be stably inherited by the next generations. Metformin might have contributed to the improvement in obesity, hyperinsulinemia, and IR in F1 female offspring. The results of this study could be used as a theoretical basis in support of using metformin in the treatment of PCOS-IR patients.

Sıçanlarda letrozolün indüklediği polikistik over sendromunda fisetinin etkileri

Amaç: Bu çalışmanın amacı sıçanlarda letrozolle oluşturulmuş PKOS (polikistik over sendromu) üzerinde fisetinin antioksidan etkilerini değerlendirmektir.&#x0D; Gereç ve Yöntem: Çalışmada 36 adet Albino Wistar dişi sıçan kullanıldı. Dişi sıçanlara, PKOS modelini indüklemek için 21 gün boyunca %1 karboksimetil selüloz (2 mL/kg) içinde çözülmüş 1 mg/kg dozunda letrozol oral yolla uygulanmıştır. PKOS oluşturulduktan sonra 7 gün boyunca metformin ve fisetin kendi gruplarına uygulandı. Hayvanların overleri alındı ve biyokimyasal, histolojik incelemeler için uygun koşullarda saklandı.&#x0D; Bulgular: PKOS grubunda sağlıklı gruba göre glutatyon (GSH) seviyelerinde düşüş, malondialdehit (MDA) seviyelerinde artış görüldü. PKOS+MET+FIS25 (PKOS+20 mg/kg metformin+25 mg/kg fisetin) ve PKOS+MET+FIS50 (PKOS+20 mg/kg metformin+50 mg/kg fisetin) gruplarında doza bağlı olarak GSH seviyelerinin yükseldiği, MDA seviyelerinin düştüğü tespit edildi. Histolojik bulgularda PKOS grubunda kontrol grubuna göre çok sayıda kistik folikül içerdiği görüldü. PKOS+MET+FIS25 ve PKOS+MET+FIS50 gruplarında doza bağlı olarak kistik foliküllerin ve foliküllerin içerdiği apoptotik ve nekrotik hücrelerin azaldığı görüldü. &#x0D; Sonuç: Sonuç olarak, fisetin metforminin ortadan kaldıramadığı oksidatif hasarı engelleyerek faydalı etkiler göstermiştir. Fisetin antioksidan aktivite göstererek yeni hücrelerin nekroza gitmesini engellemiş ve korumuştur. Bundan dolayı metformin tedavisine fisetin eklenmesi faydalı olacaktır.

Polycystic Ovary Syndrome Can Lead to Neurocognitive Changes in Female Rats Treated with Letrozole

Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in premenopausal women. Brain functions may be affected in PCOS, and studies reported that PCOS patients are at greater risk for developing mental health conditions, including anxiety or depression. Objectives: This study was designed to evaluate the neurocognitive changes in letrozole-induced PCOS model. Methods: Twenty female Wistar rats (eight-week-old; 160 ± 10 g) were divided into two groups. Group one received vehicle only (carboxymethyl cellulose, orally) once daily, and group two received letrozole (1 mg/kg, orally) once daily. Drugs or vehicles were administered for 21 days. Afterward, behavioral tests, including forced swimming test, open field test, and Y-maze alteration task, were performed. Ovaries were removed after behavioral tests and assessed histologically to confirm the induction of PCOS. Results: Animals with PCOS developed depressive-like behaviors compared with control in forced swimming test (P &lt; 0.001). Anxiety-like behaviors were detected in letrozole-induced PCOS group (P &lt; 0.05). Moreover, animals with PCOS exhibited memory impairment in comparison to normal animals in Y-maze memory assessment (P &lt; 0.05). Conclusions: Rats with PCOS showed a neurocognitive decline in the model of letrozole administration. Future studies should be conducted to clarify the exact mechanisms of these changes and possible approaches to restore them.

Intestinal Flora is a Key Factor in Insulin Resistance and Contributes to the Development of Polycystic Ovary Syndrome.

ContextThe key gut microbial biomarkers for polycystic ovarian syndrome (PCOS) and how dysbiosis causes insulin resistance and PCOS remain unclear.ObjectiveTo assess the characteristics of intestinal flora in PCOS and explore whether abnormal intestinal flora can affect insulin resistance and promote PCOS and whether chenodeoxycholic acid (CDCA) can activate intestinal farnesoid X receptor (FXR), improving glucose metabolism in PCOS.Setting and designThe intestinal flora of treatment-naïve PCOS patients and hormonally healthy controls was analyzed. Phenotype analysis, intestinal flora analysis, and global metabolomic profiling of caecal contents were performed on a letrozole-induced PCOS mouse model; similar analyses were conducted after 35 days of antibiotic treatment on the PCOS mouse model, and glucose tolerance testing was performed on the PCOS mouse model after a 35-day CDCA treatment. Mice receiving fecal microbiota transplants from PCOS patients or healthy controls were evaluated after 10 weeks.Results Bacteroides was significantly enriched in treatment-naïve PCOS patients. The enrichment in Bacteroides was reproduced in the PCOS mouse model. Gut microbiota removal ameliorated the PCOS phenotype and insulin resistance and increased relative FXR mRNA levels in the ileum and serum fibroblast growth factor 15 levels. PCOS stool-transplanted mice exhibited insulin resistance at 10 weeks but not PCOS. Treating the PCOS mouse model with CDCA improved glucose metabolism.Conclusions Bacteroides is a key microbial biomarker in PCOS and shows diagnostic value. Gut dysbiosis can cause insulin resistance. FXR activation might play a beneficial rather than detrimental role in glucose metabolism in PCOS.

Spexin and Metformin Comparative Ameliorated Ovarian and Liver Function Changes in Letrozole-Induced Polycystic Ovary Syndrome in Rats (Histological, Biochemical, Immunohistochemical and Morphometric study)

Background: Polycystic ovary syndrome (PCOS) is characterized by polycystic ovarian follicle morphology, ovulatory dysfunction, hyperandrogenism and insulin resistance. Spexin has a role in satiety control, lipid and glucose metabolism. Metformin is an insulin sensitizing agent that has some hepato-protective functions. Aim: This study aimed to declare and compare the effect of spexin and metformin treatment on ovarian and liver function changes in letrozole-induced PCOS in rats and the possible mechanisms involved.Methods: Thirty-two adult female Wistar albino rats divided into control, polycystic ovary syndrome (PCOS), PCOS metformin-treated, and PCOS spexin-treated groups. In PCOS groups, rats were given oral letrozole 0.5 mg/kg dissolved in 0.9% NaCl once daily along the study. In PCOS metformin-treated group, rats were treated with metformin hydrochloride orally (300 mg/kg/day) for the last 4 weeks. In PCOS spexin-treated group, rats were treated with spexin i.p. 35 μg/kg/day, dissolved in normal saline for the last 4 weeks. Results: In PCOS group, there was a significant increase in; BMI, relative ovarian weight, HOMA-IR, serum (LH, FSH, testosterone, insulin, glucose, TC, TG, LDL, ALT, AST, alkaline phosphatase, total & direct bilirubin) and hepatic (MDA, NO & TNF-), with a significant decrease in; serum [estradiol, progesterone, HDL, albumin and spexin] and hepatic GPX, when compared with the control group. Histopathological results showed ovaries of PCOS marked expression of caspase-3 and P53 and decreased KI67 expression of granulosa and theca cells. Vacuolated hepatocytes, dilated and congested portal vein and positive reaction of immunostaining with αSMA, caspase and TNFα. Treatment of PCOS rats with either metformin or spexin reversed these changes significantly.Conclusion: Spexin serum level could be used as a metabolic biomarker for polycystic ovary syndrome. Also, treatment with either metformin or spexin ameliorated ovarian and hepatic dysfunctions in rat model of PCOS through their insulin sensitizing, anti-oxidant and anti-inflammatory effects.

Shaoyao-Gancao Decoction Ameliorates the Inflammation State in Polycystic Ovary Syndrome Rats via Remodeling Gut Microbiota and Suppressing the TLR4/NF-κB Pathway

Background: Emerging evidence suggests that gut microbiota plays a vital role in the occurrence of multiple endocrine disorders including polycystic ovary syndrome (PCOS). Shaoyao-Gancao Decoction (SGD), a classical Chinese prescription, has been widely used in the treatment of PCOS for decades. In previous studies, we found that SGD treatment could effectively reduce ovarian inflammation in PCOS rats. However, whether the anti-inflammation effect of SGD involves the regulation of the gut microbiota remains elusive. Methods: Letrozole-induced PCOS rat models were established, and the therapeutic effects of SGD were evaluated. Specifically, body weight, serum hormone concentrations, estrus phase and ovary histopathology were assessed. Then the structure of gut microbiota was determined by 16s rRNA sequencing. Additionally, the serum levels of pro-inflammatory cytokines and LPS were measured by ELISA kits. The key gene and protein expressions of TLR4/NF-κB signaling pathway were detected by quantitative real-time PCR and western blot. Results: SGD could effectively reduce body weight, regulate estrous cycles and ameliorate hyperandrogenism in PCOS rats. In addition, SGD treatment decreased releases of pro-inflammatory cytokines, enhanced the expressions of tight junction (occludin and claudin1), and then prevented a translocation of LPS into bloodstream. SGD could significantly reduce the ratio of Firmicutes to Bacteroidetes, decrease the abundance of LPS-producing pathogens Proteobateria and enrich the abundance of Butyricicoccus, Coprococcus, Akkermansia Blautia and Bacteroides in PCOS rats. Furthermore, SGD blunted the key gene and protein expressions of TLR4/NF-κB signaling pathway both in vivo and in LPS-induced RAW264.7 cells. Conclusion: SGD administration could ameliorate the inflammatory response in PCOS rats by remodeling gut microbiome structure, protecting gut barrier, and suppressing TLR4/NF-κB signaling pathway.

Dietary proanthocyanidins alleviated ovarian fibrosis in letrozole-induced polycystic ovary syndrome in rats.

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.

LOW DOSE SPIRONOLACTONE PROTECTS EXPERIMENTALLY-INDUCED POLYCYSTIC OVARIAN SYNDROME FROM INSULIN-RESISTANT METABOLIC DISTURBANCES

Objective: Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women of reproductive age and hyperandrogenism is a prominent feature of PCOS resulting in infertility and increased risk of developing metabolic disorders including insulin resistance (IR), abdominal adiposity, glucose intolerance and cardiovascular diseases. Spironolactone (SPL), a non-selective mineralocorticoid receptor (MR) antagonist, has been in wide clinical use for several decades. In this study, we investigated the effects of SPL on IR and metabolic disturbances in letrozole-induced PCOS rats. Design and method: Eighteen adults female Wistar rats were randomly divided into 3 groups and treated with vehicle, letrozole (LET; 1 mg/kg) and LET + SPL (SPL; 0.25 mg/kg), p.o. once daily for 21 consecutive days. Results: Results showed that LET treatment induced PCOS characterized by elevated plasma testosterone and luteinizing hormone (LH) accompanied with increased body weight and visceral adiposity, IR, glucose intolerance, dyslipidemia and altered histomorphological ovaries. Treatment with SPL however attenuated the elevated testosterone in LET-induced PCOS model accompanied with a reversal in all the observed alterations. Conclusions: Taken together, analysis of the physical, biochemical and histological evidences shows that the protective effect of this very low dose spironolactone may be through its anti-androgenic mechanism. In conclusion, this study shows for first time, the protective effect of spironolactone at this dose against insulin resistance and metabolic disturbances induced by experimental PCOS. The protective mechanisms appears to be through suppression of elevated circulating testosterone. Therefore, SPL alone at this very low dose might be very effective as against its combination with other known anti-androgenic drugs in the treatment of characteristic features of PCOS.

Letrozole-Induced Polycystic Ovary Syndrome Attenuates Cystathionine-β Synthase mRNA and Protein Abundance in the Ovaries of Female Sprague Dawley Rats.

Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 10% of reproductive-aged women and leads to hyperandrogenism, anovulation, and infertility. PCOS has been associated with elevated serum homocysteine as well as altered methylation status; however, characterization of one-carbon metabolism (OCM) in PCOS remains incomplete. The aim of our research was to assess OCM in a letrozole-induced Sprague Dawley rat model of PCOS. Five-week-old female rats (n=36) were randomly assigned to letrozole [0.9mg/kg body weight (BW)] treatment or vehicle (carboxymethylcellulose) control that was administered via subcutaneously implanted slow-release pellets every 30 d. For both treatment groups, 12 rats were randomly assigned to be euthanized during proestrus at one of the following time points: 8, 16, or 24 wk of age. Daily BW was measured and estrous cyclicity was monitored during the last 30 d of the experimental period. Ovaries were collected to assess mRNA and protein abundance of OCM enzymes. Letrozole-induced rats exhibited 1.9-fold higher cumulative BW gain compared with control rats across all age groups (P <0.0001). Letrozole reduced the time spent at proestrus (P=0.0001) and increased time in metestrus (P<0.0001)of the estrous cycle. Cystathionine β-synthase (Cbs) mRNA abundance was reduced in the letrozole-induced rats at 16 (59%; P <0.05) and 24 (77%; P <0.01) wk of age. In addition, CBS protein abundance was 32% lower in 8-wk-old letrozole-induced rats (P=0.02). Interestingly, betaine-homocysteine S-methyltransferase mRNA abundance increased as a function of age in letrozole-induced rats (P=0.03). These data demonstrate that letrozole-induced PCOS Sprague Dawley rats temporally decrease the ovarian abundance of Cbs mRNA and protein in the early stages of PCOS.

Ovarian cysts disappear after 14-day oral regimen of Korean red ginseng extract in letrozole-induced polycystic ovarian syndrome.

ObjectiveHormonal and inflammatory mechanisms are involved in the pathogenesis of polycystic ovarian syndrome (PCOS), which is a prevalent metabolic disorder among women of reproductive age. We aimed to evaluate the comparative efficiency of short-term oral administration of Korean red ginseng extract (KRGE) and the standard treatment on PCOS by focusing on the histopathological parameters and serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and nuclear factor kappa B (NF-κB).MethodsA PCOS rat model was established by oral gavage of letrozole (1 mg/kg) for 21 days. The serum levels of LH, FSH, testosterone, and NF-κB were measured, and the morphological features and differences of the ovaries were examined in each group using a light microscope before and after 14 days of treatment with oral regimens—KRGE, oral contraceptives (OCPs), KRGE+OCPs, and carboxymethyl cellulose (CMC).ResultsOCPs alone could not normalize the mean ovarian weights of PCOS rats despite the 14-day oral regimen, but they were more effective in reducing the number and size of cysts compared to others. KRGE alone and in combination with OCPs was effective in normalizing abnormal ovarian weights, decreasing LH serum levels, and dissipating the ovarian cysts in PCOS rats. However, when combined with the standard regimen, KRGE showed additional therapeutic effects by efficiently reducing serum testosterone and NF-κB levels.ConclusionOur necropsy and histopathological evidence suggests the efficacy of KRGE as a novel integrative medicine against abnormal multiple follicular cysts. However, antiandrogenic and anti-inflammatory effects were only seen in animals that were administered a combination of KRGE and the standard regimen.

Combined effects of Gymnema sylvestre and Pergularia daemia on letrozole-induced polycystic ovarian syndrome in 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&lt;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.