Rat Model Of Polycystic Ovary Syndrome Research Articles

Evaluation of the Effects of Naringenin on the Hypothalamic mRNA Levels of nesfatin-1 and CRH in a rat Model of PCOS

Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder and a leading cause of infertility in women. Studies suggest that naringenin may improve ovarian function; however, its molecular mechanism within the hypothalamus-pituitary-gonad (HPG) axis remains unclear. Objectives: This study investigated the role of naringenin on the expression of corticotropin-releasing hormone (CRH) and nesfatin-1 genes in the hypothalamus of PCOS rats. Methods: Twenty rats, each weighing 180 - 200 g, were divided into four groups (n = 5). Polycystic ovary syndrome was induced by administering estradiol valerate (2 mg per rat). The control and PCOS groups received saline, while the other two PCOS groups received intraperitoneal injections of naringenin at doses of 20 and 50 mg/kg for 14 days. Hypothalamic samples were collected to measure gene expression via real-time PCR. Results: The PCOS group showed a significant decrease in CRH and nesfatin-1 gene expression compared to the control group (P ≤ 0.05). Naringenin treatment significantly increased the expression of CRH and nesfatin-1 genes in comparison to the PCOS group (P ≤ 0.05). Conclusions: Naringenin appears to have therapeutic potential in improving ovarian function in PCOS. Its effects are mediated through up-regulation of hypothalamic neuropeptides upstream of GnRH neurons.

The mechanism of NF-κB-TERT feedback regulation of granulosa cell apoptosis in PCOS rats.

Patients with Polycystic ovary syndrome (PCOS) have chronic low-grade ovarian inflammation. Inflammation can cause telomere dysfunction, and telomere and telomerase complex are also involved in regulating inflammation. However, the specific mechanisms of inflammatory signaling feedback and telomere-telomerase mutual regulation remain to be discovered. This study elucidates the role of Nuclear factor kappa-B (NF-κB)-Telomerase reverse transcriptase (TERT) feedback in PCOS granulosa cell apoptosis. Using letrozole and a high-fat diet, a PCOS rat model was established, along with a Lipopolysaccharide (LPS) -treated KGN cell inflammation model was established. NF-κB and TERT inhibitors (BAY 11-7082 and BIBR1532) were then administered to LPS-induced KGN cells. PCOS rats displayed disrupted estrous cycles, increased weight, elevated serum testosterone, cystic follicles, granulosa cell layer thinning, and reduced corpora lutea count (P are all less than 0.05). In PCOS rat ovaries, NF-κB, Interleukin-6 (IL-6), Tumor Necrosis Factor α (TNF-α), TERT, Bax, and Caspase-3 exhibited notable upregulation, while Bcl-2 decreased, with telomere elongation (P are all less than 0.05). There were significant correlations among NF-κB-related inflammatory factors, TERT and apoptotic factors, and they were positively correlated with Bax and Caspase-3, and negatively correlated with Bcl-2 (P are all less than 0.05). LPS-treated KGN cells demonstrated increased expression of inflammatory and pro-apoptotic factors, later restored post-treatment with NF-κB and TERT inhibitors (P are all less than 0.05). In conclusion, TERT may induce granulosa cell apoptosis by participating in the regulation of the NF-κB signaling pathway, thereby mediating the chronic inflammatory response of PCOS through downstream inflammatory factors IL-6 and TNF-α.

Nicotinamide Mononucleotide Improves Endometrial Homeostasis in a Rat Model of Polycystic Ovary Syndrome by Decreasing Insulin Resistance and Regulating the Glylytic Pathway.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that can lead to insulin resistance (IR) and dysregulation of glucose metabolism, resulting in an imbalance in the endometrial environment, which is unfavorable for embryo implantation of PCOS. This study aims to investigate whether nicotinamide mononucleotide (NMN) improves the stability of the endometrium in a rat model of PCOS and identifies whether it is related to reduce IR and increase glycolysis levels and its potential signaling pathway. Female Sprague-Dawley (SD) rats are fed letrozole and a high-fat diet (HFD) to form the PCOS model, then the model rats are treated with or without NMN. It randomly divided into control, PCOS, and PCOS-NMN groups according to the feeding and treating method. Compared with the PCOS group, the regular estrous cycles are restored, the serum androgen (p<0.01) and fasting insulin levels (p<0.05) are reduced, and endometrial morphology (p<0.05) is improved in NMN-PCOS group. Furthermore, NMN inhibits endometrial cell apoptosis, improves endometrial decidualization transition, reduces IR, restores the expression of glycolysis rate-limiting enzymes, and activates the PI3K/AKT pathway in the uterus. These results suggest that NMN enhances endometrial tissue homeostasis by decreasing uterine IR and regulating the glycolysis through the PI3K/AKT pathway.

Multiple Benefits of Empagliflozin in PCOS: Evidence from a Preclinical Rat Model.

Polycystic ovary syndrome (PCOS) is the most common complex endocrinological condition of women that is associated with infertility and metabolic disorders during the reproductive period. Recently, a great deal of research has focused on the etiopathogenesis of this disorder and the modulation of therapeutic approaches. There are still many controversies in the choice of therapy, and metformin is one of the most commonly used agents in the treatment of PCOS. Considering the link between metabolic disorders and PCOS, glycemic status is crucial in these patients, and sodium-glucose cotransporter type 2 inhibitors (SGLT2is) represent a potentially promising new therapeutic approach. These drugs have been shown to improve glucose metabolism, reduce adipose tissue, decrease oxidative stress, and protect the cardiovascular system. These data prompted us to investigate the effects of empagliflozin (EMPA) in a PCOS rat model and compare them with the effects of metformin. We confirmed that EMPA positively affects somatometric parameters, glucose and lipid metabolism, and the levels of sex hormones, as well as reduces oxidative stress and improves ovarian function and morphology. Administration of EMPA at doses of 5 mg/kg, 15 mg/kg, and 45 mg/kg during a 4-week treatment period improved, as induced by estradiol valerate and a high-fat diet, the metabolic and reproductive statuses in a PCOS rat model. The best effects, which were comparable to the effects of metformin, were achieved in groups receiving the middle and highest applied doses of EMPA. These results may prompt further clinical research on the use of EMPA in patients with PCOS.

Antioxidant activity of self-nanoemulsifying drug delivery system (SNEDDS) of Curcuma longa in polycystic ovary syndrome rat model

Purpose: To investigate the effect of SNEDDS containing Curcuma longa extract on hormonal and histological improvement of polycystic ovary syndrome (PCOS) rat model. Method: A total of 36 female Wistar rats, aged between 8 and 10 weeks, were randomly divided into 6 groups, including control (normal rats), PCOS (untreated PCOS rats), PCOS + M (treated with 20 mg/kg bw/day metformin), PCOS + SC25, PCOS + SC50, and PCOS + SC100 (treated with Curcuma longa extract at 25, 50, and 100 mg/kg/day with SNEDDS, respectively). This study used a posttest-only control group design. The rats were euthanized on day 15, and blood samples were taken to examine malondialdehyde (MDA) and anti-mullerian hormone (AMH) levels. Ovarian tissue was prepared on a histological slide, and various follicles were observed. Data was analyzed using analysis of variance (ANOVA) and Kruskal-Wallis tests. Results: Curcuma longa extract, at 50 and 100 mg/kg, incorporated in SNEDDS resulted in a significant reduction in the corpus luteum number and width of the granulosa layer (p &lt; 0.05). Also, Curcuma longa significantly reduced malondialdehyde (MDA), anti-mullerian hormone (AMH), preantral follicles, and follicular cysts (p &lt; 0.05). Conclusion: Curcuma longa extract in SNEDDS reduces MDA and AMH levels and improves the histology of the ovaries in PCOS model rats. There is a need to conduct further studies of C. longa extract or isolates in SNEDDS using human cell lines of PCOS model.

7872 Adiponectin Enhances Hepatic Insulin Sensitivity in a Rat Model of Polycystic Ovary Syndrome: Role of PI3K/Akt/mTORC2 Pathway

Abstract Disclosure: A. Abdelhameed: None. S. Rezq: None. R.M. Vinson: None. J. Flaherty: None. B. Kim: None. D.G. Romero: None. L.L. Yanes Cardozo: None. Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women and is associated with a high prevalence of obesity and insulin resistance (IR). Phosphoinositide-3-kinase (PI3K)/Akt/ the mammalian target of rapamycin complex 2 (mTORC2) pathway is one major insulin signaling pathway and its impairment is involved in multiple metabolic disorders by inducing IR. Phosphorylation of protein kinase B (Akt) at (Ser)-473 by mTORC2 leads to its full activation and subsequently enhances insulin sensitivity. Adiponectin is a peptide secreted by adipocytes that increases insulin sensitivity. PEG-BHD1028 is a novel potent peptide adiponectin receptor agonist that enhances insulin sensitivity in different models of diabetes. However, its potential to attenuate androgen-mediated hepatic IR by modulating PI3K/Akt/mTORC2 pathway remains unknown in PCOS. Hypothesis: We tested the hypothesis that PEG-BHD1028 attenuates hepatic IR via modulating PI3K/Akt/mTORC2 pathway in a rat model of PCOS. Methods: To induce PCOS, four-week-old female Sprague Dawley rats were implanted with dihydrotestosterone (DHT) silastic tubes (7.5mg) or placebo (PBO) for 90 days (n=4-8/group). During the final three weeks of DHT treatment, rats received PEG-BHD1028 (25μg/kg/day) subcutaneously. Body weight (BW) by gravimetry, fat and lean mass were measured by Echo-MRI. Fasting plasma insulin was measured by ELISA while fasting plasma glucose was measured with a clinical chemistry analyzer. HOMA-IR, an index of systemic IR, was calculated. Protein levels of insulin signaling markers including IRS1, p-IRS1 (Ser1101), PI3 kinase p110, Akt, p-Akt (Ser473), mTOR, p-mTOR (Ser2481) and mTORC2 regulatory protein Rictor were quantified in the liver by Western-blot. Results: DHT significantly (p&amp;lt;0.05) increased BW, fat mass and lean mass by 1.4-, 2.2-, 1.4- folds, respectively compared to PBO group. DHT significantly (p&amp;lt;0.05) increased HOMA-IR by 3.8- fold, compared to PBO group. DHT downregulated hepatic p-Akt, Akt and mTOR protein expression by 20% to 40% while upregulating IRS-1 by 1.6- fold with no impact on PI3 kinase, p-mTOR, Rictor and p-IRS1 compared to the PBO group. PEG-BHD1028 significantly decreased BW, fat mass and lean mass while attenuating IR (34.7% reduction in HOMA-IR) in PCOS rats. Interestingly, PEG-BHD1028 significantly (p&amp;lt;0.05) increased PI3K, active Akt (pAKT), mTOR and Rictor levels by 1.6-, 2.2-, 1.5-, 1.8- folds, respectively with no effect on the other insulin signaling markers compared to vehicle-treated group. Conclusion: Our findings suggest that PEG-BHD1028 is a novel and effective therapeutic agent to attenuate hepatic IR in PCOS via activating PI3K/Akt/mTORC2 pathway. Significance: Targeting adiponectin signaling could be a novel and effective therapeutic approach to mitigate metabolic dysfunction in females with excess androgens. Presentation: 6/2/2024

Effect of Vitamin D3 on Uterine Morphology and Insulin Signaling in a Polycystic Ovary Syndrome (PCOS) Rat Model

Abstract Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women of reproductive age leading to infertility. Besides reproductive and hormonal disturbances, PCOS is often characterized by vitamin D3 (VD) deficiency. This study aimed to determine the effect of VD on uterine histoarchitecture, the biochemical composition of gland secretions, and the insulin signal transduction pathway using a PCOS rat model. The experiment was conducted on four animal groups (n=8/group): control (C), VD supplemented (VD; 500 IU/day), letrozole-treated (PCOS; 1 mg/kg body weight), and VD-treated PCOS (PCOS+VD) group. Herein, VD supplementation did not improve histomorphometric parameters in the PCOS uterus, whereas clearly influenced sugar composition in uterine gland secretions, restoring their content to that observed in the C group. Furthermore, we found that VD can reduce peripheral and local uterine insulin resistance developed in the PCOS rats via activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and subsequent glucose metabolism in the uterus. To sum up, the present results suggest a possible beneficial role of VD supplementation for the maintenance of uterus functions in PCOS rats.

Dihydrotestosterone induces reactive oxygen species accumulation and mitochondrial fission leading to apoptosis of granulosa cells

Dihydrotestosterone (DHT), which has significant androgenic activity，is a major player in follicle development and ovary function in females. However, an excess of androgens may result in increased follicular apoptosis with adverse effects on female fertility. This study aimed to explore the mechanism by which DHT induces apoptosis in human ovarian granulosa cells (GCs). The association between DHT and GC apoptosis was explored by the construction of rat models of polycystic ovary syndrome (PCOS). It was found that serum DHT levels were negatively correlated with thickness of the GC layer in PCOS model rats (R2=0.8342, p＜0.0001), compared with control rats, together with significant increases in cofactors (Fis1: p=0.008; MFF: p=0.044). The GC SVOG cell line was used to clarify the mechanism by which DHT influenced GC apoptosis in in vitro experiments. The results confirmed that apoptosis in SVOG cells was positively associated with the DHT dose. The expression of the autophagy-related proteins LC3A/B (p=0.027) and the proapoptotic protein Bax (p=0.0095) were increased, while that of the anti-apoptotic protein Bcl-2 (p=0.0005) was decreased in the high-dose DHT group. ROS levels were significantly increased (p=0.0237) and the mitochondrial membrane potential ΔΨm was decreased (p=0.0194). Moreover, ultrastructural analysis of the mitochondria indicated significant damage. The results of RT-qPCR and western blotting showed that two fission cofactor-Fis1（p=0.034） and MFF (p=0.039) were significantly increased after treatment with high doses of DHT. Even though the overall expression of Drp1 did not change significantly (p=0.5961), that of activated Phosphor-Drp1(Ser616) was significantly increased (p=0.046), while the expression of Phosphor-Drp1 (Ser637) was markedly reduced (p=0.007) following exposure to high concentrations of DHT. All these effects could be reversed by the Drp1 inhibitor Mdivi-1. These findings indicated the impact of DHT on ROS aggregation and mitochondrial fission, resulting in GC apoptosis. An imbalance in Drp1 phosphorylation may be the key link in DHT-induced excessive mitochondrial fission.

Mangiferin ameliorates polycystic ovary syndrome in rats by modulating insulin resistance, gut microbiota, and ovarian cell apoptosis.

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder characterized by hyperandrogenism, prolonged anovulation and polycystic ovaries. However, there are no effective interventions to treat this disorder. As previously shown, mangiferin modulated the AMPK and NLRP3 signal pathways to alleviate nonalcoholic fatty liver disease (NAFLD). In recent years, mangiferin has emerged as a promising drug candidate for treating metabolic diseases. In this study, we evaluated the effects of mangiferin on a letrozole (LET) combined with high-fat diet (HFD)-induced PCOS rat model through estrous cycle detection, serum/tissue biochemical analysis, and hematoxylin and eosin (HE) staining of ovarian tissue. The mechanisms of mangiferin's effects on PCOS rats were analyzed using 16S rRNA sequencing, RNA-seq, western blotting (WB), and immunohistochemical (IHC) staining. Our results displayed that mangiferin showed a promising effect in PCOS rats. It improved lipid metabolism, glucose tolerance, insulin resistance, hormonal imbalance, ovarian dysfunction, and adipocyte abnormalities. RNA-seq analysis indicated that mangiferin may be involved in several signal pathways, including apoptosis, necrosis, and inflammation. Furthermore, western blot and immunohistochemical staining demonstrated that mangiferin regulates Caspase-3 and Cytc, exhibiting anti-apoptotic activity in the ovaries. Additionally, mangiferin significantly altered the gut microbiota community of PCOS rats, changing the abundance of firmicutes, bacteroidota, proteobacteria, and actinobacteria at the phylum level and the abundance of Blautia, Coprococcus, Roseburia, and Pseudomonas at the genus level. In conclusion, mangiferin is a promising and novel therapeutic agent for PCOS as it ameliorates insulin resistance, gut microbiota and ovarian cell apoptosis.

Abstract P189: Maternal Hyperandrogenemia Programs Hypoandrogenemia and Intrarenal Activation of Histone Deacetylase in Adult Male Offspring

Polycystic ovary syndrome ( PCOS ) is the most common endocrinopathy in young women. In-utero, children of ~80% of PCOS women in the US are exposed to maternal “hyperandrogenemia and obesity”. It remains unclear whether this exposure affects their cardiovascular ( CV ) health later in life. Using a well-characterized rat model of maternal PCOS, the hyperandrogenemic obese ( HAO ) dams, we previously showed that adult male, not female, offspring ( HAO F1 ) have enhanced blood pressure ( BP ) response to chronic angiotensin ( Ang ) II compared to sex-matched control offspring ( CON F1 ), suggesting their increased risk of later CV disease. Sex steroids have the potential to modulate epigenetics. Histone deacetylase ( HDAC ) and histone acetyltransferase ( HAT ) are markers of epigenetic modifications. HDACs have been shown to promote tumor necrosis factor ( TNF )-α expression and play a role in Ang II-induced hypertension. The present study was designed to test the hypothesis that male HAO F1 have intra-renal activation of HDAC and increased TNF-α that could play a role in their Ang II BP response. Methods: At 4 weeks ( wks ) of age, female SD rats were implanted (s.c.) with either 5α-dihydrotestosterone pellets (7.5 mg/90 d; HAO) or placebo pellets (CON) and mated at 9-12 wks. Offspring were obtained and weaned at 3 wks. Serum testosterone ( T; by LC/MS-MS), renal cortical TNF-α (Bioplex) and renal cortical nuclear HDAC and HAT activities (colorimetric assays) were measured in male offspring (1/litter, 16-24 wks, n=5-9). Results: Male HAO F1 had significantly lower serum T, higher renal cortical HDAC activity and TNF-α (430.2±124 vs 120.6±14 ng/dl, 0.97±0.1 vs 4.51±0.96 OD/min/mg protein and 423.7±47 vs 579.8±47 pg/g tissue, in male CON F1 vs male HAO F1 , respectively, p&lt;0.05), and no change in their renal cortical HAT activity (vs male CON F1 ). Conclusion: Male offspring born to HAO dams develop hypoandrogenemia that is associated with intra-renal activation of HDAC that could be mediating their increased intra-renal inflammation (TNF-α expression) and mediating their exaggerated BP response to Ang II. Future studies will determine the causative relationship between hypoandrogenemia, HDAC activation and TNF-a and their role in the exaggerated pressor response to Ang II in those male offspring. Funding: AHA-24DIVSUP1273026 (JA), NIH-NIGMS P20GM121334 (JFR, NMS), R01HL135089 &amp; R01AG075963 (JFR), AHA-22CDA938320 and 2024 Dean Franklin Award (NMS).

O75 INHIBITION OF PCSK9/NFAT AMELIORATES CARDIAC DYSMETABOLISM AND FIBROSIS IN EXPERIMENTAL RAT MODEL OF PCOS BY REDUCING ATHEROGENIC LIPID AND IMPROVING INSULIN SENSITIVITY

Background: Polycystic ovarian syndrome (PCOS) remains an independent risk factor of cardiovascular disease (CVD), particularly in women of child-bearing age, and contributes to global increase in the prevalence/incidence of cardiovascular mortality and morbidity in women. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target to reduce residual CVD risk. Similarly, Nuclear factor of activated T cells (NFAT) is a transcription factor that is implicated in cardiac fibrosis. However, the role of PCSK9/NFAT in PCOS-associated cardiometabolic syndrome is not clear. Short chain fatty acids (SCFAs) play a multifaceted regulatory role in metabolic health. The present study therefore investigated the role of PCSK9/NFAT in cardiometabolic syndrome associated with experimental PCOS, and the therapeutic potential of SCFAs, especially butyrate. Material and Methods: Eight-week-old female Wistar rats were allotted into four groups (n=5). Polycystic ovarian syndrome was induced by administering letrozole (1 mg/kg p.o.) once daily for 21 days, thereafter the animals were treated with 200 mg/kg (oral gavage) of sodium butyrate for six weeks. Gene expression, biochemical parameters and cardiac/ovarian morphology were evaluated with appropriate methods. Results: Rats with PCOS showed androgen excess, multiple ovarian cysts and reduced insulin sensitivity. The rats in addition displayed atherogenic dyslipidemia (triglyceride/HDLc, TC/HDLc and LDLc), hypercorticosteronemia and elevated cardiac triglyceride, inflammatory biomarkers (NF-kappaB and TNF-alpha), caspase-6, 4-hydroxynonenal, inflammasome (NLRP3), fibrosis and depleted antioxidant defense (NrF2 and glutathione) as well as increased expression of PCSK9 and NFAT when compared to the control rats. Nevertheless, these systemic and morphological alterations were ameliorated following treatment with sodium butyrate. Conclusion: The present results collectively demonstrate cardiac dysmetabolism, inflammation, fibrosis as well as apoptosis in experimental PCOS rat model, which are driven by elevated expression of PCSK9/NFAT. The results further suggest that SCFAs, butyrate alleviates cardiometabolic syndrome and its attendant cardiomorbidity by suppression of PCSK9/NFAT. The present data provide a preclinical insight to prevention and management of CVD in PCOS individuals.

Granulosa cell insight: unraveling the potential of menstrual blood-derived stem cells and their exosomes on mitochondrial mechanisms in polycystic ovary syndrome (PCOS)

BackgroundPolycystic ovary syndrome (PCOS) presents a significant challenge in women’s reproductive health, characterized by disrupted folliculogenesis and ovulatory dysfunction. Central to PCOS pathogenesis are granulosa cells, whose dysfunction contributes to aberrant steroid hormone production and oxidative stress. Mitochondrial dysfunction emerges as a key player, influencing cellular energetics, oxidative stress, and steroidogenesis. This study investigates the therapeutic potential of menstrual blood-derived stem cells (MenSCs) and their exosomes in mitigating mitochondrial dysfunction and oxidative stress in PCOS granulosa cells.MethodsUsing a rat model of PCOS induced by letrozole, granulosa cells were harvested and cultured. MenSCs and their exosomes were employed to assess their effects on mitochondrial biogenesis, oxidative stress, and estrogen production in PCOS granulosa cells.ResultsResults showed diminished mitochondrial biogenesis and increased oxidative stress in PCOS granulosa cells, alongside reduced estrogen production. Treatment with MenSCs and their exosomes demonstrated significant improvements in mitochondrial biogenesis, oxidative stress levels, and estrogen production in PCOS granulosa cells. Further analysis showed MenSCs' superior efficacy over exosomes, attributed to their sustained secretion of bioactive factors. Mechanistically, MenSCs and exosomes activated pathways related to mitochondrial biogenesis and antioxidative defense, highlighting their therapeutic potential for PCOS.ConclusionsThis study offers insights into granulosa cells mitochondria’s role in PCOS pathogenesis and proposes MenSCs and exosomes as a potential strategy for mitigating mitochondrial dysfunction and oxidative stress in PCOS. Further research is needed to understand underlying mechanisms and validate clinical efficacy, presenting promising avenues for addressing PCOS complexity.

Pterostilbene Ameliorates Cognitive Impairment in Polycystic Ovary Syndrome Rat Model through Improving Insulin Resistance via the IRS-1/PI3K/Akt/GSK-3β Pathway: A Comparative Study with Metformin.

Polycystic ovary syndrome (PCOS) is an intricate endocrine disorder that targets millions of women globally. Recent research has drawn attention to its association with cognitive impairment and Alzheimer's disease (AD) risk, yet the exact mechanism remains elusive. This study aimed to explore the potential role of PCOS-associated insulin resistance (IR) and inflammation in linking PCOS to AD pathogenesis. It additionally investigated the therapeutic merits of pterostilbene (PTS) in ameliorating PCOS and associated cognitive deficits in comparison to metformin (MET). Rats were divided into five groups; vehicle group, PTS group [30 mg/kg, per os (p.o.) for 13 days], and the remaining three groups received letrozole (1 mg/kg, p.o. for 21 days) to represent the PCOS, PCOS + MET (300 mg/kg, p.o. for 13 days), and PCOS + PTS groups, respectively. Behavioral tests were conducted, along with a histopathological investigation of brains and ovaries. Assessment of serum hormonal profile and hippocampal IRS-1/PI3K/AKT/GSK-3β insulin signaling pathway components were performed. PTS rats exhibited improved insulin sensitivity and hormonal profile, besides enhanced neurobehavioral tests performance and histopathological findings. These effects may be attributed to modulation of the IRS-1/PI3K/AKT/GSK-3β pathway, reducing GSK-3β activity, and mitigating Tau hyperphosphorylation and Aβ accumulation in the brain. Likewise, PTS attenuated nuclear factor kappa B-mediated inflammation and reversed AChE elevation, suggesting multifaceted neuroprotective effects. Comparatively, PTS showed outcomes similar to those of MET in most parameters. The obtained findings validated that dysregulated insulin signaling in PCOS rats detrimentally affects cognitive function, which is halted by PTS, unveiling the potential of PTS as a novel therapy for PCOS and related cognitive deficits.

The Beneficial Effects of Lacticaseibacillus paracasei subsp. paracasei DSM 27449 in a Letrozole-Induced Polycystic Ovary Syndrome Rat Model.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive age globally. Emerging evidence suggests that the dysregulation of microRNAs (miRNAs) and gut dysbiosis are linked to the development of PCOS. In this study, the effects of Lacticaseibacillus paracasei subsp. paracasei DSM 27449 (DSM 27449) were investigated in a rat model of PCOS induced by letrozole. The administration of DSM 27449 resulted in improved ovarian function, reduced cystic follicles, and lower serum testosterone levels. Alterations in miRNA expressions and increased levels of the pro-apoptotic protein Bax in ovarian tissues were observed in PCOS-like rats. Notably, the administration of DSM 27449 restored the expression of miRNAs, including miR-30a-5p, miR-93-5p, and miR-223-3p, leading to enhanced ovarian function through the downregulation of Bax expressions in ovarian tissues. Additionally, 16S rRNA sequencing showed changes in the gut microbiome composition after letrozole induction. The strong correlation between specific bacterial genera and PCOS-related parameters suggested that the modulation of the gut microbiome by DSM 27449 was associated with the improvement of PCOS symptoms. These findings demonstrate the beneficial effects of DSM 27449 in ameliorating PCOS symptoms in letrozole-induced PCOS-like rats, suggesting that DSM 27449 may serve as a beneficial dietary supplement with the therapeutic potential for alleviating PCOS.

Zishen Qingre Lishi Huayu Recipe May Ameliorate the Symptoms of PCOS Model Rats via Alleviating Systemic and Ovarian Inflammation.

Zishen Qingre Lishi Huayu recipe (ZQLHR) has shown significant therapeutic effects in treating sex hormone levels and follicular developmental disorders in patients with polycystic ovary syndrome (PCOS). However, little is known about the potential mechanisms of its treatment. Dehydroepiandrosterone and a high-fat diet induced the PCOS model rat. The serum of rats was collected to detect the levels of sex hormones and inflammatory cytokines by enzyme-linked immunosorbent assay, and the ovaries were collected for ovarian histopathology and qPCR assay to detect the levels of inflammatory cytokines in ovarian tissues. Granulosa cells (GCs) were collected for western blot assay to detect of IL-1β, IL-6R, and LOX protein expression levels. ZQLHR could reduce body weight, regulate estrous cycles, and improve serum sex hormone levels, follicular development, and insulin resistance (IR) in PCOS model rats. In addition, ZQLHR treatment improved the levels of inflammatory cytokines in serum and ovary, and regulated the protein expression of IL-6R, IL-1β, and LOX in GCs of PCOS model rats. The results showed that the HOMA-IR index increased with the increasing levels of IL-6, IL-1β, and CRP, and decreased with the increased IL-10. This study reveals that the treatment of endocrine disorders and ovulation disorders in PCOS with ZQLHR may be closely related to the improvement of systemic and ovarian inflammation in PCOS patients, as well as the inhibition of IL-6R, IL-1β, and LOX expression in GCs, which reemphasizes the role of reducing chronic inflammatory states in the treatment of PCOS. Moreover, this study reemphasizes the correlation between multiple inflammatory mediators and IR.

Exploring blood pressure dynamics and oxidative stress markers in an animal model of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a hormonal disorder characterized by elevated androgen levels, heightened insulin secretion, and dysregulation of luteinizing hormone and follicle-stimulating hormone. This disorder results in metabolic disruptions, while the irregular estrous cycles associated with PCOS impact cellular functions like growth, movement, and alterations in cell adhesion within the tissue matrix. This study aims to identify the blood tension, serum malondialdehyde (MDA) levels, and serum Metalloproteinase-1 (MMP-1) in rat models of PCOS. The study was conducted using female Wistar rats aged 6 months weighing between 130 and 180 g. The rats were divided into three treatment groups: negative control, induction of testosterone propionate (TP) at a dose of 100 mg/kg BW IP for 12 days, and induction of estradiol valerate (EV) at a dose of 2 mg/kg BW IP for 2 days. Data were analyzed quantitatively using a one-way analysis of variance followed by a Posthoc Test using the least significant difference with a confidence level of 95%. The research results indicate that the average blood pressure of TP Group and EV Group did not differ significantly from the negative control (p > 0.05). Serum MDA levels were significantly different in the TP Group compared to the negative control (p < 0.05). On the other hand, MMP-1 levels showed no significant difference (p > 0.05) among all the treatment groups. The findings of this study suggest that TP induction in a rat model of PCOS can potentially contribute to oxidative stress and lipid peroxidation, but does not significantly affect blood pressure or serum MMP-1 levels.

Hyperandrogenism Decreases Seizure Threshold in A Rat Model of Polycystic Ovary Syndrome.

In women of childbearing age with epilepsy, 40% experience the comorbidity of polycystic ovary syndrome (PCOS), which is marked by a higher prevalence of hyperandrogenism. Our recent clinical observations indicate the potential contribution of hyperandrogenism-induced PCOS to epilepsy susceptibility, and this study aimed to unravel the underlying factors that increase the susceptibility of females to epilepsy. A letrozole-induced PCOS rat model was employed to simulate endogenous hyperandrogenism. Susceptibility was assessed through seizure kindling rates using pentetrazol and electroencephalogram recordings. Additionally, the role of androgens in epilepsy was verified through interventions using Diane-35. This study revealed that letrozole induced elevated testosterone levels and PCOS-related changes in female rats. PCOS rats, through pentetrazol-kindling, exhibited a reduced seizure threshold compared with controls. Elevated testosterone levels were observed in both the hippocampal and frontal brain tissues, accompanied by changes in circulation. Two weeks of Diane-35 intervention showed a tendency to alleviate these changes, modifying testosterone levels in both the plasma and brain tissue. Western blotting and immunohistochemistry revealed increased expression of GABA-A receptor in the hippocampus and decreased AMPA receptor expression in the frontal cortex, correlating with anti-epileptic status in PCOS rats. This study delves into the impact of elevated androgen levels on seizure threshold, providing crucial insights into the underpinnings of the comorbidity between PCOS and epilepsy. These findings significantly contribute to the evolving field of epilepsy research, emphasizing the imperative consideration of hormonal influences for the development of targeted therapeutic interventions in individuals with epilepsy and PCOS.

The ameliorating effects of apigenin and chrysin alone and in combination on polycystic ovary syndrome induced by dehydroepiandrosterone in rats

Objective: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age and is one of the main causes of ovulation infertility, affecting 5-10% of women. Inflammation, hormonal imbalances, and disruption of the oxidant-antioxidant balance are the main factors in the pathophysiology of PCOS. This study was designed to answer the question of whether apigenin and chrysin have therapeutic effects on the dehydroepiandrosterone (DHEA)-induced rat model of PCOS. Materials and Methods: The experimental PCOS model was created by administering 6 mg/100g DHEA subcutaneously to 21-day-old female Wistar rats for 28 days, followed by treatment with natural agents 50 mg/kg apigenin and 50 mg/kg chrysin by oral gavage twice a week for one month. The predominant cell type was determined by microscopic analysis in vaginal smears daily from day 10 to day 28 of the experiment. In tissue supernatants, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities, and malondialdehyde (MDA) levels were obtained by spectrophotometric method with appropriate manual methods; follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone, interleukin (IL)-18, IL-1β, and IL-13 levels were determined by enzymelinked immunosorbent assay (ELISA) method. In addition, histological sections obtained from ovarian tissue samples were stained with hematoxylin-eosin and examined under a light microscope. Results: The results showed that treatment with apigenin and chrysin alone and in combination reduced MDA, LH, FSH, progesterone, IL-1β, IL-13, and IL-18 levels compared with PCOS rats. Furthermore, enzymatic activities of antioxidants including CAT, SOD, and GPx in the ovaries increased in therapeutic groups compared to the PCOS group. Conclusion: In conclusion, this study demonstrates the potential therapeutic efficacy of apigenin and chrysin, either alone or in combination, in alleviating the hormonal imbalances, inflammation, and oxidative stress in DHEA-induced PCOS rats. Apigenin, in particular, emerges as a promising agent for PCOS treatment, showing superiority over chrysin and combination treatments in ameliorating cystic follicles and improving various parameters associated with PCOS pathophysiology. These findings suggest that apigenin holds promise as a novel therapeutic agent for PCOS and warrants further investigation in clinical settings.

The effect of aqueous extract of orchid root on the structure of ovary and hypothalamic-pituitary-gonadal hormones in polycystic ovary syndrome rat model: An experimental study.

Some medical conditions, including polycystic ovarian syndrome (PCOs), may lead to infertility. In PCOs, hormonal imbalance is significant. Antioxidants such as natural antioxidants have many health benefits, including positive effects on hormone production. Since herbal medicines are more acceptable to people, the present study was designed to evaluate the effect of an aqueous extract of orchid (SA), with antioxidative effects, on the structure of the ovary and the hypothalamic-pituitary-gonadal axis hormones and free testosterone in PCOs rats. In this experimental study, 64 healthy female Wistar rats (180-200 gr) were randomly divided into 60 and 89 day control groups, PCOs, and 4 PCOs + SA groups that received 40, 80, 160, and 320 mg/kg of SA. Serum levels of gonadotropin-releasing hormone, estrogen, progesterone, testosterone, follicle-stimulating hormone, and luteinizing hormone were measured. In addition, the ovaries were extracted and examined histologically. The amount of primordial, primary, secondary, and Graafian follicles and serum levels of follicle-stimulating hormone and progesterone hormones decreased in PCOs groups, while atretic follicles and the serum levels of gonadotropin-releasing hormone, luteinizing hormone, estrogen, and free testosterone were increased. SA at different doses regulated hormonal and histological imbalances caused by PCOs, and 320 mg/kg was the most effective. The aqueous extract of orchids root can have a positive effect on the improvement of polycystic ovary syndrome. This effect can be achieved by regulating the level of sex hormones and correcting follicular abnormalities in the ovarian tissue.

Spirulina versus metformin for controlling some insulin signaling pathway genes in induced polycystic ovary syndrome rat model

Polycystic ovary syndrome (PCOS) is a prevalent endocrinologic and gynecologic disorder that affects women of reproductive age; besides, insulin resistance (IR) occurs in 50–70 % of PCOS cases. Metformin (Met) is commonly prescribed for IR management; however, it does not affect IR with some gastrointestinal symptoms. Spirulina platensis (SP) is a blue-green alga that may increase insulin sensitivity. Therefore, our study aims to evaluate SP as an alternative treatment to Met for improving glucose homeostasis by assessing the expression of 11 crucial genes involved in the insulin signaling pathway. After induction of the PCOS model using dehydroepiandrosterone (DHEA) (60 mg/kg bwt) for 30 consecutive days, rats were allocated into six groups. Relative liver weight, glutamic pyruvic transaminase (GPT) serum levels, glutamic-oxaloacetic transaminase (GOT), and insulin were determined. Furthermore, the gene expression of Ins1, Irs1, Pik3ca, Prkcz, Foxo1, Srebf1, Ppargc1a, Pklr, Gk, G6pc, and Pepck in the rat's liver tissue was determined using qRT-PCR. Treatment of the PCOS control group with Met or SP revealed a decrease in all these parameters compared with the PCOS model. Additionally, we found a statistically significant difference in the expression of both the Gk and Prkcz genes. To summarize our study results, SP or Met supplementation to PCOS rats had almost the same effect on assessed relative liver weight, GOT, GPT, and insulin levels compared with PCOS control rats. If further studies confirm and detect more impact of SP on IR in PCOS, SP could be used instead of Met since the latter causes many side effects.