Bushen Jieyu Tiaochong Formula reduces apoptosis of granulosa cells via the PERK-ATF4-CHOP signaling pathway in a rat model of polycystic ovary syndrome with chronic stress.
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder that is also an important cause of infertility. Adverse psychological stress can aggravate the occurrence and development of PCOS. Bushen Jieyu Tiaochong Formula (BJTF), a prescription of Traditional Chinese Medicine (TCM), has been used in the treatment of PCOS and shown to be effective in reducing negative emotion. However, the therapeutic mechanism has yet to be clearly elucidated. In the current study, we investigated the potential mechanism of action of BJTF. AIM OF THE STUDY:To investigate the role of PERK-ATF4-CHOP signaling in the molecular mechanisms that mediate the effects of BJTF in a rat model of PCOS, with chronic stress induced by letrozole and a chronic unpredictable mild stress (CUMS) paradigm. MATERIALS AND METHODS:In addition to the normal control group, the PCOS combined with CUMS model rats were randomly assigned to a model group, a Diane-35 (ethinylestradiol 35 μg/cyproterone acetate 2 mg)-treated positive control group, or one of three BJTF-treated groups receiving a low, medium, or high dose. Behavioral testing, including the sucrose preference test and open field test, was conducted, and hematoxylin and eosin (H&E) staining was used to observe changes in the pathological morphology of ovarian tissue. Free testosterone (FT), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels in serum were quantified by enzyme-linked immunosorbent assays (ELISA). The hippocampal levels of norepinephrine (NE), 5-hydroxytryptamine/serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) were measured using high-performance liquid chromatography-electrochemical detection (HPLC-ECD). Apoptotic granulosa cells were detected using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Furthermore, quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry were used to detect the expression of glucose-regulated protein 78 (GRP78) and CHOP in the ovarian tissues. The expression levels of GRP78, CHOP, PERK, and ATF4 in ovarian tissues were also measured by western blotting. RESULTS:Treatment with either BJTF or Diane-35 ameliorated the abnormal cystic dilatation of follicles in the model rats and reduced the serum levels of FT and LH, and the LH/FSH ratio. BJTF treatment also attenuated chronic psychological stress-like behavior and regulated the expression and metabolism of cerebral monoamine neurotransmitters. The efficacy of BJTF was greater than that of Diane-35, with the optimal effects observed at the medium dose. BJTF also lowered the apoptotic index of ovarian granulosa cells and downregulated the expression of GRP78, CHOP, and ATF4. Although the expression level of PERK was not significantly altered by BJTF, the mean PERK expression level was the lowest in the medium-dose BJTF group. CONCLUSIONS:Administration of BJTF has the therapeutic potential to promote the homeostasis of the reproductive endocrine environment and to restore follicular development and ovulation, possibly through the inhibition of the PERK-ATF4-CHOP signaling pathway, leading to downregulation of GRP78 expression to further delay ovarian granule cell apoptosis mediated by endoplasmic reticulum stress (ERS). Moreover, BJTF could improve behavioral performance by regulating cerebral monoamine neurotransmitters in this rat model. These findings provide a new perspective for treating PCOS related to psychological stress using TCM.
10.1016/j.jep.2021.114923
Acupuncture in clinical and experimental reproductive medicine: a review.
Franconi G,Manni L,Aloe L,Mazzilli F,Giambalvo Dal Ben G,Lenzi A,Fabbri A
Journal of endocrinological investigation
BACKGROUND:Acupuncture has been used as treatment for infertility for hundreds of years, and recently it has been studied in male and female infertility and in assisted reproductive technologies, although its role in reproductive medicine is still debated. AIM:To review studies on acupuncture in reproductive medicine, in experimental and clinical settings. METHODS:Papers were retrieved on PubMed and Google Scholar and were included in the review if at least the abstract was in English. RESULTS:There is evidence of benefit mainly when acupuncture is performed on the day of embryo transfer (ET) in the live birth rate. Benefit is also evident when acupuncture is performed for female infertility due to polycystic ovary syndrome (PCOS). There is some evidence of sperm quality improvement when acupuncture is performed on males affected by idiopathic infertility. Experimental studies suggest that acupuncture effects are mediated by changes in activity of the autonomic nervous system and stimulation of neuropeptides/neurotransmitters which may be involved in the pathogenesis of infertility. CONCLUSIONS:Acupuncture seems to have beneficial effects on live birth rate when performed on the day of ET, and to be useful also in PCOS as well as in male idiopathic infertility, with very low incidence of side effects. However, further studies are necessary to confirm the clinical results and to expand our knowledge of the mechanisms involved.
10.3275/7500
Dysregulated genes and their functional pathways in luteinized granulosa cells from PCOS patients after cabergoline treatment.
Ferrero H,Díaz-Gimeno P,Sebastián-León P,Faus A,Gómez R,Pellicer A
Reproduction (Cambridge, England)
Polycystic ovarian syndrome (PCOS) is a common reproductive disorder frequently associated with a substantial risk factor for ovarian hyperstimulation syndrome (OHSS). Dopamine receptor 2 (D2) agonists, like cabergoline (Cb2), have been used to reduce the OHSS risk. However, lutein granulosa cells (LGCs) from PCOS patients treated with Cb2 still show a deregulated dopaminergic tone (decreased D2 expression and low dopamine production) and increased vascularization compared to non-PCOS LGCs. Therefore, to understand the PCOS ovarian physiology, it is important to explore the mechanisms that underlie syndrome based on the therapeutic effects of Cb2. Here, LGCs from non-PCOS and PCOS patients were cultured with hCG in the absence/presence of Cb2 ( = 12). Subsequently, a transcriptomic-paired design that compared untreated vs treated LGCs within each patient was performed. After transcriptomic analysis, functions and genes were prioritized by systems biology approaches and validated by RT-qPCR. We identified that similar functions were altered in both PCOS and non-PCOS LGCs treated with Cb2; however, PCOS-treated LGCs exhibited more significant changes than non-PCOS. Among the prioritized functions, dopaminergic synapse, vascular endothelial growth factor (VEGF) signaling, apoptosis and ovarian steroidogenesis were highlighted. Finally, network modeling showed , , , , , , and as key genes implicated in these pathways in Cb2 response, which might be potential biomarkers for further studies in PCOS.
10.1530/REP-18-0027
Synergistic action of carvedilol and clomiphene in mitigating the behavioral phenotypes of letrozole-model of PCOS rats by modulating the NRF2/NFKB pathway.
Life sciences
INTRODUCTION:Psychiatric and cognitive impairment has been observed in premenopausal women with a hormonal disorder called polycystic ovary syndrome (PCOS). This study aimed to explore the possibility of combining pharmacological agents: Carvedilol and Clomiphene citrate, with antiestrogenic, antioxidant and anti-inflammatory properties in letrozole-induced PCOS rats. METHODS:PCOS was induced in rats by the administration of letrozole (1 mg/kg) daily for 21 days. They were subsequently divided into four groups, each receiving either the vehicle or Clomiphene citrate (1 mg/kg) or Carvedilol or a combination of Clomiphene citrate and Carvedilol, respectively from days 22-36. Neurobehavioral studies were conducted on day 35 (Elevated plus maze and Y maze) and day 36 (Novel object recognition). The serum levels of the antioxidants Superoxide dismutase, Catalase, Interleukin 1B (IL-1B), and the gene expression of nuclear factor-erythroid factor 2-related factor 2 (Nrf2), Nuclear Factor k-Beta (NFKB), and acetylcholine esterase in the frontal brain homogenate was determined. RESULT:Both Carvedilol and the combination therapy reversed the anxiety-like behavior, while Clomiphene citrate and the combination therapy ameliorated the spatial and non-spatial memory impairment observed in PCOS rats. Carvedilol, Clomiphene citrate, and the combination therapy increased the serum concentration of SOD and Catalase and decreased the serum concentration of IL-1B. The combination therapy up-regulated the NRF-2, NFKB, and acetylcholine esterase gene expression. CONCLUSION:Study showed that the combination of carvedilol and clomiphene citrate has anxiolytic potential and improved cognitive functions in PCOS rats. This might have been achieved by carvedilol and clomiphene citrate's ability to modulate the cholinergic system and the Nrf2 pathway while downregulating the NFκB signaling pathway.
10.1016/j.lfs.2023.121737
Troxerutin protects against DHT-induced polycystic ovary syndrome in rats.
Gao Zixuan,Ma Xiaochen,Liu Jing,Ge Yuhang,Wang Lei,Fu Ping,Liu Zhian,Yao Ruiqin,Yan Xiaonan
Journal of ovarian research
The exact pathogenesis of polycystic ovary syndrome (PCOS), the most common neuroendocrine disorder in women of reproductive age, has not been fully elucidated. Recent studies suggested that chronic inflammation and neurotransmitter disorder involved in the progress of PCOS. Troxerutin, a natural flavonoid, was reported to possess neuroprotective effect in several disease models by inhibiting inflammation or enhancing neurotrophic factor. In this study, we investigated the possible protective effect and mechanism of troxerutin in a dihydrotestosterone (DHT)-induced rat model of PCOS. The PCOS rat models were treated with troxerutin at a dose of 150 mg/kg or 300 mg/kg for up to 4 weeks. Results showed that 300 mg/kg troxerutin significantly decreased the body weight gain and improved the pathological changes of ovary induced by DHT. Meanwhile, the elevated gonadotrophin-releasing hormone (GnRH), gonadotrophin and testosterone in the serum of PCOS rats were reduced with the treatment of troxerutin. The expression of kisspeptin and NKB in arcuate nucleus and their receptors kiss1r and NK3r in GnRH positive neurons of median eminence were markedly decreased in troxerutin-treated rats. Of note, the GnRH inhibitory regulator GABA and stimulatory regulator glutamate were also restored to the normal level by troxerutin. The present study indicated that troxerutin may exhibit a protective effect in PCOS rat model via regulating neurotransmitter release.
10.1186/s13048-020-00701-z
The Role of Antiobesity Agents in the Management of Polycystic Ovary Syndrome.
Chatzis Panagiotis,Tziomalos Konstantinos,Pratilas Georgios C,Makris Vasileios,Sotiriadis Alexandros,Dinas Konstantinos
Folia medica
Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women of reproductive age. Obesity is frequently present in these patients and plays a key role in the pathogenesis of both the endocrine and metabolic abnormalities of the syndrome, particularly infertility, hyperandrogenism and insulin resistance (IR). Diet and exercise is the mainstay of management of obesity in patients with PCOS. In contrast, the eff ects of antiobesity agents on weight and on the obesityrelated characteristics of the syndrome remain unclear. The aim of the present review is to summarize the current data on the eff ects of antiobesity drugs approved in Europe (orlistat, liraglutide 3 mg od and naltrexone/bupropion) on weight loss in patients with PCOS and to discuss their impact on the endocrine, reproductive and metabolic abnormalities of this population. Several studies reported that orlistat induces weight loss, improves IR and reduces androgen levels in PCOS. In contrast, data regarding the eff ects of the dose of liraglutide that is approved for the treatment of obesity (3 mg od) are very limited. Liraglutide 1.2-1.8 mg od results in weight loss in these patients but does not aff ect IR or androgen levels. Finally, there are no studies that evaluated naltrexone/bupropion in patients with PCOS and early studies reported conflicting results regarding the eff ects of naltrexone monotherapy on weight, IR and androgen levels. In conclusion, orlistat appears to have a role in the management of overweight and obese patients with PCOS whereas more studies are needed to clarify the role of liraglutide and naltrexone/bupropion.
10.2478/folmed-2018-0036
Antidepressants for polycystic ovary syndrome.
Zhuang Jing,Wang Xianding,Xu Liangzhi,Wu Taixiang,Kang Deying
The Cochrane database of systematic reviews
BACKGROUND:The prevalence of depression in women with polycystic ovary syndrome (PCOS) is high; one study has shown it to be four times that of women without PCOS. Therefore, systematic evaluation of the effectiveness and safety of antidepressants for women with PCOS is important. OBJECTIVES:To evaluate the effectiveness and safety of antidepressants in treating depression and other symptoms in women with PCOS. SEARCH METHODS:We searched the following databases from inception to June 2012: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO and Chinese National Knowledge Infrastructure, the metaRegister of Controlled Trials (controlled-trials.com), the National Institute of Health Clinical Trials register (clinicaltrials.gov) and the World Health Organization International Trials Registry Platform search portal (www.who.int/trialsearch/Default.aspx). SELECTION CRITERIA:Only randomised controlled trials (RCTs) studying the effectiveness and safety of antidepressants for women with PCOS were included in this review. DATA COLLECTION AND ANALYSIS:The methodological quality of the trials was assessed independently by two review authors, in parallel with data extraction. The risk of bias in the included study was assessed in six domains: 1. sequence generation; 2. allocation concealment; 3. blinding of participants, personnel and outcome assessors; 4. completeness of outcome data; 5. selective outcome reporting; 6. other potential sources of bias. MAIN RESULTS:We found no studies reporting any of our primary review outcomes (depression and allied mood disorder scores, quality of life and adverse events). Only one study with 16 women was eligible for inclusion. This study compared sibutramine versus fluoxetine in women with PCOS, and reported only endocrine and metabolic outcomes. It was unclear whether the participants had psychological problems at baseline. No significant difference was found between the groups for any of the measured outcomes. AUTHORS' CONCLUSIONS:There is no evidence on the effectiveness and safety of antidepressants in treating depression and other symptoms in women with PCOS.
10.1002/14651858.CD008575.pub2
Effects of electroacupuncture on the kisspeptin-gonadotropin-releasing hormone (GnRH) /luteinizing hormone (LH) neural circuit abnormalities and androgen receptor expression of kisspeptin/neurokinin B/dynorphin neurons in PCOS rats.
Journal of ovarian research
BACKGROUND:Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, anovulation, and polycystic ovaries. Electroacupuncture (EA) can effectively improve hyperandrogenism and increase ovulation frequency in patients with PCOS. Pieces of suggest that androgen activity in the brain is associated with impaired steroid negative feedback in such patients. Studies have shown that EA regulated androgen receptor (AR) expression and local factor levels (such as anti-Müllerian hormone and inhibin B) in the ovary of PCOS rats. However, few studies have explored the effect of EA on androgen activity in the brain. OBJECTIVE:This study investigated the effect of EA on the kisspeptin-gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) neural circuit and sex hormone receptor expression in the hypothalamus of PCOS rats. METHODS:PCOS signs were induced by letrozole administration, and the induced rats were treated with low-frequency EA at Guan Yuan acupoint (CV4). The effect of EA on PCOS-like signs was evaluated by observing changes in the body weight, ovarian quality, ovarian morphology, and serum sex hormone levels in rats. To explore the mechanism of the effect of EA on PCOS-like signs, the neuropeptide content of the kisspeptin-GnRH/LH neural circuit was assessed using enzyme-linked immunosorbent assay(ELISA); AR and estrogen receptor α (ERα) coexpression on kisspeptin/neurokinin B/dynorphin (KNDy) neurons was determined via triple-label immunofluorescence; and protein and mRNA expression of Kiss1, Ar, Esr1, and kisspeptin receptor (Kiss1r) was evaluated via western blotting and Reverse Transcription-Polymerase Chain Reaction (RT-PCR). RESULTS:The results revealed that the estrous cycle of rats in the EA treatment group recovered, and their body and ovary weight reduced; ovarian morphology improved; serum testosterone and LH levels significantly decreased; and kisspeptin, GnRH, and dynorphin levels in hypothalamic arcuate nucleus significantly decreased. Compared with controls, the number of AR/Kiss1-positive cells increased, number of ERα/Kiss1-positive cells decreased, and protein and mRNA expression of Kiss1, Ar, and Kiss1r significantly increased in PCOS rats. However, EA treatment reversed these changes and reduced the expression of Kiss1, Ar, and Kiss1r significantly. CONCLUSION:Improvement in the reproductive hallmarks of PCOS rats via EA may be achieved by regulating the kisspeptin-GnRH/LH circuit via androgen activity attenuation. Thus, the results provide an experimental basis for acupuncture as an adjuvant medical therapy on PCOS.
10.1186/s13048-022-01078-x
Modulation of GABA by sodium butyrate ameliorates hypothalamic inflammation in experimental model of PCOS.
BMC neuroscience
Polycystic ovarian syndrome (PCOS) is a known endocrine disorder that has affected many women of childbearing age, and is accompanied by various neurodegenerative conditions. Hence, this study investigates the impact of butyrate in reversing hypothalamic-related disorder, possibly through γ aminobutyric acid (GABA) in a rat model of PCOS. Eight-week-old female Wistar rats were allotted into four groups (n = 5), which include control, butyrate, letrozole, and letrozole + butyrate groups. PCOS was induced by administering 1 mg/kg of letrozole (oral gavage) for 21 days. After confirmation of PCOS, 200 mg/kg of butyrate (oral gavage) was administered for 6 weeks. Rats with PCOS were characterized by elevated levels of plasma insulin and testosterone. Increases in plasma and hypothalamic triglyceride levels, inflammatory biomarker (SDF-1), apoptotic marker (caspase-6), and decreased plasma GnRH were observed. Additionally, a decrease in hypothalamic GABA was revealed. Nevertheless, the administration of butyrate attenuated these alterations. The present study suggests that butyrate ameliorates hypothalamic inflammation in an experimental model of PCOS, a beneficial effect that is accompanied by enhanced GABA production.
10.1186/s12868-023-00834-z