Combined use of Diane-35 and metformin improves the ovulation in the PCOS rat model possibly via regulating glycolysis pathway

Zhang, Shun; Tu, Haoyan; Yao, Jun; Le, Jianghua; Jiang, Zhengxu; Tang, Qianqian; Zhang, Rongrong; Huo, Peng; Lei, Xiaocan

doi:10.1186/s12958-020-00613-z

Cited by 42 publications

(32 citation statements)

References 39 publications

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“…In the current study, rats with letrozole exposure showed PCOS-like reproductive and metabolic phenotypes compared with the controls. Consistently with previous study (27) A successful PCOS model was crucial for the continuation of the study. In our study, letrozole treated rats showed increased body weight, and PCOS-like reproductive and metabolic phenotypes, including signi cant alters in serum T, E2, LH, FSH and P, impaired insulin resistance and widespread metabolic abnormalities, as well as disrupted estrous cycles and poly ovaries.…”

Section: Discussionsupporting

confidence: 88%

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

Xie

Xiao

Shi

et al. 2020

Preprint

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Background: Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disorder that has many characteristic features including hyperandrogenemia, insulin resistance and obesity. The beneficial effects of metformin on reproduction, metabolism and endocrine, especially with the capacity to ameliorate insulin resistance (IR) in polycystic ovary syndrome (PCOS), place it as a good alternative for its widely prescribed, but its association with PCOS offspring remains uncertain. We aim to investigate the impact of metformin on reproductive, endocrine and metabolic characteristics in female offspring born to letrozole-induced PCOS-IR rats.Methods: 45 female wistar rats were implanted with letrozole-continuous-release pellets or placebo, subsequently treated with metformin or vehicle control, then mated with healthy male wistar rats. Estrous cycle, endocrine hormone profile, fasting insulin measurements and glucose tolerance test have been investigated and the expression of INSR in pancreas, FSHR and LHCGR in ovaries have been analyzed with Quantitative Real-time Polymerase Chain Reaction and Western Blotting assay.Results: Decreased conception rate and increased multiple pregnancy rates were found in PCOS-IR rats, which significantly improved after metformin treatment. Metformin significantly decreased the risk of body weight gain and increased INSR expression of pancreas in female F1 offspring in PCOS-IR rats. Decreased FSHR and increased LHCGR expressions in ovary were observed in female F1 rats of PCOS-IR and PCOS-IR+Met group. Nevertheless, there were no significant differences of INSR, FSHR and LHCGR expressions in female F2 offspring of PCOS-IR rats, as well as other PCOS phenotypes.Conclusions: The current study indicates that widespread reproductive, endocrine and metabolic changes in letrozole induced PCOS-IR rat model, but those PCOS phenotypes could not be inherit to offspring generations stably. Metformin may contribute to improve obesity, hyperinsulinemia and insulin resistance of female F1 offspring in PCOS-IR. The results of this study can be used as a theoretical basis for supporting metformin-using in the treatment of PCOS-IR patients.

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Section: Discussionsupporting

confidence: 88%

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

Xie

Xiao

Shi

et al. 2020

Preprint

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“…Rats exposed to letrozole in this study showed PCOS-like reproductive and metabolic phenotypes in contrast to the controls. Similar to a previous study (24), we established a PCOS-IR animal model using continuous letrozole administration through a slow-release implant. This model was used to further investigate the effects of metformin on the offspring of animals with PCOS-IR.…”

Section: Discussionmentioning

confidence: 98%

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

Xie

Xiao

2021

Front. Endocrinol.

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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.

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“…Another popular PCOS treatment (metformin and Diane-35 (cyproterone acetate and ethinyl estradiol)) has been shown to normalise ATP and lactate levels and increase expression levels of glycolysis-related rate-limiting enzymes (PKM2 (pyruvate kinase isozyme M2 isoform) and LDH-A) and NAD + -dependent deacetylase SIRT1 (silent information regulator 1) [ 87 ]. SIRT1 maintains blood glucose levels via the regulation of gluconeogenic/glycolytic pathways in the liver and improves oxidative stress-related insulin resistance [ 88 ].…”

Section: Pcos Treatments: Classical and Modern Mitochondria–oriented Approachesmentioning

confidence: 99%

Mitochondrial Dysfunction and Chronic Inflammation in Polycystic Ovary Syndrome

Dabravolski

Nikiforov

Eid

et al. 2021

IJMS

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Polycystic ovarian syndrome (PCOS) is the most common endocrine–metabolic disorder affecting a vast population worldwide; it is linked with anovulation, mitochondrial dysfunctions and hormonal disbalance. Mutations in mtDNA have been identified in PCOS patients and likely play an important role in PCOS aetiology and pathogenesis; however, their causative role in PCOS development requires further investigation. As a low-grade chronic inflammation disease, PCOS patients have permanently elevated levels of inflammatory markers (TNF-α, CRP, IL-6, IL-8, IL-18). In this review, we summarise recent data regarding the role of mtDNA mutations and mitochondrial malfunctions in PCOS pathogenesis. Furthermore, we discuss recent papers dedicated to the identification of novel biomarkers for early PCOS diagnosis. Finally, traditional and new mitochondria-targeted treatments are discussed. This review intends to emphasise the key role of oxidative stress and chronic inflammation in PCOS pathogenesis; however, the exact molecular mechanism is mostly unknown and requires further investigation.

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Combined use of Diane-35 and metformin improves the ovulation in the PCOS rat model possibly via regulating glycolysis pathway

Cited by 42 publications

References 39 publications

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

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

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

Mitochondrial Dysfunction and Chronic Inflammation in Polycystic Ovary Syndrome

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