Role of the PI3K-Akt Signaling Pathway in the Pathogenesis of Polycystic Ovary Syndrome

Abstract Background It is reported that growth hormone (GH) can alleviate oxidative stress (OS) induced apoptosis in some types of cells by activating the PI3K/Akt signaling pathway. This study investigated the role and underlying mechanism of GH in OS and apoptosis in granulosa cells (GCs) of patients with polycystic ovary syndrome (PCOS). Methods Primary GCs were collected from patients with and without PCOS (controls, n = 32) during oocyte retrieval. The patients with PCOS were randomly assigned to take GH treatment (PCOS-GH, n = 30) or without GH treatment (PCOS-C, n = 31). Reactive oxygen species (ROS) level was determined by spectrophotometry and fluorescence microscopy. GC apoptosis and mitochondrial membrane potential (MMP) were detected by Annexin V-FITC/PI double-staining and JC-1 staining, respectively (flow cytometry). The expression of apoptosis-related genes and proteins involved in PI3K/Akt signaling was determined by quantitative reverse-transcription polymerase chain reaction and western blotting, while active caspase-9 and caspase-3 levels of GCs were determined by enzyme-linked immunosorbent assay. Results Our study found that in GCs of the PCOS-GH group, the ROS levels and apoptotic rates were significantly decreased, whereas MMP was significantly increased when compared to those in the PCOS-C group (P < 0.05). The mRNA levels of FOXO1, Bax, caspase-9, and caspase-3 were significantly decreased, whereas Bcl-2 was increased in GCs of the PCOS-GH group than those in the PCOS-C group (P < 0.05). The protein levels of FOXO1, Bax, cleaved caspase-9/caspase-9 and cleaved caspase-3/caspase-3 were decreased, whereas p-PI3K/PI3K, p-Akt/Akt, p-FOXO1 and Bcl-2 were increased in GCs of the PCOS-GH group, compared with those in the PCOS-C group (P < 0.05). Conclusion OS induced apoptosis and downregulated the PI3K/Akt signaling pathway in patients with PCOS. GH could alleviate apoptosis and activate the PI3K/Akt signaling pathway. Clinical trial registration number Chinese Clinical Trial Registry. ChiCTR1800019437. Prospectively registered on October 20, 2018.

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Effects of Nesfatin-1 and Wnt /β-Catenin Pathway on OGCs in PCOS

10.21203/rs.3.rs-104450/v1 ◽

2020 ◽

Author(s):

Peihui Ding ◽

Ding-Ding Ai ◽

Kai-Xue Lao ◽

Ying Huang ◽

Yan Zhang ◽

...

Keyword(s):

Polycystic Ovary Syndrome ◽

Signaling Pathway ◽

Granulosa Cells ◽

Complex Disease ◽

Polycystic Ovary ◽

Hormone Production ◽

Ovary Syndrome ◽

Ovarian Granulosa Cells

Abstract Background Polycystic ovary syndrome is a complex disease related to the endocrine and metabolism. Its specific cause and pathogenesis have not been clear. Nesfatin-1 could not only regulate energy balance and glucose metabolism, but also affect the reproductive system. The Wnt/β-catenin signaling pathway affects follicle development, ovulation, corpus luteum formation, and steroid hormone production. Results Here, we studied the roles of nesfatin-1 and Wnt/β-catenin signaling pathway in the pathogenesis of polycystic ovary syndrome. Firstly, the human primary ovarian granulosa cells in vitro was cultured. The results showed that the apoptosis rate of ovarian granulosa cells in polycystic ovary syndrome patients was significantly higher than that of granular cells in normal people. Moreover, nesfatin-1 and Wnt/β-catenin pathway inhibitor IWR-1could inhibit the expressions of ovarian granulosa cells apoptosis genes and promote their proliferation, as well as nesfatin-1 affected the expressions of foxo3a and its downstream factors. Then, an in vitro culture system for ovarian granulosa cells (OGCs) was established by employing a rat model. The results are the same with those mentioned above. Conclusion This strongly proves that the nesfatin-1 participates in regulating the apoptosis and proliferation of granulosa cells by the Wnt/β-catenin pathway. According to the role of nesfatin-1 and IWR in polycystic ovary syndrome, nesfatin-1 and Wnt/β-catenin pathway can provide a guideline for the diagnosis and treatment of Polycystic ovary syndrome (PCOS).

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A Potential Pathological Role of Wingless Type1 Inducible Signaling Pathway Protein-1 and Betatrophin in Obese Women with Polyststic Ovary Syndrome

Asian Journal of Biochemistry, Genetics and Molecular Biology ◽

10.9734/ajbgmb/2020/v3i330085 ◽

2020 ◽

pp. 1-11

Author(s):

Abrar Gomaa Abd-Elfatah Hassan ◽

Mohammed Ali Mohammed Mohammed ◽

Doaa Mohammed Mohammed Abd-Elatif ◽

Ashraf Taha Abd-Elmouttaleb Mohammed

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Signaling Pathway ◽

Polycystic Ovary ◽

Pancreatic Beta Cell ◽

Normal Weight ◽

Control Group ◽

Beta Cell Proliferation ◽

Ovary Syndrome

Background: Polycystic Ovary Syndrome is a common female endocrinopathy. It is associated with adipokines dysfunctional secretion pattern and insulin resistance, which is considered as the main reason for its clinical feature. Wingless type1 inducible signaling pathway protein-1 is a novel adipokine that displays insulin resistance and adipose tissue inflammation where it strongly related to adipocyte accumulation and regeneration. Betatrophin has a potential role in pancreatic beta-cell proliferation and obesity and several studies showed inconsistent betatrophin levels in patients with diabetes and obesity but, its relation to polycystic ovary syndrome is unclear. Aim: Investigation of the role of serum wingless type1 inducible signaling pathway protein-1 and betatrophin in normal weight and obese patients with polycystic ovary syndrome. Studying their association with other markers, then determine whether obesity and insulin resistance is associated with them. Methods: Wingless type1 inducible signaling pathway protein-1 and betatrophin serum levels were measured in 44 patients with polycystic ovary syndrome (22 obese and 22 non-obese) and 44 matched control (22 obese and 22 non-obese) females using specific ELISA kits. Results: Betatrophin and wingless type1 inducible signaling pathway protein-1 levels were elevated in the polycystic ovary syndrome group (49.4 pg/ml, 187.6 pg/ml) than in the control group (32.08 pg/ml, 108.4 pg/ml) respectively. Moreover, their levels were higher in the obese subgroup than in normal weight subgroup. There were positive correlations between wingless type1 inducible signaling pathway protein-1 and betatrophin in non-obese (r=0.89, p=0.0001***) and in obese (r=0.78, p=0.0001***) polycystic ovary syndrome groups. Conclusion: Betatrophin and wingless type1 inducible signaling pathway protein-1 are associated with adiposity and insulin resistance in polycystic ovary syndrome. Hence wingless type1 inducible signaling pathway protein-1 and betatrophin may play a role in the incidence of polycystic ovary syndrome. They may be valuable in diagnosis and prediction of polycystic ovary syndrome patients.

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The role of serum inflammatory cytokines and berberine in the insulin signaling pathway among women with polycystic ovary syndrome

PLoS ONE ◽

10.1371/journal.pone.0235404 ◽

2020 ◽

Vol 15 (8) ◽

pp. e0235404 ◽

Cited By ~ 1

Author(s):

Hongying Kuang ◽

Yuwei Duan ◽

Dan Li ◽

Yanwen Xu ◽

Wenxia Ai ◽

...

Keyword(s):

Polycystic Ovary Syndrome ◽

Signaling Pathway ◽

Inflammatory Cytokines ◽

Insulin Signaling ◽

Polycystic Ovary ◽

Insulin Signaling Pathway ◽

Ovary Syndrome

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Growth Hormone Activates PI3K/Akt Signaling and Inhibits ROS Accumulation and Apoptosis in Granulosa Cells of Patients With Polycystic Ovary Syndrome

10.21203/rs.3.rs-76999/v1 ◽

2020 ◽

Author(s):

Yan Gong ◽

Shan Luo ◽

Ping Fan ◽

Huili Zhu ◽

Yujing Li ◽

...

Keyword(s):

Clinical Trial ◽

Growth Hormone ◽

Signaling Pathway ◽

Caspase 3 ◽

Polycystic Ovary ◽

Akt Signaling ◽

Akt Signaling Pathway ◽

Caspase 9 ◽

Ovary Syndrome ◽

Induced Apoptosis

Abstract Background: Growth hormone (GH) can reduce oxidative stress (OS) induced apoptosis in some types of cells by activating the PI3K/Akt signaling pathway. This study investigated the role and underlying mechanism of GH in OS and apoptosis in GCs of patients with polycystic ovary syndrome (PCOS). Methods: Primary GCs were collected from patients with and without PCOS (controls, n = 32) during oocyte retrieval. The patients with PCOS were randomly assigned to receive treatment with GH (PCOS-GH, n = 30) or without GH (PCOS-C, n = 31). Reactive oxygen species (ROS) level was determined by spectrophotometry and ﬂuorescence microscopy. GC apoptosis and mitochondrial membrane potential (MMP) were detected by Annexin V-FITC/PI double-staining and JC-1 staining, respectively (flow cytometry). The expression of apoptosis-related genes and proteins involved in PI3K/Akt signaling was determined by quantitative reverse-transcription polymerase chain reaction and western blotting, while active caspase-9 and caspase-3 levels were determined by enzyme-linked immunosorbent assay. Result(s): The present study found that compared with those in the non-PCOS and PCOS-GH groups, the ROS levels and apoptotic rates were significantly increased, whereas MMP was significantly decreased in the PCOS-C group GCs (P < 0.05). Compared with those in non-PCOS and PCOS-GH groups, mRNA levels of FOXO1, Bax, caspase-9, and caspase-3 were significantly increased, whereas Bcl-2 was decreased in the GCs of the PCOS-C group (P < 0.05). The protein levels of FOXO1, Bax, cleaved caspase-9/caspase-9 and cleaved caspase-3/caspase-3 were increased, whereas p-PI3K/PI3K, p-Akt/Akt, p-FOXO1 and Bcl-2 were decreased in the GCs of the PCOS-C group, compared with those in the non-PCOS and PCOS-GH groups (P < 0.05). Conclusion: OS induced apoptosis and inactivated the PI3K/Akt signaling pathway in patients with PCOS. GH could improve apoptosis and activate the PI3K/Akt signaling pathway.Clinical Trial Registration Number: Chinese Clinical Trial Registry (www.chictr.org.cn/index.aspx). ChiCTR1800019437. Prospectively registered on October 20, 2018, http://www.chictr.org.cn/edit.aspx?pid=28663&htm= 4

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The role of vitamin D in metabolic and reproductive disturbances of polycystic ovary syndrome: A narrative mini-review

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000691 ◽

2020 ◽

pp. 1-8

Author(s):

Daniela Menichini ◽

Gianpiero Forte ◽

Beatrice Orrù ◽

Giuseppe Gullo ◽

Vittorio Unfer ◽

...

Keyword(s):

Vitamin D ◽

Polycystic Ovary Syndrome ◽

Embryo Quality ◽

Polycystic Ovary ◽

Vitamin D Supplementation ◽

Endometrial Receptivity ◽

Metabolic Disturbances ◽

Ovary Syndrome ◽

Beneficial Role

Abstract. Vitamin D is a secosteroid hormone that plays a pivotal role in several metabolic and reproductive pathways in humans. Increasing evidence supports the role of vitamin D deficiency in metabolic disturbances and infertility in women with polycystic ovary syndrome (PCOS). Indeed, supplementation with vitamin D seems to have a beneficial role on insulin resistance and endometrial receptivity. On the other hand, exceedingly high levels of vitamin D appear to play a detrimental role on oocytes development and embryo quality. In the current review, we summarize the available evidence about the topic, aiming to suggest the best supplementation strategy in women with PCOS or, more generally, in those with metabolic disturbances and infertility. Based on the retrieved data, vitamin D seems to have a beneficial role on IR, insulin sensitivity and endometrial receptivity, but high levels and incorrect timing of administration seem to have a detrimental role on oocytes development and embryo quality. Therefore, we encourage a low dose supplementation (400–800 IU/day) particularly in vitamin D deficient women that present metabolic disturbances like PCOS. As far as the reproductive health, we advise vitamin D supplementation in selected populations, only during specific moments of the ovarian cycle, to support the luteal phase. However, ambiguities about dosage and timing of the supplementation still emerge from the clinical studies published to date and further studies are required.

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