Insulin and Insulin-Like Growth Factor Stimulation of Vascular Endothelial Growth Factor Production by Luteinized Granulosa Cells: Comparison between Polycystic Ovarian Syndrome (PCOS) and Non-PCOS Women

Stanek, Meghan B.; Borman, Sherri; Molskness, Theodore A.; Larson, Jason; Stouffer, Richard L.; Patton, Phillip E.

doi:10.1210/jc.2006-2846

Cited by 56 publications

(34 citation statements)

References 25 publications

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“…These findings are compatible with the concept that VEGF through the stimulation of ovarian angiogenesis may be a key mediator of OHSS (90). The observed reduction of VEGF levels may significantly rely upon the insulinlowering effect of metformin since insulin stimulates VEGF production by cultured luteinized granulosa cells from women with and without PCOS (91).…”

Section: Metformin In Pcossupporting

confidence: 87%

Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome

Diamanti-Kandarakis

Christakou

Kandaraki

et al. 2010

European Journal of Endocrinology

208

184

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Polycystic ovary syndrome (PCOS) is now recognized to be the most common endocrinopathy in women of reproductive age with a prevalence of 6.6-6.8%. PCOS, a syndrome of unknown etiology, was initially regarded as a reproductive disorder. However, in the last 15 years the role of insulin resistance (IR) has been identified as a significant contributor to the pathogenesis of PCOS, and the metabolic and cardiovascular sequelae of the syndrome have been increasingly appreciated. The coexistence and interaction of reproductive and cardiometabolic abnormalities in the context of PCOS have created a need for a modified therapeutic management of affected women. Insulin sensitizers, particularly metformin, have been introduced as a pharmaceutical option targeting not only IR, but several other aspects of the syndrome, including reproductive abnormalities. The landscape of the multifaceted actions of metformin evolves to broaden the therapeutic implications of this old drug in a new fashion for patients with PCOS. Most recently, the spectrum of metformin's targets has been expanded, and molecular studies have explored the tissue-specific mechanisms of metformin in the liver, the muscle, the endothelium, and the ovary. The use of metformin in pregnant women with PCOS comprises another scarcely explored, but promising area of research. This review attempts to cover the spectrum of metformin's cellular actions in different tissues and to summarize the current literature regarding the potential medical value of this medication in PCOS. Even if many of these actions are individually modest, they seem to be collectively sufficient to confer therapeutic benefits not only in cardiometabolic aspects but also in reproductive aspects of PCOS.

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Section: Metformin In Pcossupporting

confidence: 87%

Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome

Diamanti-Kandarakis

Christakou

Kandaraki

et al. 2010

European Journal of Endocrinology

208

184

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“…Given the known anti-angiogenic nature of TSP-1, it is probable that the inability of follicles overexpressing TSP-1 to reach maturation results from inadequate local vascular development. Since IGF-1 signalling promotes vascularization through increased VEGF expression in the developing follicle [23] and elsewhere [34,35], our findings suggest an intriguing mechanism for suppressing TSP-1 in order to favour angiogenesis in this context. Since TSP-1 directly modulates endothelial responses, and is also involved in the LRP-1-dependent clearance of VEGF [20], transient TSP-1 suppression in response to IGF-1 may represent another mechanism by which the follicle becomes cyclically proangiogenic at key developmental stages.…”

Section: Discussionmentioning

confidence: 74%

Rapid Insulin-like Growth Factor-1-induced Changes in Granulosa Cell Thrombospondin-1 Expression In Vitro

McGray

Gingerich

Petrik

et al. 2011

Journal of Reproduction and Development

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Abstract. Thrombospondin-1 (TSP-1) is a large extracellular matrix-associated protein that is important for normal follicular development, is rapidly modulated during follicular growth and plays important roles in cellular proliferation and angiogenesis. TSP-1 mRNA is post-transcriptionally regulated, although the underlying mechanisms are largely unknown. Insulin-like growth factor-1 is a potent signalling molecule that participates in folliculogenesis. We hypothesized that IGF-1 modulates TSP-1 expression in granulosa cells, and that such modulation requires rapid turnover of the TSP-1 mRNA and protein. Spontaneously-immortalized rat granulosa cells (SIGC) were cultured in the presence or absence of IGF-1, after which the expression and turnover of TSP-1 mRNA and protein was evaluated by western blot and quantitative PCR. RNA stability reporter constructs were prepared in which wild-type and mutated AU-rich elements from the TSP-1 3'UTR were cloned downstream of the luciferase gene in a mammalian expression vector. These were transfected into SIGC cells in order to characterize mRNA elements that regulate the stability of the TSP-1 mRNA. TSP-1 expression decreased rapidly at the mRNA and protein levels in IGF-1 treated cultures. Following 12 h of IGF-I treatment, TSP-1 protein decreased by 25% and was 73% lower than in untreated cultures. The half-life of endogenous TSP-1 mRNA in SIGC was 2.0 h. This was not changed in the presence of IGF-1, however, transcription of new TSP-1 mRNA was inhibited. Reporter mRNAs with mutated AU-rich elements demonstrated a longer half-life than mRNAs in which the wild type AU-rich elements were present. These studies reveal that IGF-1 rapidly inhibits TSP-1 expression at the protein and mRNA levels in cultured granulosa cells through apparent inhibition of TSP-1 transcription. The decrease depends on an intrinsically short half-life of TSP-1 mRNA and protein. The short mRNA half life is due, at least in part, to AU-rich elements in the 3'UTR of the TSP-1 mRNA. Key words: Extracellular matrix, Gene expression, mRNA stability, Ovary, Post-transcriptional (J. Reprod. Dev. 57: [76][77][78][79][80][81][82][83] 2011) uccessful mammalian folliculogenesis is dependent on the rapid and precise regulation of specific gene expression during various stages of follicle development in response to endocrine, paracrine, and autocrine factors that vary through the estrous cycle (reviewed in [1,2]). The ability of follicular cells to respond appropriately to such stimuli is one key factor in the progression of any individual follicle to dominance, and failure to do so is one key reason for follicular atresia [3]. The complex mechanisms that control follicular gene expression in granulosa and other ovarian cells are poorly understood.Although gonadotrophin-mediated signalling pathways are clearly indispensable for most aspects of follicle growth, the importance of other soluble and local factors in promoting follicular "success" is increasingly apparent. One such factor is Insulin-like growth ...

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“…Our finding is in disagreement with Agrawal et al (2002 (4) , Artini et al (2006) (20) , Artini et al (2009) (21) and Mary et al (2016) (22) who found elevated levels of VEGF in serum and follicular fluid of patients with PCOS undergoing IVF. The increased levels of VEGF explained by the finding that the release of VEGF by granulosa lutein cells is augmented by insulin (4,23) and that luteinized granulose cells in women with PCOS are more sensitive to insulin (23) . Since many women with PCOS have hyperinsulinemia, hypersecretion of VEGF in women with PCOS may be due to hyperinsulinemia (24) , whereas Lee et al (25) explained the high levels of VEGF by the investigation of single nucleotide polymorphisms of VEGF gene, in 134 Korean women with PCOS and they concluded that the single nucleotide polymorphisms regulating the expression and activity of VEGF may be significantly associated with pathogenesis of PCOS.…”

Section: Discussion:-mentioning

confidence: 99%

The Effect of Different Ovarian Stimulation Protocols on Vascular Endothelial Growth Factor (Vegf) Concentration in the Serum and Follicular Fluid of Women With Pcos Undergoing Icsi/Ivf.

Aboudy¹,

RedaAlKawaz²,

Ani³

2017

IJAR

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Objective:To measure the concentration of vascular endothelial growth factor (VEGF) in serum and follicular fluid of patients with PCOS at day of ova pick up after using of different IVF/ICSI protocols and to assess the pregnancy outcome. Study design: A total of 90 infertile women (55 women with Polycystic ovary syndrome and the other 35 women as a control (non PCOS) undergoing controlled ovarian hyperstimulation for intracytoplasmic sperm injection cycle were prospectively recruited for this study in High Institute of Infertility Diagnosis and Assisted Reproductive Technology / AL-Nahrian University and Kamal ALSamarai Hospital, center of fertility and IVF (Baghdad/Iraq) during the period from December 2015 to the end of April 2017.The fifty five PCOS women were divided into three groups: twenty five (25) infertile women have had PCOS undergoing long Agonist protocol for ICSI cycle, fifteen (15) infertile women have had PCOS undergoing Antagonist protocol for ICSI and fifteen (15) infertile women have had PCOS undergoing short Agonist protocol for ICSI. The controlled group included 35 women were free of signs and symptoms of PCOS with regular cycles and no endocrine abnormalities undergoing ICSI cycle (15 infertile women underwent long agonist protocol, 10 women underwent short agonist and 10 women underwent antagonist protocol). In all patients, serum and follicular fluid VEGF levels were measured on the day of oocyte retrieval by using Enzyme linked immuno sorbent assay.

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Insulin and Insulin-Like Growth Factor Stimulation of Vascular Endothelial Growth Factor Production by Luteinized Granulosa Cells: Comparison between Polycystic Ovarian Syndrome (PCOS) and Non-PCOS Women

Abstract: Insulin and IGFs promote VEGF-A production in LGCs, but the response patterns are different when cells from PCOS and non-PCOS women are compared.

Cited by 56 publications

References 25 publications

Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome

Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome

Rapid Insulin-like Growth Factor-1-induced Changes in Granulosa Cell Thrombospondin-1 Expression In Vitro

The Effect of Different Ovarian Stimulation Protocols on Vascular Endothelial Growth Factor (Vegf) Concentration in the Serum and Follicular Fluid of Women With Pcos Undergoing Icsi/Ivf.

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