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Metformin Inhibits Follicle-Stimulating Hormone (FSH) Action in Human Granulosa Cells: Relevance to Polycystic Ovary Syndrome

Rice, S; Elia, A; Jawad, Z; Pellatt, L; Mason, HD (2013) Metformin Inhibits Follicle-Stimulating Hormone (FSH) Action in Human Granulosa Cells: Relevance to Polycystic Ovary Syndrome. JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 98 (9). E1491 - E1500 (10). ISSN 0021-972X https://doi.org/10.1210/jc.2013-1865
SGUL Authors: Elia, Androulla Mason, Helen Diane Rice, Suman

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Abstract

Background: Women with anovulatory polycystic ovary syndrome (PCOS) are generally insulin-resistant and as a consequence are often treated with the biguanide metformin. Results with metformin have, however, been variable with some studies demonstrating induction of regular cycles and an increase in ovulation, whereas others do not. Hence more understanding is needed regarding the mechanism of metformin's actions in ovarian granulosa cells especially in light of previous demonstrations of direct actions. Objective: The aim of this study was to investigate metformin's interaction with the FSH/cAMP/protein kinase A pathway, which is the primary signaling pathway controlling CYP19A1 (aromatase) expression in the ovary. Methods: The effect of metformin on FSH and forskolin-stimulated aromatase expression in human granulosa cells was measured by quantitative real-time PCR. Activity was assessed after transfection with a promoter II-luciferase construct, and by an RIA measuring conversion of androgen to estrogens. The effect on FSH receptor (FSHR) mRNA was assessed by quantitative PCR. Levels of phosphorylated cAMP response element binding protein (CREB) and CREB-regulated transcription coactivator 2 (CRTC2) were measured by Western blotting and cAMP by a bioluminescent assay. Results: Metformin markedly reduced FSH but not forskolin-stimulated aromatase expression and activity. This effect was exerted by inhibition of basal and ligand-induced up-regulation of FSHR expression. Metformin also reduced FSH-induced phosphorylation of CREB and hence CRE activity, which could potentially disrupt the CREB–CREB-binding protein–CRTC2 coactivator complex that binds to CRE in promoter II of the aromatase gene. This is mediated in an AMP-activated protein kinase-independent manner, and does not involve alteration of cAMP levels. Conclusion: These finding have implications for the use of metformin in the treatment of anovulation in women with PCOS.

Item Type: Article
Additional Information: This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/us/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Aromatase, Cell Line, Tumor, Colforsin, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Female, Follicle Stimulating Hormone, Granulosa Cells, Humans, Hypoglycemic Agents, Insulin Resistance, Metformin, Phosphorylation, Polycystic Ovary Syndrome, Receptors, FSH, Signal Transduction, Up-Regulation, Science & Technology, Life Sciences & Biomedicine, Endocrinology & Metabolism, ENDOCRINOLOGY & METABOLISM, IN-VITRO FERTILIZATION, P450 CYP19 GENE, DOUBLE-BLIND, PROTEIN-KINASE, LUTEINIZING-HORMONE, SIGNALING PATHWAYS, AROMATASE-ACTIVITY, PROXIMAL PROMOTER, CONTROLLED-TRIAL, MESSENGER-RNA, Endocrinology & Metabolism, 1103 Clinical Sciences, 1114 Paediatrics And Reproductive Medicine
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Academic Structure > Institute of Medical & Biomedical Education (IMBE) > Centre for Biomedical Education (INMEBE)
Journal or Publication Title: JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
ISSN: 0021-972X
Related URLs:
Dates:
DateEvent
1 September 2013Published
Web of Science ID: WOS:000324175200007
Download EPMC Full text (HTML)
URI: http://sgultest.da.ulcc.ac.uk/id/eprint/103039
Publisher's version: https://doi.org/10.1210/jc.2013-1865

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