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Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
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Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Department of Integrative Medicine and Neurobiology, State Key Lab of Medical Neurobiology, Shanghai Medical College and Institute of Acupuncture Research (WHO Collaborating Center for Traditional Medicine), Institute of Brain Science, Fudan University, Shanghai, China
Institute of Integrative Medicine of Fudan University, Shanghai, China
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Department of Gynecology Obstetrics and Gynecology, Hospital of Fudan University, Shanghai, China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
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Impaired progesterone (P4) signaling is linked to endometrial dysfunction and infertility in women with polycystic ovary syndrome (PCOS). Here, we report for the first time that elevated expression of progesterone receptor (PGR) isoforms A and B parallels increased estrogen receptor (ER) expression in PCOS-like rat uteri. The aberrant PGR-targeted gene expression in PCOS-like rats before and after implantation overlaps with dysregulated expression of Fkbp52 and Ncoa2, two genes that contribute to the development of uterine P4 resistance. In vivo and in vitro studies of the effects of metformin on the regulation of the uterine P4 signaling pathway under PCOS conditions showed that metformin directly inhibits the expression of PGR and ER along with the regulation of several genes that are targeted dependently or independently of PGR-mediated uterine implantation. Functionally, metformin treatment corrected the abnormal expression of cell-specific PGR and ER and some PGR-target genes in PCOS-like rats with implantation. Additionally, we documented how metformin contributes to the regulation of the PGR-associated MAPK/ERK/p38 signaling pathway in the PCOS-like rat uterus. Our data provide novel insights into how metformin therapy regulates uterine P4 signaling molecules under PCOS conditions.
Université Paris-Sud, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France
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Université Paris-Sud, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France
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Université Paris-Sud, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France
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Université Paris-Sud, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France
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Université Paris-Sud, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France
Assistance Publique-Hôpitaux de Paris, Service d’Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre, Le Kremlin Bicêtre, France
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Université Paris-Sud, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France
Assistance Publique-Hôpitaux de Paris, Service d’Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre, Le Kremlin Bicêtre, France
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Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene predispose humans to pituitary adenomas, particularly of the somatotroph lineage. Mice with global heterozygous inactivation of Aip (Aip +/−) also develop pituitary adenomas but differ from AIP-mutated patients by the high penetrance of pituitary disease. The endocrine phenotype of these mice is unknown. The aim of this study was to determine the endocrine phenotype of Aip +/− mice by assessing the somatic growth, ultradian pattern of GH secretion and IGF1 concentrations of longitudinally followed male mice at 3 and 12 months of age. As the early stages of pituitary tumorigenesis are controversial, we also studied the pituitary histology and somatotroph cell proliferation in these mice. Aip +/− mice did not develop gigantism but exhibited a leaner phenotype than wild-type mice. Analysis of GH pulsatility by deconvolution in 12-month-old Aip +/− mice showed a mild increase in total GH secretion, a conserved GH pulsatility pattern, but a normal IGF1 concentration. No pituitary adenomas were detected up to 12 months of age. An increased ex vivo response to GHRH of pituitary explants from 3-month-old Aip +/− mice, together with areas of enlarged acini identified on reticulin staining in the pituitary of some Aip +/− mice, was suggestive of somatotroph hyperplasia. Global heterozygous Aip deficiency in mice is accompanied by subtle increase in GH secretion, which does not result in gigantism. The absence of pituitary adenomas in 12-month-old Aip +/− mice in our experimental conditions demonstrates the important phenotypic variability of this congenic mouse model.
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Molecular Neuroscience, Faculty of Medicine, Toyama University.
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) Aguilar-Roblero R Verduzco-Carbajal L Rodriguez C Mendez-Franco J Moran J de la Mora MP 1993 Circadian rhythmicity in the GABAergic system in the suprachiasmatic nuclei of the rat . Neuroscience Letters 157 199 – 202 . ( doi
Departamento de Biología Celular, Facultad de Biología, Universidad Complutense, E-28040 Madrid, Spain
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Departamento de Biología Celular, Facultad de Biología, Universidad Complutense, E-28040 Madrid, Spain
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Departamento de Biología Celular, Facultad de Biología, Universidad Complutense, E-28040 Madrid, Spain
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scientific work. References Azcoitia I , Sierra A & Garcia-Segura LM 1999 Neuroprotective effects of estradiol in the adult rat hippocampus: interaction with insulin-like growth factor-I signalling. Journal of Neuroscience
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Centro de Biología Molecular ‘Severo Ochoa’, Departamento de Neuropatología Molecular CSIC-UAM, Madrid, Spain
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
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Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
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induction in cultured hippocampal slices . European Journal of Neuroscience 29 447 – 454 . ( https://doi.org/10.1111/j.1460-9568.2008.06591.x ) 10.1111/j.1460-9568.2008.06591.x Aguirre C Jayaraman A Pike C Baudry M 2010 Progesterone inhibits
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glucocorticoid receptor-like immunoreactivity in the rat central nervous system . Neuroscience 39 579 – 604 . ( doi:10.1016/0306-4522(90)90244-X ) Ahima R Krozowski Z Harlan R 1991 Type I corticosteroid receptor-like immunoreactivity in the rat CNS
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-serum Rb 7 (diluted to a final concentration of 1:30 000) was provided courtesy of Dr W Engeland (University of Minnesota, twin cities campus, Department of Neuroscience). The detection limit for this assay was 15 pg/ml; the intra-assay coefficient of
University of Groningen, University Medical Center, Groningen, The Netherlands
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plasticity, altered synaptic functioning, and differential responsiveness to glucocorticoids and stress . Journal of Neuroscience 28 6037 – 6045 . ( doi:10.1523/JNEUROSCI.0526-08.2008 ) Chapman K Holmes M Seckl J 2013 11β
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neurotrophin receptors . Annual Reviews of Neuroscience 18 223 – 253 . Bova R Micheli MR Quadralucci P Zucconi GG 1998 BDNF and trkB mRNA oscillate in the rat brain during the light-dark cycle . Molecular Brain Research 57 321 – 324 . Castrèn E
