Metformin and Female Reproduction: Comparison
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Metformin (MF), a first-line drug to treat type 2 diabetes mellitus (T2DM), alone and in combination with other drugs, restores the ovarian function in women with polycystic ovary syndrome (PCOS) and improves fetal development, pregnancy outcomes and offspring health in gestational diabetes mellitus (GDM) and T2DM. MF treatment is demonstrated to improve the efficiency of in vitro fertilization and is considered a supplementary drug in assisted reproductive technologies. MF lacks teratogenic effects and has positive health effect in newborns. The entry is focused on use of MF therapy for restoration of female reproductive functions and improvement of pregnancy outcomes in metabolic and endocrine disorders. 

  • : metformin
  • diabetes mellitus
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References

  1. Rena, G.; Hardie, D.G.; Pearson, E.R. The mechanisms of action of metformin. Diabetologia 2017, 60, 1577–1585, doi:10.1007/s00125-017-4342-z.
  2. Li, M.; Li, X.; Zhang, H.; Lu, Y. Molecular Mechanisms of Metformin for Diabetes and Cancer Treatment. Front. Physiol. 2018, 9, 1039, doi:10.3389/fphys.2018.01039.
  3. Agius, L.; Ford, B.E.; Chachra, S.S. The Metformin Mechanism on Gluconeogenesis and AMPK Activation: The Metabolite Perspective. Int. J. Mol. Sci. 2020, 21, 3240, doi:10.3390/ijms21093240.
  4. An, H.; He, L. Current understanding of metformin effect on the control of hyperglycemia in diabetes. J. Endocrinol. 2016, 228, R97–R106, doi:10.1530/JOE-15-0447.
  5. He, L. Metformin and Systemic Metabolism. Trends Pharm. Sci. 2020, 41, 868–881, doi:10.1016/j.tips.2020.09.001.
  6. Cioce, M.; Pulito, C.; Strano, S.; Blandino, G.; Fazio, V.M. Metformin: Metabolic Rewiring Faces Tumor Heterogeneity. Cells 2020, 9, 2439, doi:10.3390/cells9112439.
  7. Chan, P.; Shao, L.; Tomlinson, B.; Zhang, Y.; Liu, Z.M. Metformin transporter pharmacogenomics: Insights into drug dispo-sition-where are we now? Expert Opin. Drug Metab. Toxicol. 2018, 14, 1149–1159, doi:10.1080/17425255.2018.1541981
  8. Lee, N.; Hebert, M.F.; Wagner, D.J.; Easterling, T.R.; Liang, C.J.; Rice, K.; Wang, J. Organic Cation Transporter 3 Facilitates Fetal Exposure to Metformin during Pregnancy. Mol. Pharmacol. 2018, 94, 1125–1131, doi:10.1124/mol.118.112482.
  9. Hardie, D.G.; Ross, F.A.; Hawley, S.A. AMPK: A nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 2012, 13, 251–262, doi:10.1038/nrm3311.
  10. Hardie, D.G.; Schaffer, B.E.; Brunet, A. AMPK: An Energy-Sensing Pathway with Multiple Inputs and Outputs. Trends Cell Biol. 2016, 27, 190–201, doi:10.1016/j.tcb.2015.10.013.
  11. Lin, S.C.; Hardie, D.G. AMPK: Sensing Glucose as well as Cellular Energy Status. Cell Metab. 2018, 27, 299–313, doi:10.1016/j.cmet.2017.10.009.
  12. Hardie, D.G. AMPK: A key regulator of energy balance in the single cell and the whole organism. Int. J. Obes. 2008, 32, S7–S12, doi:10.1038/ijo.2008.116.
  13. Hardie, DG. Keeping the home fires burning: AMP-activated protein kinase. J. R. Soc. Interface. 2018, 15, 20170774, doi:10.1098/rsif.2017.0774.
  14. Lizcano, J.M.; Göransson, O.; Toth, R.; Deak, M.; Morrice, N.A.; Boudeau, J.; Hawley, S.A.; Udd, L.; Mäkelä, T.P.; Hardie, D.G.; et al. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J. 2004, 23, 833–843, doi:10.1038/sj.emboj.7600110
  15. Hawley, S.A.; Pan, D.A.; Mustard, K.J.; Ross, L.; Bain, J.; Edelman, A.M.; Frenguelli, B.G.; Hardie, D.G. Calmodu-lin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2005, 2, 9–19, doi:10.1016/j.cmet.2005.05.009.
  16. Woods, A.; Dickerson, K.; Heath, R.; Hong, S.P.; Momcilovic, M.; Johnstone, S.R.; Carlson, M.; Carling, D. Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2005, 2, 21–33, doi:10.1016/j.cmet.2005.06.005.
  17. Momcilovic, M.; Hong, S.P.; Carlson, M. Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J. Biol. Chem. 2006, 281, 25336–25343, doi:10.1074/jbc.M604399200.
  18. Ross, F.A.; Jensen, T.E.; Hardie, D.G. Differential regulation by AMP and ADP of AMPK complexes containing different γ subunit isoforms. Biochem. J. 2016, 473, 189–199, doi:10.1042/BJ20150910.
  19. Jia, J.; Abudu, Y.P.; Claude-Taupin, A.; Gu, Y.; Kumar, S.; Choi, S.W.; Peters, R.; Mudd, M.H.; Allers, L.; Salemi, M.; et al. Ga-lectins Control mTOR in Response to Endomembrane Damage. Mol. Cell 2018, 70, 120–135, doi:10.1016/j.molcel.2018.03.009.
  20. Jia, J.; Bissa, B.; Brecht, L.; Allers, L.; Choi, S.W.; Gu, Y.; Zbinden, M.; Burge, M.R.; Timmins, G.; Hallows, K.; et al. AMPK, a Regulator of Metabolism and Autophagy, Is Activated by Lysosomal Damage via a Novel Galectin-Directed Ubiquitin Sig-nal Transduction System. Mol. Cell. 2020, 77, 951–969, doi:10.1016/j.molcel.2019.12.028.
  21. Zhou, G.; Myers, R.; Li, Y.; Chen, Y.; Shen, X.; Fenyk-Melody, J.; Wu, M.; Ventre, J.; Doebber, T.; Fujii, N.; et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 2001, 108, 1167–1174, doi:10.1172/JCI13505.
  22. Woods, A.; Johnstone, S.R.; Dickerson, K.; Leiper, F.C.; Fryer, L.G.; Neumann, D.; Schlattner, U.; Wallimann, T.; Carlson, M.; Carling, D. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 2003, 13, 2004–2008, doi:10.1016/j.cub.2003.10.031.
  23. Cao, J.; Meng, S.; Chang, E.; Beckwith-Fickas, K.; Xiong, L.; Cole, R.N.; Radovick, S.; Wondisford, F.E.; He, L. Low concentrations of metformin suppress glucose production in hepatocytes through AMP-activated protein kinase (AMPK). J. Biol. Chem. 2014, 289, 20435–20446, doi:10.1074/jbc.M114.567271.
  24. Oakhill, J.S.; Steel, R.; Chen, Z.P.; Scott, J.W.; Ling, N.; Tam, S.; Kemp, B.E. AMPK is a direct adenylate charge-regulated pro-tein kinase. Science 2011, 332, 1433–1435, doi:10.1126/science.1200094.
  25. Xiao, B.; Sanders, M.J.; Underwood, E.; Heath, R.; Mayer, F.V.; Carmena, D.; Jing, C.; Walker, P.A.; Eccleston, J.F.; Haire, L.F.; et al. Structure of mammalian AMPK and its regulation by ADP. Nature 2011, 472, 230–233, doi:10.1038/nature09932.
  26. Zhang, C.S.; Hawley, S.A.; Zong, Y.; Li, M.; Wang, Z.; Gray, A.; Ma, T.; Cui, J.; Feng, J.W.; Zhu, M.; et al. Fruc-tose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature 2017, 548, 112–116, doi:10.1038/nature23275.
  27. Zong, Y.; Zhang, C.S.; Li, M.; Wang, W.; Wang, Z.; Hawley, S.A.; Ma, T.; Feng, J.W.; Tian, X.; Qi, Q.; et al. Hierarchical activa-tion of compartmentalized pools of AMPK depends on severity of nutrient or energy stress. Cell Res. 2019, 29, 460–473, doi:10.1038/s41422-019-0163-6.
  28. Davies, S.P.; Helps, N.R.; Cohen, P.T.; Hardie, D.G. 5’-AMP inhibits dephosphorylation, as well as promoting phosphoryla-tion, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and na-tive bovine protein phosphatase-2AC. FEBS Lett. 1995, 377, 421–425, doi:10.1016/0014-5793(95)01368-7.
  29. Suter, M.; Riek, U.; Tuerk, R.; Schlattner, U.; Wallimann, T.; Neumann, D. Dissecting the role of 5’-AMP for allosteric stimu-lation, activation, and deactivation of AMP-activated protein kinase. J. Biol. Chem. 2006, 281, 32207–32216, doi:10.1074/jbc.M606357200.
  30. El-Mir, M.Y.; Nogueira, V.; Fontaine, E.; Averet, N.; Rigoulet, M.; Leverve, X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 2000, 275, 223–228, doi:10.1074/jbc.275.1.223.
  31. Owen, M.R.; Doran, E.; Halestrap, A.P. Evidence that metformin exerts its anti-diabetic effects through inhibition of com-plex 1 of the mitochondrial respiratory chain. Biochem. J. 2000, 348, 607–614, doi:10.1042/bj3480607.
  32. Foretz, M.; Hébrard, S.; Leclerc, J.; Zarrinpashneh, E.; Soty, M.; Mithieux, G.; Sakamoto, K.; Andreelli, F.; Viollet, B. Metfor-min inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Investig. 2010, 120, 2355–2369, doi:10.1172/JCI40671.
  33. Bridges, H.R.; Jones, A.J.; Pollak, M.N.; Hirst, J. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem. J. 2014, 462, 475–487, doi:10.1042/BJ20140620.
  34. Ouyang, J.; Parakhia, R.A.; Ochs, R.S. Metformin activates AMP kinase through inhibition of AMP deaminase. J. Biol. Chem. 2011, 286, 1–11, doi:10.1074/jbc.M110.121806.
  35. Meng, S.; Cao, J.; He, Q.; Xiong, L.; Chang, E.; Radovick, S.; Wondisford, F.E.; He, L. Metformin activates AMP-activated protein kinase by promoting formation of the αβγ heterotrimeric complex. J. Biol. Chem. 2015, 290, 3793–3802, doi:10.1074/jbc.M114.604421.
  36. Foretz, M.; Guigas, B.; Viollet, B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat. Rev. Endocrinol. 2019, 15, 569.
  37. Sliwinska, A.; Drzewoski, J. Molecular action of metformin in hepatocytes: An updated insight. Curr. Diabetes Rev. 2015, 11, 175–181, doi:10.2174/1573399811666150325233108.
  38. Karnewar, S.; Neeli, P.K.; Panuganti, D.; Kotagiri, S.; Mallappa, S.; Jain, N.; Jerald, M.K.; Kotamraju, S. Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation: Relevance in age-associated vascular dysfunction. Biochim. Biophys. Acta Mol. Basis Dis. 2018, 1864, 1115–1128, doi:10.1016/j.bbadis.2018.01.018.
  39. Rattan, R.; Giri, S.; Hartmann, L.C.; Shridhar, V. Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispen-sable manner. J. Cell. Mol. Med. 2011, 15, 166–178, doi:10.1111/j.1582-4934.2009.00954.x
  40. Fullerton, M.D.; Galic, S.; Marcinko, K.; Sikkema, S.; Pulinilkunnil, T.; Chen, Z.P.; O’Neill, H.M.; Ford, R.J.; Palanivel, R.; O’Brien, M.; et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing ef-fects of metformin. Nat. Med. 2013, 19, 1649–1654, doi:10.1038/nm.3372.
  41. Kim, J.; Yang, G.; Kim, Y.; Kim, J.; Ha, J. AMPK activators: Mechanisms of action and physiological activities. Exp. Mol. Med. 2016, 48, e224, doi:10.1038/emm.2016.16.
  42. Rattan, R.; Giri, S.; Hartmann, L.C.; Shridhar, V. Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J. Cell. Mol. Med. 2011, 15, 166–178, doi:10.1111/j.1582-4934.2009.00954.x
  43. Motoshima, H.; Goldstein, B.J.; Igata, M.; Araki, E. AMPK and cell proliferation—AMPK as a therapeutic target for atherosclerosis and cancer. J. Physiol. 2006, 574, 63–71, doi:10.1113/jphysiol.2006.108324.
  44. Choi, Y.K.; Park, K.G. Metabolic roles of AMPK and metformin in cancer cells. Mol. Cells 2013, 36, 279–87, doi:10.1007/s10059-013-0169-8.
  45. Gao, F.; Chen, J.; Zhu, H. A potential strategy for treating atherosclerosis: Improving endothelial function via AMP-activated protein kinase. Sci. China Life Sci. 2018, 61, 1024–1029, doi:10.1007/s11427-017-9285-1.
  46. Lyons, C.L.; Roche. H.M. Nutritional Modulation of AMPK-Impact upon Metabolic-Inflammation. Int. J. Mol. Sci. 2018, 19, 3092, doi:10.3390/ijms19103092.
  47. Viollet, B.; Foretz, M. Revisiting the mechanisms of metformin action in the liver. Ann. Endocrinol. 2013, 74, 123–129, doi:10.1016/j.ando.2013.03.006.
  48. Johanns, M.; Lai, Y.C.; Hsu, M.F.; Jacobs, R.; Vertommen, D.; Van Sande, J.; Dumont, J.E.; Woods, A.; Carling, D.; Hue, L.; et al. AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B. Nat. Commun. 2016, 7, 10856, doi:10.1038/ncomms10856.
  49. Miller, R.A.; Chu, Q.; Xie, J.; Foretz, M.; Viollet, B.; Birnbaum, M.J. Biguanides suppress hepatic glucagon signalling by de-creasing production of cyclic AMP. Nature 2013, 494, 256–260, doi:10.1038/nature11808.
  50. He, L.; Sabet, A.; Djedjos, S.; Miller, R.; Sun, X.; Hussain, M.A.; Radovick, S.; Wondisford, F.E. Metformin and insulin sup-press hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 2009, 137, 635–646, doi:10.1016/j.cell.2009.03.016.
  51. Madiraju, A.K.; Erion, D.M.; Rahimi, Y.; Zhang, X.M.; Braddock, D.T.; Albright, R.A.; Prigaro, B.J.; Wood, J.L.; Bhanot, S.; MacDonald, M.J.; et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogen-ase. Nature 2014, 510, 542–546, doi:10.1038/nature13270.
  52. Madiraju, A.K.; Qiu, Y.; Perry, R.J.; Rahimi, Y.; Zhang, X.M.; Zhang, D.; Camporez, J.G.; Cline, G.W.; Butrico, G.M.; Kemp, B.E.; et al. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat. Med. 2018, 24, 1384–1394, doi:10.1038/s41591-018-0125-4.
  53. Cuyàs, E.; Verdura, S.; Llorach-Pares, L.; Fernández-Arroyo, S.; Luciano-Mateo, F.; Cabré, N.; Stursa, J.; Werner, L.; Mar-tin-Castillo, B.; Viollet, B.; et al. Metformin directly targets the H3K27me3 demethylase KDM6A/UTX. Aging Cell. 2018, 17, e12772, doi:10.1111/acel.12772.
  54. Wu, H.; Esteve, E.; Tremaroli, V.; Khan, M.T.; Caesar, R.; Mannerås-Holm, L.; Ståhlman, M.; Olsson, L.M.; Serino, M.; Planas-Fèlix, M.; et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contrib-uting to the therapeutic effects of the drug. Nat. Med. 2017, 23, 850–858, doi:10.1038/nm.4345.
  55. Shin, N.R.; Lee, J.C.; Lee, H.Y.; Kim, M.S.; Whon, T.W.; Lee, M.S.; Bae, J.W. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 2014, 63, 727–735, doi:10.1136/gutjnl-2012-303839.
  56. Duca, F.A.; Côté, C.D.; Rasmussen, B.A.; Zadeh-Tahmasebi, M.; Rutter, G.A.; Filippi, B.M.; Lam, T.K. Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats. Nat. Med. 2015, 21, 506–511, doi:10.1038/nm.3787.
  57. Hattori, Y.; Suzuki, K.; Hattori, S.; Kasai, K. Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension 2006, 47, 1183–1188, doi:10.1161/01.HYP.0000221429.94591.72.
  58. Huang, N.L.; Chiang, S.H.; Hsueh, C.H.; Liang, Y.J.; Chen, Y.J.; Lai, L.P. Metformin inhibits TNF-alpha-induced IkappaB ki-nase phosphorylation, IkappaB-alpha degradation and IL-6 production in endothelial cells through PI3K-dependent AMPK phosphorylation. Int. J. Cardiol. 2009, 134, 169–175, doi:10.1016/j.ijcard.2008.04.010.
  59. Okamura, H.; Yoshida, K.; Sasaki, E.; Qiu, L.; Amorim, B.R.; Morimoto, H.; Haneji, T. Expression of PTEN and Akt phos-phorylation in lipopolysaccharide-treated NIH3T3 cells. Cell Biol. Int. 2007, 31, 119–125, doi:10.1016/j.cellbi.2006.09.014.
  60. Lee, S.K.; Lee, J.O.; Kim, J.H.; Kim, S.J.; You, G.Y.; Moon, J.W.; Jung, J.H.; Park, S.H.; Uhm, K.O.; Park, J.M.; et al. Metformin sensitizes insulin signaling through AMPK-mediated PTEN down-regulation in preadipocyte 3T3-L1 cells. J. Cell. Biochem. 2011, 112, 1259–1267, doi:10.1002/jcb.23000.
  61. Balen, A.H.; Morley, L.C.; Misso, M.; Franks, S.; Legro, R.S.; Wijeyaratne, C.N.; Stener-Victorin, E.; Fauser, B.C.; Norman, R.J.; Teede, H. The management of anovulatory infertility in women with polycystic ovary syndrome: An analysis of the evidence to support the development of global WHO guidance. Hum. Reprod. Update 2016, 22, 687–708, doi:10.1093/humupd/dmw025.
  62. Norman, R.J.; Dewailly, D.; Legro, R.S.; Hickey, T.E. Polycystic ovary syndrome. Lancet 2007, 370, 685–697, doi:10.1016/S0140-6736(07)61345-2.
  63. Fauser, B.C.; Tarlatzis, B.C.; Rebar, R.W.; Legro, R.S.; Balen, A.H.; Lobo, R.; Carmina, E.; Chang, J.; Yildiz, B.O.; Laven, J.S.; et al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS): The Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil. Steril. 2012, 97, 28–38.e25, doi:10.1016/j.fertnstert.2011.09.024.
  64. Abbott, D.H.; Dumesic, D.A.; Levine, J.E. Hyperandrogenic origins of polycystic ovary syndrome—Implications for patho-physiology and therapy. Expert Rev. Endocrinol. Metab. 2019, 14, 131–143, doi:10.1080/17446651.2019.1576522.
  65. Witchel, S.F.; Oberfield, S.E.; Peña, A.S. Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment with Emphasis on Adolescent Girls. J. Endocr. Soc. 2019, 3, 1545–1573, doi:10.1210/js.2019-00078.
  66. Alvarez-Blasco, F.; Botella-Carretero, J.I.; San Millán, J.L.; Escobar-Morreale, H.F. Prevalence and characteristics of the pol-ycystic ovary syndrome in overweight and obese women. Arch. Intern. Med. 2006, 166, 2081–2086, doi:10.1001/archinte.166.19.2081.
  67. Legro, R.S.; Barnhart, H.X.; Schlaff, W.D.; Carr, B.R.; Diamond, M.P.; Carson, S.A.; Steinkampf, M.P.; Coutifaris, C.; McGov-ern, P.G.; Cataldo, N.A.; et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N. Engl. J. Med. 2007, 356, 551–566, doi:10.1056/NEJMoa063971.
  68. Azziz, R.; Carmina, E.; Dewailly, D.; Diamanti-Kandarakis, E.; Escobar-Morreale, H.F.; Futterweit, W.; Janssen, O.E.; Legro, R.S.; Norman, R.J.; Taylor, A.E.; et al. The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: The complete task force report. Fertil. Steril. 2009, 91, 456–488, doi:10.1016/j.fertnstert.2008.06.035.
  69. Li, R.; Zhang, Q.; Yang, D.; Li, S.; Lu, S.; Wu, X.; Wei, Z.; Song, X.; Wang, X.; Fu, S.; et al. Prevalence of polycystic ovary syn-drome in women in China: A large community-based study. Hum. Reprod. 2013, 28, 2562–2569, doi:10.1093/humrep/det262.
  70. Kollmann, M.; Klaritsch, P.; Martins, W.P.; Guenther, F.; Schneider, V.; Herzog, S.A.; Craciunas, L.; Lang, U.; Obermay-er-Pietsch, B.; Lerchbaum, E.; et al. Maternal and neonatal outcomes in pregnant women with PCOS: Comparison of differ-ent diagnostic definitions. Hum. Reprod. 2015, 30, 2396–2403, doi:10.1093/humrep/dev187.
  71. Cassar, S.; Misso, M.L.; Hopkins, W.G.; Shaw, C.S.; Teede, H.J.; Stepto, N.K. Insulin resistance in polycystic ovary syndrome: A systematic review and meta-analysis of euglycaemic-hyperinsulinaemic clamp studies. Hum. Reprod. 2016, 31, 2619–2631, doi:10.1093/humrep/dew243.
  72. Spritzer, P.M. Polycystic ovary syndrome: Reviewing diagnosis and management of metabolic disturbances. Arq. Bras. En-docrinol. Metabol. 2014, 58, 182–187, doi:10.1590/0004-2730000003051.
  73. Dumesic, D.A.; Oberfield, S.E.; Stener-Victorin, E.; Marshall, J.C.; Laven, J.S.; Legro, R.S. Scientific Statement on the Diagnos-tic Criteria, Epidemiology, Pathophysiology, and Molecular Genetics of Polycystic Ovary Syndrome. Endocr. Rev. 2015, 36, 487–525, doi:10.1210/er.2015-1018.
  74. Faure, M.; Bertoldo, M.J.; Khoueiry, R.; Bongrani, A.; Brion, F.; Giulivi, C.; Dupont, J.; Froment, P. Metformin in Reproduc-tive Biology. Front. Endocrinol. 2018, 9, 675, doi:10.3389/fendo.2018.00675.
  75. Jones, M.R.; Goodarzi, M.O. Genetic determinants of polycystic ovary syndrome: Progress and future directions. Fertil. Steril. 2016, 106, 25–32, doi:10.1016/j.fertnstert.2016.04.040.
  76. Liu, H.; Zhao, H.; Chen, Z.J. Genome-Wide Association Studies for Polycystic Ovary Syndrome. Semin. Reprod. Med. 2016, 34, 224–229, doi:10.1055/s-0036-1585403.
  77. Khan, M.J.; Ullah, A.; Basit, S. Genetic Basis of Polycystic Ovary Syndrome (PCOS): Current Perspectives. Appl. Clin. Genet. 2019, 12, 249–260, doi:10.2147/TACG.S200341.
  78. Dapas, M.; Lin, F.T.J.; Nadkarni, G.N.; Sisk, R.; Legro, R.S.; Urbanek, M.; Hayes, M.G.; Dunaif, A. Distinct subtypes of poly-cystic ovary syndrome with novel genetic associations: An unsupervised, phenotypic clustering analysis. PLoS Med. 2020, 17, e1003132, doi:10.1371/journal.pmed.1003132.
  79. Xita, N.; Tsatsoulis, A. Review: Fetal programming of polycystic ovary syndrome by androgen excess: Evidence from ex-perimental, clinical, and genetic association studies. J. Clin. Endocrinol. Metab. 2006, 91, 1660–1666, doi:10.1210/jc.2005-2757.
  80. Ilie, I.R.; Georgescu, C.E. Polycystic Ovary Syndrome-Epigenetic Mechanisms and Aberrant MicroRNA. Adv. Clin. Chem. 2015, 71, 25–45, doi:10.1016/bs.acc.2015.06.001.
  81. Yu, Y.Y.; Sun, C.X.; Liu, Y.K.; Li, Y.; Wang, L.; Zhang, W. Genome-wide screen of ovary-specific DNA methylation in poly-cystic ovary syndrome. Fertil. Steril. 2015, 104, 145–153, doi:10.1016/j.fertnstert.2015.04.005.
  82. Wang, S.; Alvero, R. Racial and ethnic differences in physiology and clinical symptoms of polycystic ovary syndrome. Semin. Reprod. Med. 2013, 31, 365–369, doi:10.1055/s-0033-1348895.
  83. Merkin, S.S.; Phy, J.L.; Sites, C.K.; Yang, D. Environmental determinants of polycystic ovary syndrome. Fertil. Steril. 2016, 106, 16–24, doi:10.1016/j.fertnstert.2016.05.011.
  84. Abdolahian, S.; Tehrani, F.R.; Amiri, M.; Ghodsi, D.; Yarandi, R.B.; Jafari, M.; Majd, H.A.; Nahidi, F. Effect of lifestyle modi-fications on anthropometric, clinical, and biochemical parameters in adolescent girls with polycystic ovary syndrome: A systematic review and meta-analysis. BMC Endocr. Disord. 2020, 20, 71, doi:10.1186/s12902-020-00552-1.
  85. Abbott, D.H.; Barnett, D.K.; Bruns, C.M.; Dumesic, D.A. Androgen excess fetal programming of female reproduction: A de-velopmental etiology for polycystic ovary syndrome? Hum. Reprod. Update 2005, 11, 357–374, doi:10.1093/humupd/dmi013.
  86. Abbott, D.H.; Bacha, F. Ontogeny of polycystic ovary syndrome and insulin resistance in utero and early childhood. Fertil. Steril. 2013, 100, 2–11, doi:10.1016/j.fertnstert.2013.05.023.
  87. de Melo, A.S.; Dias, S.V.; Cavalli, Rde.C.; Cardoso, V.C.; Bettiol, H.; Barbieri, M.A.; Ferriani, R.A.; Vieira, C.S. Pathogenesis of polycystic ovary syndrome: Multifactorial assessment from the foetal stage to menopause. Reproduction 2015, 150, 1–24, doi:10.1530/REP-14-0499.
  88. Morley, L.C.; Tang, T.; Yasmin, E.; Norman, R.J.; Balen, A.H. Insulin-sensitising drugs (metformin, rosiglitazone, pioglita-zone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst. Rev. 2017, 11, CD003053, doi:10.1002/14651858.CD003053.pub6.
  89. Practice Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org; Practice Committee of the American Society for Reproductive Medicine. Role of metformin for ovulation induction in infertile pa-tients with polycystic ovary syndrome (PCOS): A guideline. Fertil. Steril. 2017, 108, 426–441, doi:10.1016/j.fertnstert.2017.06.026.
  90. Abdalla, M.A.; Deshmukh, H.; Atkin, S.; Sathyapalan, T. A review of therapeutic options for managing the metabolic aspects of polycystic ovary syndrome. Ther. Adv. Endocrinol. Metab. 2020, 11, 2042018820938305, doi:10.1177/2042018820938305.
  91. Bordewijk, E.M.; Nahuis, M.; Costello, M.F.; Van der Veen, F.; Tso, L.O.; Mol, B.W.; van Wely, M. Metformin during ovula-tion induction with gonadotrophins followed by timed intercourse or intrauterine insemination for subfertility associated with polycystic ovary syndrome. Cochrane Database Syst. Rev. 2017, 1, CD009090, doi:10.1002/14651858.CD009090.pub2.
  92. Sharpe, A.; Morley, L.C.; Tang, T.; Norman, R.J.; Balen, A.H. Metformin for ovulation induction (excluding gonadotrophins) in women with polycystic ovary syndrome. Cochrane Database Syst. Rev. 2019, 12, CD013505, doi:10.1002/14651858.CD013505.
  93. Gadalla, M.A.; Norman, R.J.; Tay, C.T.; Hiam, D.S.; Melder, A.; Pundir, J.; Thangaratinam, S.; Teede, H.J.; Mol, B.W.J.; Moran, L.J. Medical and Surgical Treatment of Reproductive Outcomes in Polycystic Ovary Syndrome: An Overview of Systematic Reviews. Int. J. Fertil. Steril. 2020, 13, 257–270, doi:10.22074/ijfs.2020.5608.
  94. Wu, Y.; Tu, M.; Huang, Y.; Liu, Y.; Zhang, D. Association of Metformin With Pregnancy Outcomes in Women With Polycys-tic Ovarian Syndrome Undergoing In Vitro Fertilization: A Systematic Review and Meta-analysis. JAMA Netw. Open 2020, 3, e2011995, doi:10.1001/jamanetworkopen.2020.11995.
  95. Rojas, J.; Chávez-Castillo, M.; Bermúdez, V. The Role of Metformin in Metabolic Disturbances during Pregnancy: Polycystic Ovary Syndrome and Gestational Diabetes Mellitus. Int. J. Reprod. Med. 2014, 2014, 797681, doi:10.1155/2014/797681.
  96. Teede, H.J.; Misso, M.L.; Costello, M.F.; Dokras, A.; Laven, J.; Moran, L.; Piltonen, T.; Norman, R.J.; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of pol-ycystic ovary syndrome. Clin. Endocrinol. 2018, 89, 251–268, doi:10.1111/cen.13795.
  97. Gormsen, L.C.; Søndergaard, E.; Christensen, N.L.; Brøsen, K.; Jessen, N.; Nielsen, S. Metformin increases endogenous glu-cose production in non-diabetic individuals and individuals with recent-onset type 2 diabetes. Diabetologia 2019, 62, 1251–1256, doi:10.1007/s00125-019-4872-7.
  98. McCreight, L.J.; Mari, A.; Coppin, L.; Jackson, N.; Umpleby, A.M.; Pearson, E.R. Metformin increases fasting glucose clear-ance and endogenous glucose production in non-diabetic individuals. Diabetologia 2020, 63, 444–447, doi:10.1007/s00125-019-05042-1.
  99. Bryrup, T.; Thomsen, C.W.; Kern, T.; Allin, K.H.; Brandslund, I.; Jørgensen, N.R.; Vestergaard, H.; Hansen, T.; Hansen, T.H.; Pedersen, O.; et al. Metformin-induced changes of the gut microbiota in healthy young men: Results of a non-blinded, one-armed intervention study. Diabetologia 2019, 62, 1024–1035, doi:10.1007/s00125-019-4848-7.
  100. Derkach, K.V.; Kuznetsova, L.A.; Sharova, T.S.; Ignat’eva, P.A.; Bondareva, V.M.; Shpakov, A.O. The effect of prolonged metformin treatment on the activity of the adenylate cyclase system and NO-synthase in the brain and myocardium of obese rats. Cell Tissue Biol. 2015, 9, 385–394, doi:10.1134/S1990519X1505003X.
  101. Practice Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org; Practice Committee of the American Society for Reproductive Medicine. Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): A guideline. Fertil. Steril. 2017, 108, 426–441, doi:10.1016/j.fertnstert.2017.06.026.
  102. Lautatzis, M.E.; Goulis, D.G.; Vrontakis, M. Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: A systematic review. Metabolism 2013, 62, 1522–1534, doi:10.1016/j.metabol.2013.06.006.
  103. Sivalingam, V.N.; Myers, J.; Nicholas, S.; Balen, A.H.; Crosbie, E.J. Metformin in reproductive health, pregnancy and gynaecological cancer: Established and emerging indications. Hum. Reprod. Update 2014, 20, 853–868, doi:10.1093/humupd/dmu037.
  104. Feng, L.; Lin, X.F.; Wan, Z.H.; Hu, D.; Du, Y.K. Efficacy of metformin on pregnancy complications in women with polycystic ovary syndrome: A meta-analysis. Gynecol. Endocrinol. 2015, 31, 833–839, doi:10.3109/09513590.2015.1041906.
  105. Sinai Talaulikar, V.; Tang, T.; Yasmin, E. Role of Metformin in Women’s Health: Review of Its Current Place in Clinical Practice and Emerging Indications for Future. Obstet. Gynecol. Surv. 2016, 71, 307–317, doi:10.1097/OGX.0000000000000312.
  106. Tan, X.; Li, S.; Chang, Y.; Fang, C.; Liu, H.; Zhang, X.; Wang, Y. Effect of metformin treatment during pregnancy on women with PCOS: A systematic review and meta-analysis. Clin. Invest. Med. 2016, 39, 120–131, doi:10.25011/cim.v39i4.27091.
  107. Zeng, X.L.; Zhang, Y.F.; Tian, Q.; Xue, Y.; An, R.F. Effects of metformin on pregnancy outcomes in women with polycystic ovary syndrome: A meta-analysis. Medicine 2016, 95, e4526, doi:10.1097/MD.0000000000004526.
  108. Løvvik, T.S.; Carlsen, S.M.; Salvesen, Ø.; Steffensen, B.; Bixo, M.; Gómez-Real, F.; Lønnebotn, M.; Hestvold, K.V.; Zabielska, R.; Hirschberg, A.L.; Trouva, A.; et al. Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): A randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2019, 7, 256–266, doi:10.1016/S2213-8587(19)30002-6.
  109. Morley, L.C.; Tang, T.; Yasmin, E.; Norman, R.J.; Balen, A.H. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst. Rev. 2017, 11, CD003053, doi:10.1002/14651858.CD003053.pub6.
  110. Wu, Y.; Tu, M.; Huang, Y.; Liu, Y.; Zhang, D. Association of Metformin With Pregnancy Outcomes in Women With Polycystic Ovarian Syndrome Undergoing In Vitro Fertilization: A Systematic Review and Meta-analysis. JAMA Netw. Open 2020, 3, e2011995, doi:10.1001/jamanetworkopen.2020.11995.
  111. Baillargeon, J.P.; Jakubowicz, D.J.; Iuorno, M.J.; Jakubowicz, S.; Nestler, J.E. Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertil. Steril. 2004, 82, 893–902, doi:10.1016/j.fertnstert.2004.02.127.
  112. Carmina, E.; Lobo, R.A. Does metformin induce ovulation in normoandrogenic anovulatory women? Am. J. Obstet. Gynecol. 2004, 191, 1580–1584, doi:10.1016/j.ajog.2004.05.030.
  113. Bordewijk, E.M.; Nahuis, M.; Costello, M.F.; Van der Veen, F.; Tso, L.O.; Mol, B.W.; van Wely, M. Metformin during ovulation induction with gonadotrophins followed by timed intercourse or intrauterine insemination for subfertility associated with polycystic ovary syndrome. Cochrane Database Syst. Rev. 2017, 1, CD009090, doi:10.1002/14651858.CD009090.pub2.
  114. Tang, T.; Lord, J.M.; Norman, R.J.; Yasmin, E.; Balen, A.H. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst. Rev. 2010, 1, CD003053, doi:10.1002/14651858.CD003053.pub4.
  115. Kjøtrød, S.B.; Carlsen, S.M.; Rasmussen, P.E.; Holst-Larsen, T.; Mellembakken, J.; Thurin-Kjellberg, A.; Haapaniemikouru, K.; Morin-Papunen, L.; Humaidan, P.; Sunde, A.; et al. Use of metformin before and during assisted reproductive technology in non-obese young infertile women with polycystic ovary syndrome: A prospective, randomized, double-blind, multi-centre study. Hum. Reprod. 2011, 26, 2045–2053, doi:10.1093/humrep/der154.
  116. Morin-Papunen, L.; Rantala, A.S.; Unkila-Kallio, L.; Tiitinen, A.; Hippeläinen, M.; Perheentupa, A.; Tinkanen, H.; Bloigu, R.; Puukka, K.; Ruokonen, A.; et al. Metformin improves pregnancy and live-birth rates in women with polycystic ovary syndrome (PCOS): A multicenter, double-blind, placebo-controlled randomized trial. J. Clin. Endocrinol. Metab. 2012, 97, 1492–1500, doi:10.1210/jc.2011-3061.
  117. Tang, T.; Lord, J.M.; Norman, R.J.; Yasmin, E.; Balen, A.H. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst. Rev. 2012, 5, CD003053, doi:10.1002/14651858.CD003053.pub5.
  118. Tso, L.O.; Costello, M.F.; Albuquerque, L.E.; Andriolo, R.B.; Macedo, C.R. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst. Rev. 2014, 2014, CD006105, doi:10.1002/14651858.CD006105.pub3.
  119. Kollmann, M.; Martins, W.P.; Lima, M.L.; Craciunas, L.; Nastri, C.O.; Richardson, A.; Raine-Fenning, N. Strategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: Systematic review and meta-analysis. Ultrasound Obstet. Gynecol. 2016, 48, 709–718, doi:10.1002/uog.15898.
  120. Palomba, S.; Falbo, A.; Carrillo, L.; Villani, M.T.; Orio, F.; Russo, T.; Di Cello, A.; Cappiello, F., Capasso, S.; Tolino, A.; et al. Metformin reduces risk of ovarian hyperstimulation syndrome in patients with polycystic ovary syndrome during gonad-otropin-stimulated in vitro fertilization cycles: A randomized, controlled trial. Fertil. Steril. 2011, 96, 1384–1390, doi:10.1016/j.fertnstert.2011.09.020.
  121. Palomba, S.; Falbo, A.; La Sala, G.B. Effects of metformin in women with polycystic ovary syndrome treated with gonado-trophins for in vitro fertilisation and intracytoplasmic sperm injection cycles: A systematic review and meta-analysis of randomised controlled trials. BJOG 2013, 120, 267–276, doi:10.1111/1471-0528.12070.
  122. Palomba, S.; Falbo, A.; La Sala, G.B. Effects of metformin in women with polycystic ovary syndrome treated with gonadotrophins for in vitro fertilisation and intracytoplasmic sperm injection cycles: A systematic review and meta-analysis of randomised controlled trials. BJOG 2013, 120, 267–276, doi:10.1111/1471-0528.12070.
  123. Costello, M.F.; Chapman, M.; Conway, U. A systematic review and meta-analysis of randomized controlled trials on metformin co-administration during gonadotrophin ovulation induction or IVF in women with polycystic ovary syndrome. Hum. Reprod. 2006, 21, 1387–1399, doi:10.1093/humrep/dei501.
  124. Tso, L.O.; Costello, M.F.; Albuquerque, L.E.; Andriolo, R.B.; Freitas, V. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst. Rev. 2009, 2, CD006105, doi:10.1002/14651858.CD006105.pub2.
  125. Palomba, S.; Falbo, A.; Zullo, F.; Orio, F., Jr. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: A comprehensive review. Endocr. Rev. 2009, 30, 1–50, doi:10.1210/er.2008-0030.
  126. Abdalmageed, O.S.; Farghaly, T.A.; Abdelaleem, A.A.; Abdelmagied, A.E.; Ali, M.K.; Abbas, A.M. Impact of Metformin on IVF Outcomes in Overweight and Obese Women With Polycystic Ovary Syndrome: A Randomized Double-Blind Con-trolled Trial. Reprod. Sci. 2019, 26, 1336–1342, doi:10.1177/1933719118765985.
  127. Barbieri, R.L. Metformin for the treatment of polycystic ovary syndrome. Obstet. Gynecol. 2003, 101, 785–793, doi:10.1016/s0029-7844(03)00045-0.
  128. Abu Hashim, H.; Shokeir, T.; Badawy, A. Letrozole versus combined metformin and clomiphene citrate for ovulation in-duction in clomiphene-resistant women with polycystic ovary syndrome: A randomized controlled trial. Fertil. Steril. 2010, 94, 1405–1409, doi:10.1016/j.fertnstert.2009.07.985.
  129. Bjelica, A.; Trninić-Pjević, A.; Mladenović-Segedi, L.; Cetković, N.; Petrović, D. Comparison of the efficiency of clomiphene citrate and letrozole in combination with metformin in moderately obese clomiphene citrate-resistant polycystic ovarian syndrome patients. Srp. Arh. Celok. Lek. 2016, 144, 146–150, doi:10.2298/SARH1604146B.
  130. Nemati, M.; Nemati, S.; Taheri, A.M.; Heidari, B. Comparison of metformin and N-acetyl cysteine, as an adjuvant to clomi-phene citrate, in clomiphene-resistant women with polycystic ovary syndrome. J. Gynecol. Obstet. Hum. Reprod. 2017, 46, 579–585, doi:10.1016/j.jogoh.2017.07.004.
  131. Yu, Y.; Fang, L.; Zhang, R.; He, J.; Xiong, Y.; Guo, X.; Du, Q.; Huang, Y.; Sun, Y. Comparative effectiveness of 9 ovula-tion-induction therapies in patients with clomiphene citrate-resistant polycystic ovary syndrome: A network meta-analysis. Sci. Rep. 2017, 7, 3812, doi:10.1038/s41598-017-03803-9.
  132. Sawant, S.; Bhide, P. Fertility Treatment Options for Women with Polycystic Ovary Syndrome. Clin. Med. Insights Reprod. Health 2019, 13, 1179558119890867, doi:10.1177/1179558119890867.
  133. Maged, A.M.; Elsawah, H.; Abdelhafez, A.; Bakry, A.; Mostafa, W.A. The adjuvant effect of metformin and N-acetylcysteine to clomiphene citrate in induction of ovulation in patients with Polycystic Ovary Syndrome. Gynecol. Endocrinol. 2015, 31, 635–638, doi:10.3109/09513590.2015.1037269.
  134. Abu Hashim, H.; Shokeir, T.; Badawy, A. Letrozole versus combined metformin and clomiphene citrate for ovulation induction in clomiphene-resistant women with polycystic ovary syndrome: A randomized controlled trial. Fertil. Steril. 2010, 94, 1405–1409, doi:10.1016/j.fertnstert.2009.07.985.
  135. Nemati, M.; Nemati, S.; Taheri, A.M.; Heidari, B. Comparison of metformin and N-acetyl cysteine, as an adjuvant to clomiphene citrate, in clomiphene-resistant women with polycystic ovary syndrome. J. Gynecol. Obstet. Hum. Reprod. 2017, 46, 579–585, doi:10.1016/j.jogoh.2017.07.004.
  136. Rezk, M.; Shaheen, A.E.; Saif El-Nasr, I. Clomiphene citrate combined with metformin versus letrozole for induction of ovulation in clomiphene-resistant polycystic ovary syndrome: A randomized clinical trial. Gynecol. Endocrinol. 2018, 34, 298–300, doi:10.1080/09513590.2017.1395838.
  137. Chang, H.H.; Hsueh, Y.S.; Cheng, Y.W.; Ou, H.T.; Wu, M.H. Association between Polymorphisms of OCT1 and Metabolic Response to Metformin in Women with Polycystic Ovary Syndrome. Int. J. Mol. Sci. 2019, 20, 1720, doi:10.3390/ijms20071720.
  138. Yu, Y.; Fang, L.; Zhang, R.; He, J.; Xiong, Y.; Guo, X.; Du, Q.; Huang, Y.; Sun, Y. Comparative effectiveness of 9 ovulation-induction therapies in patients with clomiphene citrate-resistant polycystic ovary syndrome: A network meta-analysis. Sci. Rep. 2017, 7, 3812, doi:10.1038/s41598-017-03803-9.
  139. Hoeger, K.; Davidson, K.; Kochman, L.; Cherry, T.; Kopin, L.; Guzick, D.S. The impact of metformin, oral contraceptives, and lifestyle modification on polycystic ovary syndrome in obese adolescent women in two randomized, place-bo-controlled clinical trials. J. Clin. Endocrinol. Metab. 2008, 93, 4299–4306, doi:10.1210/jc.2008-0461.
  140. Palomba, S.; Materazzo, C.; Falbo, A.; Orio, F.; La Sala, G.B.; Sultan, C. Metformin, oral contraceptives or both to manage oligo-amenorrhea in adolescents with polycystic ovary syndrome? A clinical review. Gynecol. Endocrinol. 2014, 30, 335–340, doi:10.3109/09513590.2013.876001.
  141. Stefanaki, C.; Bacopoulou, F.; Kandaraki, E.; Boschiero, D.; Diamandi-Kandarakis, E. Lean Women on Metformin and Oral Contraceptives for Polycystic Ovary Syndrome Demonstrate a Dehydrated Osteosarcopenic Phenotype: A Pilot Study. Nu-trients 2019, 11, 2055, doi:10.3390/nu11092055.
  142. Douchi, T.; Yamamoto, S.; Oki, T.; Maruta, K.; Kuwahata, R.; Nagata, Y. Serum androgen levels and muscle mass in women with polycystic ovary syndrome. Obstet. Gynecol. 1999, 94, 337–340, doi:10.1016/s0029-7844(99)00311-7.
  143. Cetrone, M.; Mele, A.; Tricarico, D. Effects of the antidiabetic drugs on the age-related atrophy and sarcopenia associated with diabetes type II. Curr. Diabetes Rev. 2014, 10, 231–237, doi:10.2174/1573399810666140918121022.
  144. Kim, K.H.; Lee, M.S. FGF21 as a mediator of adaptive responses to stress and metabolic benefits of anti-diabetic drugs. J. Endocrinol. 2015, 226, 1–16, doi:10.1530/JOE-15-0160.
  145. Gupta, A.; Jelinek, H.F.; Al-Aubaidy, H. Glucagon like peptide-1 and its receptor agonists: Their roles in management of Type 2 diabetes mellitus. Diabetes Metab. Syndr. 2017, 11, 225–230, doi:10.1016/j.dsx.2016.09.003.
  146. Drucker, D.J. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab. 2018, 27, 740–756, doi:10.1016/j.cmet.2018.03.001.
  147. Gentilella, R.; Pechtner, V.; Corcos, A.; Consoli, A. Glucagon-like peptide-1 receptor agonists in type 2 diabetes treatment: Are they all the same? Diabetes Metab. Res. Rev. 2019, 35, e3070, doi:10.1002/dmrr.3070.
  148. Gillani, S.W.; Moosvi, A.F. Clinical Review: Safety and Efficacy Comparison between Sulfonylureas and Dipeptidyl Pepti-dase-4 Inhibitors as Second-Line Therapies in Type 2 Diabetes Mellitus. Curr. Pharm. Des. 2020, 26, 4315–4322, doi:10.2174/1381612826666200408095310.
  149. Pani, A.; Gironi, I.; Di Vieste, G.; Mion, E.; Bertuzzi, F.; Pintaudi, B. From Prediabetes to Type 2 Diabetes Mellitus in Women with Polycystic Ovary Syndrome: Lifestyle and Pharmacological Management. Int. J. Endocrinol. 2020, 2020, 6276187, doi:10.1155/2020/6276187.
  150. Romualdi, D.; Versace, V.; Lanzone, A. What is new in the landscape of insulin-sensitizing agents for polycystic ovary syn-drome treatment. Ther. Adv. Reprod. Health 2020, 14, 2633494120908709, doi:10.1177/2633494120908709.
  151. Jensterle, M.; Kravos, N.A.; Goričar, K.; Janez, A. Short-term effectiveness of low dose liraglutide in combination with met-formin versus high dose liraglutide alone in treatment of obese PCOS: Randomized trial. BMC Endocr. Disord. 2017, 17, 5, doi:10.1186/s12902-017-0155-9.
  152. Tao, T.; Wu, P.; Wang, Y.; Liu, W. Comparison of glycemic control and β-cell function in new onset T2DM patients with PCOS of metformin and saxagliptin monotherapy or combination treatment. BMC Endocr. Disord. 2018, 18, 14, doi:10.1186/s12902-018-0243-5.
  153. Elkind-Hirsch, K.E.; Paterson, M.S.; Seidemann, E.L.; Gutowski, H.C. Short-term therapy with combination dipeptidyl pep-tidase-4 inhibitor saxagliptin/metformin extended release (XR) is superior to saxagliptin or metformin XR monotherapy in prediabetic women with polycystic ovary syndrome: A single-blind, randomized, pilot study. Fertil. Steril. 2017, 107, 253–260, doi:10.1016/j.fertnstert.2016.09.023.
  154. Lamos, E.M.; Malek, R.; Davis, S.N. GLP-1 receptor agonists in the treatment of polycystic ovary syndrome. Expert. Rev. Clin. Pharmacol. 2017, 10, 401–408, doi:10.1080/17512433.2017.1292125.
  155. Tzotzas, T.; Karras, S.N.; Katsiki, N. Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in the Treatment of Obese Women with Polycystic Ovary Syndrome. Curr. Vasc. Pharmacol. 2017, 15, 218–229, doi:10.2174/1570161114666161221115324.
  156. Cena, H.; Chiovato, L.; Nappi, R.E. Obesity, Polycystic Ovary Syndrome, and Infertility: A New Avenue for GLP-1 Receptor Agonists. J. Clin. Endocrinol. Metab. 2020, 105, e2695–e2709, doi:10.1210/clinem/dgaa285.
  157. Livadas, S.; Androulakis, I.; Angelopoulos, N.; Lytras, A.; Papagiannopoulos, F.; Kassi, G. Liraglutide administration im-proves hormonal/metabolic profile and reproductive features in women with HAIR-AN syndrome. Endocrinol. Diabetes Metab. Case Rep. 2020, 2020, 19–0150, doi:10.1530/EDM-19-0150.
  158. Hoeger, K.; Davidson, K.; Kochman, L.; Cherry, T.; Kopin, L.; Guzick, D.S. The impact of metformin, oral contraceptives, and lifestyle modification on polycystic ovary syndrome in obese adolescent women in two randomized, placebo-controlled clinical trials. J. Clin. Endocrinol. Metab. 2008, 93, 4299–4306, doi:10.1210/jc.2008-0461.
  159. Nestler, J.E.; Jakubowicz, D.J. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after re-duction of insulin secretion in polycystic ovary syndrome. N. Engl. J. Med. 1996, 335, 617–623, doi:10.1056/NEJM199608293350902.
  160. Chou, K.H.; von Eye Corleta, H.; Capp, E.; Spritzer, P.M. Clinical, metabolic and endocrine parameters in response to met-formin in obese women with polycystic ovary syndrome: A randomized, double-blind and placebo-controlled trial. Horm. Metab. Res. 2003, 35, 86–91, doi:10.1055/s-2003-39056.
  161. Allen, H.F.; Mazzoni, C.; Heptulla, R.A.; Murray, M.A.; Miller, N.; Koenigs, L.; Reiter, E.O. Randomized controlled trial evaluating response to metformin versus standard therapy in the treatment of adolescents with polycystic ovary syndrome. J. Pediatr. Endocrinol. Metab. 2005, 18, 761–768, doi:10.1515/jpem.2005.18.8.761.
  162. Bridger, T.; MacDonald, S.; Baltzer, F.; Rodd, C. Randomized placebo-controlled trial of metformin for adolescents with polycystic ovary syndrome. Arch. Pediatr. Adolesc. Med. 2006, 160, 241–246, doi:10.1001/archpedi.160.3.241.
  163. Diamanti-Kandarakis, E.; Christakou, C.D.; Kandaraki, E.; Economou, F.N. Metformin: An old medication of new fashion: Evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome. Eur. J. Endocrinol. 2010, 162, 193–212, doi:10.1530/EJE-09-0733.
  164. Al-Zubeidi, H.; Klein, K.O. Randomized clinical trial evaluating metformin versus oral contraceptive pills in the treatment of adolescents with polycystic ovarian syndrome. J. Pediatr. Endocrinol. Metab. 2015, 28, 853–858, doi:10.1515/jpem-2014-0283.
  165. Al Khalifah, R.A.; Florez, I.D.; Dennis, B.; Thabane, L.; Bassilious, E. Metformin or Oral Contraceptives for Adolescents With Polycystic Ovarian Syndrome: A Meta-analysis. Pediatrics 2016, 137, e20154089, doi:10.1542/peds.2015-4089.
  166. Sam, S.; Ehrmann, D.А. Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome. Diabetologia 2017, 60, 1656–1661, doi:10.1007/s00125-017-4306-3.
  167. Kupreeva, M.; Diane, A.; Lehner, R.; Watts, R.; Ghosh, M.; Proctor, S.; Vine, D. Effect of metformin and flutamide on insulin, lipogenic and androgen-estrogen signaling, and cardiometabolic risk in a PCOS-prone metabolic syndrome rodent model. Am. J. Physiol. Endocrinol. Metab. 2019, 316, E16–E33, doi:10.1152/ajpendo.00018.2018.
  168. Diri, H.; Bayram, F.; Simsek, Y.; Caliskan, Z.; Kocer, D. Comparison of finasteride, metformin, and finasteride plus metfor-min in PCOS. Acta Endocrinol. 2017, 13, 84–89, doi:10.4183/aeb.2017.84.
  169. Diamanti-Kandarakis, E.; Christakou, C.D.;
  170. Kandaraki, E.; Economou, F.N. Metformin: An old medication of new fashion: Evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome. Eur. J. Endocrinol. 2010, 162, 193–212, doi:10.1530/EJE-09-0733.
  171. Kurzthaler, D.; Hadziomerovic-Pekic, D.; Wildt, L.; Seeber, B.E. Metformin induces a prompt decrease in LH-stimulated testosterone response in women with PCOS independent of its insulin-sensitizing effects. Reprod. Biol. Endocrinol. 2014, 12, 98, doi:10.1186/1477-7827-12-98.
  172. Barber, T.M.; Wass, J.A.; McCarthy, M.I.; Franks, S. Metabolic characteristics of women with polycystic ovaries and oli-go-amenorrhoea but normal androgen levels: Implications for the management of polycystic ovary syndrome. Clin. Endo-crinol. 2007, 66, 513–517, doi:10.1111/j.1365-2265.2007.02764.x.
  173. Adams, J.M.; Taylor, A.E.; Crowley, W.F.Jr.; Hall, J.E. Polycystic ovarian morphology with regular ovulatory cycles: In-sights into the pathophysiology of polycystic ovarian syndrome. J. Clin. Endocrinol. Metab. 2004, 89, 4343–4350, doi:10.1210/jc.2003-031600.
  174. Attia, G.R.; Rainey, W.E.; Carr, B.R. Metformin directly inhibits androgen production in human thecal cells. Fertil. Steril. 2001, 76, 517–524, doi:10.1016/s0015-0282(01)01975-6.
  175. Mansfield, R.; Galea, R.; Brincat, M.; Hole, D.; Mason, H. Metformin has direct effects on human ovarian steroidogenesis. Fertil. Steril. 2003, 79, 956–962, doi:10.1016/s0015-0282(02)04925-7.
  176. Tosca, L.; Chabrolle, C.; Uzbekova, S.; Dupont, J. Effects of metformin on bovine granulosa cells steroidogenesis: Possible involvement of adenosine 5’ monophosphate-activated protein kinase (AMPK). Biol. Reprod. 2007, 76, 368–378, doi:10.1095/biolreprod.106.055749.
  177. Tosca, L.; Froment, P.; Solnais, P.; Ferré, P.; Foufelle, F.; Dupont, J. Adenosine 5′-monophosphate-activated protein kinase regulates progesterone secretion in rat granulosa cells. Endocrinology 2005, 146, 4500–4513, doi:10.1210/en.2005-0301.
  178. Fontaine, E. Metformin-Induced Mitochondrial Complex I Inhibition: Facts, Uncertainties, and Consequences. Front. Endo-crinol. 2018, 9, 753, doi:10.3389/fendo.2018.00753.
  179. Tosca, L.; Crochet, S.; Ferré, P.; Foufelle, F.; Tesseraud, S.; Dupont, J. AMP-activated protein kinase activation modulates progesterone secretion in granulosa cells from hen preovulatory follicles. J. Endocrinol. 2006, 190, 85–97, doi:10.1677/joe.1.06828.
  180. Downs, S.M.; Chen, J. Induction of meiotic maturation in mouse oocytes by adenosine analogs. Mol. Reprod. Dev. 2006, 73, 1159–1168, doi:10.1002/mrd.20439.
  181. LaRosa, C.; Downs, S.M. Meiotic induction by heat stress in mouse oocytes: Involvement of AMP-activated protein kinase and MAPK family members. Biol. Reprod. 2007, 76, 476–486, doi:10.1095/biolreprod.106.057422.
  182. Mayes, M.A.; Laforest, M.F.; Guillemette, C.; Gilchrist, R.B.; Richard, F.J. Adenosine 5′-monophosphate kinase-activated protein kinase (PRKA) activators delay meiotic resumption in porcine oocytes. Biol. Reprod. 2007, 76, 589–597, doi:10.1095/biolreprod.106.057828.
  183. Bilodeau-Goeseels, S. Cows are not mice: The role of cyclic AMP, phosphodiesterases, and adenosine monophosphate-activated protein kinase in the maintenance of meiotic arrest in bovine oocytes. Mol. Reprod. Dev. 2011, 78, 734–743, doi:10.1002/mrd.21337.
  184. Bertoldo, M.J.; Faure, M.; Dupont, J.; Froment, P. AMPK: A master energy regulator for gonadal function. Front. Neurosci. 2015, 9, 235, doi:10.3389/fnins.2015.00235.
  185. Reverchon, M.; Cornuau, M.; Cloix, L.; Ramé, C.; Guerif, F.; Royère, D.; Dupont, J. Visfatin is expressed in human granulosa cells: Regulation by metformin through AMPK/SIRT1 pathways and its role in steroidogenesis. Mol. Hum. Reprod. 2013, 19, 313–326, doi:10.1093/molehr/gat002.
  186. Bertoldo, M.J.; Guibert, E.; Faure, M.; Ramé, C.; Foretz, M.; Viollet, B.; Dupont, J.; Froment, P. Specific deletion of AMP-activated protein kinase (α1AMPK) in murine oocytes alters junctional protein expression and mitochondrial physi-ology. PLoS ONE 2015, 10, e0119680, doi:10.1371/journal.pone.0119680.
  187. Tosca, L.; Solnais, P.; Ferré, P.; Foufelle, F.; Dupont, J. Metformin-induced stimulation of adenosine 5’ monophosphate-activated protein kinase (PRKA) impairs progesterone secretion in rat granulosa cells. Biol. Reprod. 2006, 75, 342–351, doi:10.1095/biolreprod.106.050831
  188. Tosca, L.; Ramé, C.; Chabrolle, C.; Tesseraud, S.; Dupont, J. Metformin decreases IGF1-induced cell proliferation and protein synthesis through AMP-activated protein kinase in cultured bovine granulosa cells. Reproduction 2010, 139, 409–418, doi:10.1530/REP-09-0351.
  189. Xu, Y.; Gao, Y.; Huang, Z.; Zheng, Y.; Teng, W.; Zheng, D.; Zheng, X. LKB1 suppresses androgen synthesis in a mouse model of hyperandrogenism via IGF-1 signaling. FEBS Open Bio 2019, 9, 1817–1825, doi:10.1002/2211-5463.12723.
  190. Huhtala, M.S.; Tertti, K.; Juhila, J.; Sorsa, T.; Rönnemaa, T. Metformin and insulin treatment of gestational diabetes: Effects on inflammatory markers and IGF-binding protein-1—Secondary analysis of a randomized controlled trial. BMC Pregnancy Childbirth 2020, 20, 401, doi:10.1186/s12884-020-03077-6.
  191. Nestler, J.E.; Powers, L.P.; Matt, D.W.; Steingold, K.A.; Plymate, S.R.; Rittmaster, R.S.; Clore, J.N.; Blackard, W.G. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syn-drome. J. Clin. Endocrinol. Metab. 1991, 72, 83–89, doi:10.1210/jcem-72-1-83.
  192. Botwood, N.; Hamilton-Fairley, D.; Kiddy, D.; Robinson, S.; Franks, S. Sex hormone-binding globulin and female reproduc-tive function. J. Steroid Biochem. Mol. Biol. 1995, 53, 529–531, doi:10.1016/0960-0760(95)00108-c.
  193. Franks, S.; Kiddy, D.S.; Hamilton-Fairley, D.; Bush, A.; Sharp, P.S.; Reed, M.J. The role of nutrition and insulin in the regula-tion of sex hormone binding globulin. J. Steroid Biochem. Mol. Biol. 1991, 39, 835–838, doi:10.1016/0960-0760(91)90033-2.
  194. Jiang, Z.Z.; Hu, M.W.; Ma, X.S.; Schatten, H.; Fan, H.Y.; Wang, Z.B.; Sun, Q.Y. LKB1 acts as a critical gatekeeper of ovarian primordial follicle pool. Oncotarget 2016, 7, 5738–5753, doi:10.18632/oncotarget.6792.
  195. Morris, D.V.; Falcone, T. The relationship between insulin sensitivity and insulin-like growth factor-binding protein-1. Gy-necol. Endocrinol. 1996, 10, 407–412, doi:10.3109/09513599609023605.
  196. Landay, M.; Huang, A.; Azziz, R. Degree of hyperinsulinemia, independent of androgen levels, is an important determinant of the severity of hirsutism in PCOS. Fertil. Steril. 2009, 92, 643–647, doi:10.1016/j.fertnstert.2008.06.021.
  197. Firmansyah, A.; Chalid, M.T.; Farid, R.B.; Nusratuddin, N. The correlation between insulin-like growth factor binding pro-tein 1 (IGFBP-1) and homeostasis model assessment of insulin resistance (HOMA-IR) in polycystic ovarian syndrome with insulin resistance. Int. J. Reprod. Biomed. 2018, 16, 679–682.
  198. Barbieri, R.L. Hyperandrogenism, insulin resistance and acanthosis nigricans. 10 years of progress. J. Reprod. Med. 1994, 39, 327–336.
  199. Kelly, C.J.; Stenton, S.R.; Lashen, H. Insulin-like growth factor binding protein-1 in PCOS: A systematic review and me-ta-analysis. Hum. Reprod. Update 2011, 17, 4–16, doi:10.1093/humupd/dmq027.
  200. Bergh, C.; Carlsson, B.; Olsson, J.H.; Selleskog, U.; Hillensjö, T. Regulation of androgen production in cultured human thecal cells by insulin-like growth factor I and insulin. Fertil. Steril. 1993, 59, 323–331, doi:10.1016/s0015-0282(16)55675-1.
  201. Mason, H.D.; Margara, R.; Winston, R.M.; Seppala, M.; Koistinen, R.; Franks, S. Insulin-like growth factor-I (IGF-I) inhibits production of IGF-binding protein-1 while stimulating estradiol secretion in granulosa cells from normal and polycystic human ovaries. J. Clin. Endocrinol. Metab. 1993, 76, 1275–1279, doi:10.1210/jcem.76.5.7684393.
  202. Cibula, D.; Fanta, M.; Vrbikova, J.; Stanicka, S.; Dvorakova, K.; Hill, M.; Skrha, J.; Zivny, J.; Skrenkova, J. The effect of com-bination therapy with metformin and combined oral contraceptives (COC) versus COC alone on insulin sensitivity, hy-perandrogenaemia, SHBG and lipids in PCOS patients. Hum. Reprod. 2005, 20, 180–184, doi:10.1093/humrep/deh588.
  203. Wei, W.; Zhao, H.; Wang, A.; Sui, M.; Liang, K.; Deng, H.; Ma, Y.; Zhang, Y.; Zhang, H.; Guan, Y. A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur. J. Endocrinol. 2012, 166, 99–105, doi:10.1530/EJE-11-0616.
  204. Pasquali, R.; Gambineri, A.; Biscotti, D.; Vicennati, V.; Gagliardi, L.; Colitta, D.; Fiorini, S.; Cognigni, G.E.; Filicori, M.; Morselli-Labate, A.M. Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syn-drome. J. Clin. Endocrinol. Metab. 2000, 85, 2767–2774, doi:10.1210/jcem.85.8.6738.
  205. Wassell, J.; Michail, M.; Soliman, N.; Wardle, P.G. The value of sex hormone binding globulin (SHBG) in predicting treat-ment response in polycystic ovary syndrome (PCOS). Clin. Lab. 2011, 57, 95–98.
  206. Zhang, J.; Si, Q.; Li, J. Therapeutic effects of metformin and clomiphene in combination with lifestyle intervention on infer-tility in women with obese polycystic ovary syndrome. Pak. J. Med. Sci. 2017, 33, 8–12, doi:10.12669/pjms.331.11764.
  207. Furat Rencber, S.; Kurnaz Ozbek, S.; Eraldemır, C.; Sezer, Z.; Kum, T.; Ceylan, S.; Guzel, E. Effect of resveratrol and metfor-min on ovarian reserve and ultrastructure in PCOS: An experimental study. J. Ovarian Res. 2018, 11, 55, doi:10.1186/s13048-018-0427-7.
  208. Kadoura, S.; Alhalabi, M.; Nattouf, A.H. Effect of Calcium and Vitamin D Supplements as an Adjuvant Therapy to Metfor-min on Menstrual Cycle Abnormalities, Hormonal Profile, and IGF-1 System in Polycystic Ovary Syndrome Patients: A Randomized, Placebo-Controlled Clinical Trial. Adv. Pharmacol. Sci. 2019, 2019, 9680390, doi:10.1155/2019/9680390.
  209. Song, Y.; Wang, H.; Huang, H.; Zhu, Z. Comparison of the efficacy between NAC and metformin in treating PCOS patients: A meta-analysis. Gynecol. Endocrinol. 2020, 36, 204–210, doi:10.1080/09513590.2019.1689553.
  210. Morales, A.J.; Laughlin, G.A.; Bützow, T.; Maheshwari, H.; Baumann, G.; Yen, S.S. Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: Common and distinct features. J. Clin. Endocrinol. Metab. 1996, 81, 2854–2864, doi:10.1210/jcem.81.8.8768842.
  211. Chang, R.J. The reproductive phenotype in polycystic ovary syndrome. Nat. Clin. Pract. Endocrinol. Metab. 2007, 3, 688–695, doi:10.1038/ncpendmet0637.
  212. Sinha, P.; Chitra, T.; Papa, D.; Nandeesha, H. Laparoscopic Ovarian Drilling Reduces Testosterone and Luteinizing Hor-mone/Follicle-Stimulating Hormone Ratio and Improves Clinical Outcome in Women with Polycystic Ovary Syndrome. J. Hum. Reprod. Sci. 2019, 12, 224–228, doi:10.4103/jhrs.JHRS_161_18.
  213. Dulka, E.A.; Burger, L.L.; Moenter, S.M. Ovarian Androgens Maintain High GnRH Neuron Firing Rate in Adult Prenatal-ly-Androgenized Female Mice. Endocrinology 2020, 161, bqz038, doi:10.1210/endocr/bqz038.
  214. McCartney, C.R.; Campbell, R.E. Abnormal GnRH Pulsatility in Polycystic Ovary Syndrome: Recent Insights. Curr. Opin. Endocr. Metab. Res. 2020, 12, 78–84, doi:10.1016/j.coemr.2020.04.005.
  215. Woo, I.; Tobler, K.; Khafagy, A.; Christianson, M.S.; Yates, M.; Garcia, J. Predictive Value of Elevated LH/FSH Ratio for Ov-ulation Induction in Patients with Polycystic Ovary Syndrome. J. Reprod. Med. 2015, 60, 495–500.
  216. Roland, A.V.; Moenter, S.M. Prenatal androgenization of female mice programs an increase in firing activity of gonadotro-pin-releasing hormone (GnRH) neurons that is reversed by metformin treatment in adulthood. Endocrinology 2011, 152, 618–628, doi:10.1210/en.2010-0823.
  217. Maciel, G.A.; Hayashida, S.A.; da Costa, L.C.; Marcondes, J.A.; da Fonseca, A.M.; Soares, J.M.Jr.; Baracat, E.C. Influence of LH and high-density lipoprotein cholesterol (HDL-C) on metformin response in women with polycystic ovary syndrome. Eur. J. Obstet. Gynecol. Reprod. Biol. 2011, 157, 180–184, doi:10.1016/j.ejogrb.2011.03.028.
  218. Lv, W.S.; Wen, J.P.; Li, L.; Sun, R.X.; Wang, J.; Xian, Y.X.; Cao, C.X.; Wang, Y.L.; Gao, Y.Y. The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats. Brain Res. 2012, 1444, 11–19, doi:10.1016/j.brainres.2012.01.028.
  219. McIlwraith, E.K.; Belsham, D.D. Hypothalamic reproductive neurons communicate through signal transduction to control reproduction. Mol. Cell. Endocrinol. 2020, 110971, doi:10.1016/j.mce.2020.110971.
  220. Malin, S.K.; Kashyap, S.R. Effects of metformin on weight loss: Potential mechanisms. Curr. Opin. Endocrinol. Diabetes Obes. 2014, 21, 323–329, doi:10.1097/MED.0000000000000095.
  221. Derkach, K.V.; Zakharova, I.O.; Romanova, I.V.; Zorina, I.I.; Mikhrina, A.L.; Shpakov, A.O. Metabolic parameters and func-tional state of hypothalamic signaling systems in AY/a mice with genetic predisposition to obesity and the effect of met-formin. Dokl. Biochem. Biophys. 2017, 477, 377–381, doi:10.1134/S1607672917060096.
  222. Derkach, K.V.; Zakharova, I.O.; Zorina, I.I.; Bakhtyukov, A.A.; Romanova, I.V.; Bayunova, L.V.; Shpakov, A.O. The evidence of metabolic-improving effect of metformin in Ay/a mice with genetically-induced melanocortin obesity and the contribu-tion of hypothalamic mechanisms to this effect. PLoS ONE 2019, 14, e0213779, doi:10.1371/journal.pone.0213779.
  223. Yerevanian, A.; Soukas, A.A. Metformin: Mechanisms in Human Obesity and Weight Loss. Curr. Obes. Rep. 2019, 8, 156–164, doi:10.1007/s13679-019-00335-3.
  224. Hausman, G.J.; Barb, C.R.; Lents, C.A. Leptin and reproductive function. Biochimie 2012, 94, 2075–2081, doi:10.1016/j.biochi.2012.02.022.
  225. Zhang, J.; Gong, M. Review of the role of leptin in the regulation of male reproductive function. Andrologia 2018, doi:10.1111/and.12965.
  226. Huang, Y.; Yu, Y.; Gao, J.; Li, R.; Zhang, C.; Zhao, H.; Zhao, Y.; Qiao, J. Impaired oocyte quality induced by dehydroepi-androsterone is partially rescued by metformin treatment. PLoS ONE 2015, 10, e0122370, doi:10.1371/journal.pone.0122370.
  227. Jin, J.; Ma, Y.; Tong, X.; Yang, W.; Dai, Y.; Pan, Y.; Ren, P.; Liu, L.; Fan, H.Y.; Zhang, Y.; et al. Metformin inhibits testos-terone-induced endoplasmic reticulum stress in ovarian granulosa cells via inactivation of p38 MAPK. Hum. Reprod. 2020, 35, 1145–1158, doi:10.1093/humrep/deaa077.
  228. Harada, M.; Nose, E.; Takahashi, N.; Hirota, Y.; Hirata, T.; Yoshino, O.; Koga, K.; Fujii, T.; Osuga, Y. Evidence of the activa-tion of unfolded protein response in granulosa and cumulus cells during follicular growth and maturation. Gynecol. Endo-crinol. 2015, 31, 783–787, doi:10.3109/09513590.2015.1062862.
  229. Park, H.J.; Park, J.Y.; Kim, J.W.; Yang, S.G.; Jung, J.M.; Kim, M.J.; Kang, M.J.; Cho, Y.H.; Wee, G.; Yang, H.Y.; et al. Melatonin improves the meiotic maturation of porcine oocytes by reducing endoplasmic reticulum stress during in vitro maturation. J. Pineal Res. 2018, 64, e12458, doi:10.1111/jpi.12458.
  230. Tobiume, K.; Matsuzawa, A.; Takahashi, T.; Nishitoh, H.; Morita, K.; Takeda, K.; Minowa, O.; Miyazono, K.; Noda, T.; Ichijo, H. ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO Rep. 2001, 2, 222–228, doi:10.1093/embo-reports/kve046.
  231. Kim, H.S.; Kim, Y.; Lim, M.J.; Park, Y.G.; Park, S.I.; Sohn, J. The p38-activated ER stress-ATF6α axis mediates cellular senes-cence. FASEB J. 2019, 33, 2422–2434, doi:10.1096/fj.201800836R.
  232. Azhary, J.M.K.; Harada, M.; Takahashi, N.; Nose, E.; Kunitomi, C.; Koike, H.; Hirata, T.; Hirota, Y.; Koga, K.; Wada-Hiraike, O.; et al. Endoplasmic Reticulum Stress Activated by Androgen Enhances Apoptosis of Granulosa Cells via Induction of Death Receptor 5 in PCOS. Endocrinology 2019, 160, 119–132, doi:10.1210/en.2018-00675.
  233. Rice, S.; Pellatt, L.; Ramanathan, K.; Whitehead, S.A.; Mason, H.D. Metformin inhibits aromatase via an extracellular sig-nal-regulated kinase-mediated pathway. Endocrinology 2009, 150, 4794–4801, doi:10.1210/en.2009-0540.
  234. Rice, S.; Elia, A.; Jawad, Z.; Pellatt, L.; Mason, H.D. Metformin inhibits follicle-stimulating hormone (FSH) action in human granulosa cells: Relevance to polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2013, 98, 1491–1500, doi:10.1210/jc.2013-1865.
  235. Fuhrmeister, I.P.; Branchini, G.; Pimentel, A.M.; Ferreira, G.D.; Capp, E.; Brum, I.S.; von Eye Corleta, H. Human granulosa cells: Insulin and insulin-like growth factor-1 receptors and aromatase expression modulation by metformin. Gynecol. Ob-stet. Invest. 2014, 77, 156–162, doi:10.1159/000358829.
  236. Catteau-Jonard, S.; Jamin, S.P.; Leclerc, A.; Gonzalès, J.; Dewailly, D.; di Clemente, N. Anti-Mullerian hormone, its receptor, FSH receptor, and androgen receptor genes are overexpressed by granulosa cells from stimulated follicles in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2008, 93, 4456–4461, doi:10.1210/jc.2008-1231.
  237. González-Fernández, R.; Peña, Ó.; Hernández, J.; Martín-Vasallo, P.; Palumbo, A.; Ávila, J. Patients with endometriosis and patients with poor ovarian reserve have abnormal follicle-stimulating hormone receptor signaling pathways. Fertil. Steril. 2011, 95, 2373–2378, doi:10.1016/j.fertnstert.2011.03.030.
  238. Dewailly, D.; Robin, G.; Peigne, M.; Decanter, C.; Pigny, P.; Catteau-Jonard, S. Interactions between androgens, FSH, an-ti-Müllerian hormone and estradiol during folliculogenesis in the human normal and polycystic ovary. Hum. Reprod. Update 2016, 22, 709–724, doi:10.1093/humupd/dmw027.
  239. Geng, Y.; Sui, C.; Xun, Y.; Lai, Q.; Jin, L. MiRNA-99a can regulate proliferation and apoptosis of human granulosa cells via targeting IGF-1R in polycystic ovary syndrome. J. Assist. Reprod. Genet. 2019, 36, 211–221, doi:10.1007/s10815-018-1335-x.
  240. He, T.; Liu, Y.; Zhao, S.; Liu, H.; Wang, Z.; Shi, Y. Comprehensive assessment the expression of core elements related to IG-FIR/PI3K pathway in granulosa cells of women with polycystic ovary syndrome. Eur. J. Obstet. Gynecol. Reprod. Biol. 2019, 233, 134–140, doi:10.1016/j.ejogrb.2018.12.010.
  241. He, T.; Sun, Y.; Zhang, Y.; Zhao, S.; Zheng, Y.; Hao, G.; Shi, Y. MicroRNA-200b and microRNA-200c are up-regulated in PCOS granulosa cell and inhibit KGN cell proliferation via targeting PTEN. Reprod. Biol. Endocrinol. 2019, 17, 68, doi:10.1186/s12958-019-0505-8.
  242. Mason, H.D.; Willis, D.S.; Holly, J.M.; Franks, S. Insulin preincubation enhances insulin-like growth factor-II (IGF-II) action on steroidogenesis in human granulosa cells. J. Clin. Endocrinol. Metab. 1994, 78, 1265–1267, doi:10.1210/jcem.78.5.8175988.
  243. Willis, D.S.; Mason, H.D.; Watson, H.; Franks, S. Developmentally regulated responses of human granulosa cells to insu-lin-like growth factors (IGFs): IGF-I and IGF-II action mediated via the type-I IGF receptor. J. Clin. Endocrinol. Metab. 1998, 83, 1256–1259, doi:10.1210/jcem.83.4.4699.
  244. Palomba, S.; Falbo, A.; Orio, F., Jr.; Manguso, F.; Russo, T.; Tolino, A.; Annamaria, C.; Dale, B.; Zullo, F. A randomized con-trolled trial evaluating metformin pre-treatment and co-administration in non-obese insulin-resistant women with poly-cystic ovary syndrome treated with controlled ovarian stimulation plus timed intercourse or intrauterine insemination. Hum. Reprod. 2005, 20, 2879–2886, doi:10.1093/humrep/dei130.
  245. Huang, X.; Wang, P.; Tal, R.; Lv, F.; Li, Y.; Zhang, X. A systematic review and meta-analysis of metformin among patients with polycystic ovary syndrome undergoing assisted reproductive technology procedures. Int. J. Gynaecol. Obstet. 2015, 131, 111–116, doi:10.1016/j.ijgo.2015.04.046.
  246. Wu, L.L.; Russell, D.L.; Norman, R.J.; Robker, R.L. Endoplasmic reticulum (ER) stress in cumulus-oocyte complexes impairs pentraxin-3 secretion, mitochondrial membrane potential (DeltaPsi m), and embryo development. Mol. Endocrinol. 2012, 26, 562–573, doi:10.1210/me.2011-1362.
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